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1. Maternal Inheritance of Familial Hypercholesterolemia Gene Mutation Predisposes to Coronary Atherosclerosis as Assessed by Calcium Score in Adulthood

Author: Florian Mourre, Roch Giorgi, Antonio Gallo, Franck Boccara, Eric Bruckert, Alain Carrié, Regis Hankard, Jocelyn Inamo, Sandrine Laboureau, Philippe Moulin, René Valéro, Sophie Béliard, Denis Angoulvant, Sophie Beliard, Bertrand Cariou, Valérie Carreau, Alain Carrie, Sybil Charrieres, Yves Cottin, Mathilde Di Filippo, Pierre Henri Ducluzeau, Sonia Dulong, Vincent Durlach, Michel Farnier, Emile Ferrari, Dorota Ferrieres, Jean Ferrieres, Olga Kalmykova, Michel Krempf, Julie Lemale, François Paillard, Noel Peretti, Agnes Perrin, Alain Pradignac, Jean Pierre Rabes, Vincent Rigalleau, François Schiele, Ariane Sultan, Patrick Tounian, René Valero, Bruno Verges, Cecile Yelnik, Olivier Ziegler, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Nutrition, croissance et cancer (U 1069) (N2C), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)
Subjects: [SDV]Life Sciences [q-bio], hyperlipidemia, maternal inheritance, risk factors, atherosclerosis, Cardiology and Cardiovascular Medicine, cardiovascular diseases
Abstract: Background: Animal studies have demonstrated that fetal exposure to high maternal cholesterol levels during pregnancy predisposes to aortic atheroma in the offspring. In humans, little is known about the consequences of this exposure on the development of atherosclerotic cardiovascular disease later in life. We wanted to assess whether maternal/paternal inheritance of familial hypercholesterolemia (FH) gene mutation could be associated with subclinical coronary atherosclerosis. Methods: We retrospectively included 1350 patients, followed in the French registry of FH, with a documented genetic diagnosis. We selected 556 age- and sex-matched pair of patients based on the sex of the parents who transmitted the FH gene mutation, free of coronary cardiovascular event, and with a subclinical coronary atherosclerosis evaluation assessed using coronary artery calcium (CAC) score. We performed univariate and multivariate analysis to assess the individual effect of parental inheritance of the FH gene mutation on the CAC score. Results: In the whole population, patients with maternal inheritance of FH gene mutation (n=639) less frequently had a family history of premature cardiovascular events (27.7% versus 45%, P P =0.02) than those with paternal inheritance (n=711). There was no difference in the prevalence of cardiovascular events between the two groups. In the matched subgroup, maternal inheritance was significantly associated with an increase in CAC score value by 86% (95% CI, 23%–170%; P =0.003), a 1.81-fold risk of having a CAC score ≥100 Agatston units (95% CI, 1.06–3.11; P =0.03), and a 2.72-fold risk of having a CAC score ≥400 Agatston units (95% CI, 1.39–5.51; P =0.004) when compared with paternal inheritance in multivariate analysis. Conclusions: Maternal inheritance of FH gene mutation was associated with more severe subclinical coronary atherosclerosis assessed by CAC score and may be considered as a potential cardiovascular risk factor.
Published: 2023
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2. Bariatric Surgery Improves the Atherogenic Profile of Circulating Methylarginines in Obese Patients: Results from a Pilot Study

Author: Mikaël Croyal, Chloé Cloteau, Xavier Billot, Audrey Aguesse, Julie Poirier, René Valéro, Marie Maraninchi, Etienne A. Thévenot, Michel Krempf, Centre de Recherche en Nutrition Humaine Ouest (CRNH Ouest), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Laboratoire Sciences des Données et de la Décision (LS2D), Département Métrologie Instrumentation & Information (DM2I), Laboratoire d'Intégration des Systèmes et des Technologies (LIST (CEA)), Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Laboratoire d'Intégration des Systèmes et des Technologies (LIST (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, MetaboHUB, Clinique Bretéché [Nantes], Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Structure fédérative de recherche François Bonamy (SFR François Bonamy), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche en Santé de l'Université de Nantes (IRS-UN), Centre hospitalier universitaire de Nantes (CHU Nantes), We are grateful to the Biogenouest Corsaire Core Facility for their financial support, and RANCHON, GUILLAUME
Subjects: medicine.medical_specialty, [SDV.MHEP.CHI] Life Sciences [q-bio]/Human health and pathology/Surgery, Endocrinology, Diabetes and Metabolism, bariatric surgery, Renal function, [SDV.MHEP.CHI]Life Sciences [q-bio]/Human health and pathology/Surgery, Microbiology, Biochemistry, Article, Insulin resistance, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], SDMA, medicine, methylarginines, Molecular Biology, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, business.industry, Fatty liver, Retrospective cohort study, NMMA, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, medicine.disease, QR1-502, Surgery, ADMA, Basal (medicine), DMGV, Statistical analysis, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Liver function, business, Body mass index, Dyslipidemia, data processing
Abstract: Bariatric surgery improves obesity-related comorbidities. Methylarginines are biomarkers of cardiometabolic risk, liver steatosis, and insulin resistance. Here, we aimed to investigate methylarginines in obese patients undergoing bariatric surgery and compared them to age- and sex-matched healthy subjects. Thirty-one obese patients who underwent bariatric surgery and 31 healthy individuals were used for this retrospective study. The basal serum methylarginine levels were determined in the healthy individuals and the obese patients, before surgery and 6 and 12 months after surgery, by mass spectrometry. Compared with the healthy individuals, the obese patients displayed elevated monomethylarginine (mean change: +95%, p &lt, 0.001), asymmetric-dimethylarginine (+105%, p &lt, 0.001), symmetric-dimethylarginine (+25%, p = 0.003), and dimethylguanidino valerate (+32%, p = 0.008) concentrations. Bariatric surgery durably reduced the body mass index by 28% (12 months, 95%CI: 24–33, p = 0.002) and improved plasma lipids, insulin resistance, and liver function. Bariatric surgery reduced the serum levels of monomethylarginine and asymmetric-dimethylarginine by 12% (95%CI: 6–17) and 36% (95%CI: 27–45) (12 months, p = 0.003), respectively, but not symmetric-dimethylarginine or dimethylguanidino valerate. The monomethylarginine and asymmetric-dimethylarginine concentrations were strongly correlated with markers of dyslipidemia, insulin resistance, and a fatty liver. Serum dimethylguanidino valerate was primarily correlated with glycemia and renal function, whereas serum symmetric-dimethylarginine was almost exclusively associated with renal function. In conclusion, the monomethylarginine and asymmetric-dimethylarginine levels are efficiently decreased by bariatric surgery, leading to a reduced atherogenic profile in obese patients. Methylarginines follow different metabolic patterns, which could help for the stratification of cardiometabolic disorders in obese patients.
Published: 2021
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3. Large-scale screening of lipase acid deficiency in at risk population

Author: Victor de Ledinghen, Marie-Thérèse Abi Warde, Eric Nguyen-Khac, Marietta Musikas, Soumeya Bekri, Eloi Blanchet, Alice Thebaut, Isabelle Tragin, Anaïs Brassier, Dominique Larrey, Sarah Snanoudj, Myriam Dabbas, Michel Krempf, Edouard Bardou-Jacquet, Carine Pilon, Denis Ouzan, Corinne Borderon, Jean-Marc Perarnau, Armand Abergel, Maeva Guillaume, Reda Belbouab, Thierry Thevenot, Claire Carette, Valérie Triolo, Jean-Pierre Bronowicki, Hélène Dranguet, Jean Ferrières, Rodolphe Anty, Sabrina Vergnaud, Vincent Leroy, Vlad Ratzlu, Bertrand Cariou, Bruno Vergès, Abdellah Tebani, Bénédicte Sudrié-Arnaud, Hela Boudabous, Florence Lacaille, Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Rouen, Normandie Université (NU), Université de Tunis El Manar (UTM), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), CHU Clermont-Ferrand, CHU Strasbourg, Nutrition, Métabolismes et Cancer (NuMeCan), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), CHU Pontchaillou [Rennes], Centre Hospitalo-Universitaire Mustapha Bacha, Service de psychiatrie, groupe hospitalier de La Rochelle-Ré-Aunis, CH La Rochelle, Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), CHU Pessac, Epidémiologie et analyses en santé publique : risques, maladies chroniques et handicaps (LEASP), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Clinique Bretéché [Nantes], Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Groupe de Recherche sur l'alcool et les pharmacodépendances - UMR INSERM_S 1247 (GRAP), Université de Picardie Jules Verne (UPJV)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Arnault Tzanck, CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), CHU Nice [Cimiez], Hôpital Cimiez [Nice] (CHU), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, CHU Grenoble, This research was funded by Alexion Pharmaceuticals., Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Université Nice Sophia Antipolis (... - 2019) (UNS), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), CRHU Nancy, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Toulouse [Toulouse], Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Jonchère, Laurent
Subjects: 0301 basic medicine, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Clinical Biochemistry, Acid lipase deficiency, DBS, Spleen, Dried blood spot, Lysosomal acid lipase deficiency, Biochemistry, Gastroenterology, CESD, Cholesterol ester storage disease, 03 medical and health sciences, 0302 clinical medicine, Pregnancy, Lysosome, Internal medicine, medicine, Humans, Allele, business.industry, Biochemistry (medical), Infant, Newborn, Wolman Disease, Lipase, General Medicine, LAL, Sterol Esterase, medicine.disease, Phenotype, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, medicine.anatomical_structure, Wolman, 030220 oncology & carcinogenesis, Cohort, Screening, Female, Cholesterol Esters, business
Abstract: International audience; BACKGROUND: Lysosomal acid lipase deficiency (LALD, OMIM#278000) is a rare lysosomal disorder with an autosomal recessive inheritance. The main clinical manifestations are related to a progressive accumulation of cholesteryl esters, triglycerides or both within the lysosome in different organs such as the liver, spleen, and cardiovascular system. A wide range of clinical severity is associated with LALD including a severe very rare antenatal/neonatal/infantile phenotype named Wolman disease and a late-onset form named cholesteryl ester storage disease (CESD). METHODS: This study aimed to investigate a cohort of at-risk patients (4174) presenting with clinical or biological signs consistent with LALD using the assessment of LAL activity on dried blood spots. RESULTS: LAL activity was lower than 0.05 nmol/punch/L (cut-off: 0.12) in 19 patients including 13 CESD and 6 Wolman. Molecular study has been conducted in 17 patients and succeeded in identifying 34 mutated alleles. Fourteen unique variants have been characterized, 7 of which are novel. CONCLUSION: This study allowed to identify a series of patients and expanded the molecular spectrum knowledge of LALD. Besides, a new screening criteria grid based on the clinical/biological data from our study and the literature has been proposed in order to enhance the diagnosis rate in at risk populations.
Published: 2021
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4. Carrot Supplementation Improves Blood Pressure and Reduces Aortic Root Lesions in an Atherosclerosis-Prone Genetic Mouse Model

Author: Patricia Mallegol, Julien Chaigneau, Khadija Ouguerram, Ramaroson Andriantsitohaina, Michel Krempf, Jérôme Boursier, Raffaella Soleti, Fatima Kasbi-Chadli, Emmanuel Geoffriau, Lionel Fizanne, Marine Coué, Charlotte Trenteseaux, Grégory Hilairet, Stress Oxydant et Pathologies Métaboliques (SOPAM), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre de Recherche en Nutrition Humaine Ouest [Nantes] (UN), Université de Nantes (UN), Hémodynamique, Interaction Fibrose et Invasivité tumorales Hépatiques (HIFIH), Université d'Angers (UA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Clinique Bretéché [Nantes], Institut de Recherche en Horticulture et Semences (IRHS), Université d'Angers (UA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-INSTITUT AGRO Agrocampus Ouest, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), 'Region Pays de la Loire' INUMAMET project, Universite d'Angers, Institut National de la Sante et de la Recherche Medicale (Inserm), European Commission., BOURGEAIS, Véronique, Université d'Angers (UA)-AGROCAMPUS OUEST, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Angers (UA)
Subjects: Apolipoprotein E, ApoE(-/-), Apolipoprotein B, 030309 nutrition & dietetics, [SDV]Life Sciences [q-bio], Hemodynamics, Blood Pressure, Lipoproteins, VLDL, Weight Gain, Mice, Cardiac Output, Cecum, Aorta, 2. Zero hunger, Mice, Knockout, 0303 health sciences, Nutrition and Dietetics, biology, ApoE−/−, high fat diet, atheroscleros, Plaque, Atherosclerotic, ishigh fat diet, 3. Good health, Daucus carota, [SDV] Life Sciences [q-bio], Cardiovascular Diseases, Lipogenesis, medicine.symptom, lcsh:Nutrition. Foods and food supply, ApoE, medicine.medical_specialty, lcsh:TX341-641, Diet, High-Fat, Article, Lesion, 03 medical and health sciences, Apolipoproteins E, Lipid oxidation, Internal medicine, medicine, Animals, carrot supplementation, Triglycerides, 030304 developmental biology, business.industry, Cardiometabolic Risk Factors, Disease Models, Animal, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, Endocrinology, Blood pressure, hemodynamic parameter, Dietary Supplements, biology.protein, Lipid Peroxidation, Propionates, atherosclerosis, business, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, Food Science, Lipoprotein
Abstract: International audience; Epidemiological studies have shown that carrot consumption may be associated with a lower risk of developing several metabolic dysfunctions. Our group previously determined that the Bolero (Bo) carrot variety exhibited vascular and hepatic tropism using cellular models of cardiometabolic diseases. The present study evaluated the potential metabolic and cardiovascular protective effect of Bo, grown under two conditions (standard and biotic stress conditions (BoBS)), in apolipoprotein E-knockout (ApoE−/−) mice fed with high fat diet (HFD). Effects on metabolic/hemodynamic parameters and on atherosclerotic lesions have been assessed. Both Bo and BoBS decreased plasma triglyceride and expression levels of genes implicated in hepatic de novo lipogenesis and lipid oxidation. BoBS supplementation decreased body weight gain, secretion of very-low-density lipoprotein, and increased cecal propionate content. Interestingly, Bo and BoBS supplementation improved hemodynamic parameters by decreasing systolic, diastolic, and mean blood pressure. Moreover, Bo improved cardiac output. Finally, Bo and BoBS substantially reduced the aortic root lesion area. These results showed that Bo and BoBS enriched diets corrected most of the metabolic and cardiovascular disorders in an atherosclerosis-prone genetic mouse model and may therefore represent an interesting nutritional approach for the prevention of cardiovascular diseases.
Published: 2021
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5. Stable Isotope Abundance and Fractionation in Human Diseases

Author: Illa, Tea, Arnaud, De Luca, Anne-Marie, Schiphorst, Mathilde, Grand, Sophie, Barillé-Nion, Eric, Mirallié, Delphine, Drui, Michel, Krempf, Régis, Hankard, Guillaume, Tcherkez, Nantes Université, Bibliothèque universitaire, Réseau de Génomique des animaux d'élevage GENANIMAL - Approche intégrée combinant la génétique, la génomique et la biologie musculaire pour gérer la qualité de la viande bovine selon le potentiel de croissance des animaux et les facteurs d'élevage. - - Mugene2005 - ANR-05-GANI-0005 - GANI - VALID, Chimie Et Interdisciplinarité : Synthèse, Analyse, Modélisation (CEISAM), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Nantes université - UFR des Sciences et des Techniques (Nantes univ - UFR ST), Nantes Université - pôle Sciences et technologie, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Sciences et technologie, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Australian National University (ANU), Nutrition, croissance et cancer (U 1069) (N2C), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Stress Adaptation and Tumor Escape in Breast Cancer (CRCINA-ÉQUIPE 8), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Service de Chirurgie Digestive et Endocrinienne [CHU Nantes] (Hôtel Dieu), Centre hospitalier universitaire de Nantes (CHU Nantes), Institut des Maladies de l'Appareil Digestif, Université de Nantes (UN), Clinique Bretéché [Nantes], Institut de Recherche en Horticulture et Semences (IRHS), Université d'Angers (UA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-INSTITUT AGRO Agrocampus Ouest, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Region Pays de la Loire, Angers Loire Metropole via the research grant Connect Talent Isoseed, Centre National de la Recherche Scientifique (CNRS), European Commission., ANR-05-GANI-0005,Mugene,Approche intégrée combinant la génétique, la génomique et la biologie musculaire pour gérer la qualité de la viande bovine selon le potentiel de croissance des animaux et les facteurs d'élevage.(2005), Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Université de Tours (UT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Université d'Angers (UA)-AGROCAMPUS OUEST, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Australian National University - Joint College of Sciences, (ANU), and Université de Tours
Subjects: [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, diabetes, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Review, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Microbiology, QR1-502, metal homeostasis, [SDV.CAN] Life Sciences [q-bio]/Cancer, cancer, fractionation, isotope effect, metabolic partitioning
Abstract: The natural abundance of heavy stable isotopes (13C, 15N, 18O, etc.) is now of considerable importance in many research fields, including human physiology. In fact, it varies between tissues and metabolites due to isotope effects in biological processes, that is, isotope discriminations between heavy and light isotopic forms during enzyme or transporter activity. The metabolic deregulation associated with many diseases leads to alterations in metabolic fluxes, resulting in changes in isotope abundance that can be identified easily with current isotope ratio technologies. In this review, we summarize the current knowledge on changes in natural isotope composition in samples (including various tissues, hair, plasma, saliva) found in patients compared to controls, caused by human diseases. We discuss the metabolic origin of such isotope fractionations and highlight the potential of using isotopes at natural abundance for medical diagnosis and/or prognostic.
Published: 2021
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6. SAFEHEART risk-equation and cholesterol-year-score are powerful predictors of cardiovascular events in French patients with familial hypercholesterolemia

Author: Antonio Gallo, Sybil Charriere, Alexandre Vimont, M. John Chapman, Denis Angoulvant, Franck Boccara, Bertrand Cariou, Valérie Carreau, Alain Carrié, Eric Bruckert, Sophie Béliard, Sophie Beliard, Alain Carrie, Yves Cottin, Mathilde DI. Filippo, Sonia Dulong, Vincent Durlach, Michel Farnier, Emile Ferrari, Dorota Ferrieres, Jean Ferrieres, Philippe Giral, Sophie Gonbert, Regis Hankard, Jocelyn Inamo, Olga Kalmykova, Michel Krempf, Philippe Moulin, François Paillard, Noel Peretti, Agnes Perrin, Jean Pierre Rabes, Ariane Sultan, Patrick Tounian, René Valero, Bruno Verges, Cecile Yelnik, Olivier Ziegler, Inserm UMR1069, Nutrition, croissance et cancer (U 1069) (N2C), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire catalyse et spectrochimie (LCS), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Cardiologie (CHU Trousseau, Tours), CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Centre recherche en CardioVasculaire et Nutrition (C2VN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Service d'endocrinologie-métabolisme [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), CHU Pitié-Salpêtrière [AP-HP], Station d'Amélioration Génétique des Animaux (SAGA), Institut National de la Recherche Agronomique (INRA), Centre Hospitalier Universitaire de Lyon, Service de Cardiologie [CHU de Dijon], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Pôle Thoracique Cardiovasculaire et Neurologique, Hôpital Robert Debré, Point médical (Dijon), Hôpital Pasteur [Nice] (CHU), Epidémiologie et analyses en santé publique : risques, maladies chroniques et handicaps (LEASP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Istituto di Scienze degli Alimenti e della Nutrizione, Università Cattolica del Sacro Cuore, Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Centre d' investigation clinique-plurithématique du CHU de Poitiers, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Service de cardiologie, Hôpital Pierre Zobda-Quitman [CHU de la Martinique], CHU de la Martinique [Fort de France]-CHU de la Martinique [Fort de France], Samara State Technical University, Biologie et physiopathologie intestinales. Pharmacologie nutritionnelle, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Hôpital Femme Mère Enfant, Laboratoire Interuniversitaire des Systèmes Atmosphériques (LISA (UMR_7583)), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut national des sciences de l'Univers (INSU - CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Service de gastro-entérologie [CHU Trousseau], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Nutrition, obésité et risque thrombotique (NORT), Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Endocrinologie, Diabétologie et Maladies Métaboliques (CHU de Dijon), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Hôpital Jeanne d'Arc, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Tours, Institut national des sciences de l'Univers (INSU - CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Hospices Civils de Lyon (HCL), Public Health Expertise [Paris, France], Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU), Service d'Endocrinologie, Métabolisme et Prévention des Maladies Cardio-vasculaires [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Service de Cardiologie [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Unité de recherche de l'institut du thorax (ITX-lab), Service d'endocrinologie, diabète, maladies métaboliques [Hôpital de la Conception - APHM], Aix Marseille Université (AMU), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), French REgistry of Familial hypERCHOLesterolemia (REFERCHOL) investigators, ANR-16-RHUS-0007,CHOPIN,CHOPIN(2016), Gestionnaire, Hal Sorbonne Université, CHOPIN - - CHOPIN2016 - ANR-16-RHUS-0007 - RHUS - VALID, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d’Endocrinologie, Métabolisme et Prévention des Risques Cardio-Vasculaires [CHU Pitié-Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS)
Subjects: cardiovascular risk, 0301 basic medicine, medicine.medical_specialty, cardiovascular risk equation, Population, Familial hypercholesterolemia, 030204 cardiovascular system & hematology, Risk Assessment, Cohort Studies, Hyperlipoproteinemia Type II, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, medicine, Humans, education, ComputingMilieux_MISCELLANEOUS, Risk equation, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Entire population, education.field_of_study, familial hypercholesterolemia, business.industry, Cholesterol, External validation, Cholesterol, LDL, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, medicine.disease, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, 030104 developmental biology, cholesterol-year-score, chemistry, Cardiovascular Diseases, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Clinical diagnosis, primary cardiovascular prevention, Cohort, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Cardiology and Cardiovascular Medicine, business, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition
Abstract: Background and aims Patients with heterozygous familial hypercholesterolemia (HeFH) present elevated cardiovascular (CV) risk. Current CV risk stratification algorithms developed for the general population are not adapted for heFH patients. It is therefore of singular importance to develop and validate CV prediction tools, which are dedicated to the HeFH population. Methods Our first objective was to validate the Spanish SAFEHEART-risk equation (RE) in the French HeFH cohort (REFERCHOL), and the second to compare SAFEHEART-RE with the low-density-lipoprotein-cholesterol (LDL-C)-year-score for the prediction of CV events in the HeFH French population. Results We included HeFH (n = 1473) patients with a genetic or clinical diagnosis (DLCN score ≥8). Among them, 512 patients with a 5-year follow-up were included to validate the 5 year-CV-RE. A total of 152 events (10.3%) occurred in the entire population of 1473 patients during a mean follow-up of 3.9 years. Over the five-year follow-up, non-fatal CV events occurred in 103 patients (20.2%). Almost all the parameters used in the SAFEHEART-RE were confirmed as strong predictors of CV events in the REFERCHOL cohort. The C-statistic revealed a satisfactory performance of both the SAFEHEART-RE and LDL-C-year-scores in predicting CV events for all the patients (primary and secondary prevention) (C-index 0.77 and 0.70, respectively) as well as for those in primary prevention at inclusion (C-index 0.78 and 0.77, respectively). Conclusions This analysis represents the first external validation of the SAFEHEART-RE and demonstrated that both SAFEHEART-RE and the LDL-C-year-score are good predictors of CV events in primary prevention HeFH patients.
Published: 2020
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7. Efficacy and Safety of Alirocumab in Patients With Autosomal Dominant Hypercholesterolemia Associated With Proprotein Convertase Subtilisin/Kexin Type 9 Gain-of-Function or Apolipoprotein B Loss-of-Function Mutations

Author: Eric Bruckert, Shane Lee, Michel Krempf, Paul N. Hopkins, Stephen Donahue, University of Utah, CIC Pitié BT, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Adult, Male, medicine.medical_specialty, Genotype, Apolipoprotein B, Familial hypercholesterolemia, 030204 cardiovascular system & hematology, Antibodies, Monoclonal, Humanized, Gastroenterology, law.invention, Hyperlipoproteinemia Type II, 03 medical and health sciences, 0302 clinical medicine, Double-Blind Method, Randomized controlled trial, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Loss of Function Mutation, law, Internal medicine, medicine, Humans, 030212 general & internal medicine, Adverse effect, Genes, Dominant, Alirocumab, Chromosome Aberrations, biology, business.industry, PCSK9, Middle Aged, Proprotein convertase, Long-Term Care, 3. Good health, Clinical trial, Treatment Outcome, Gain of Function Mutation, Apolipoprotein B-100, biology.protein, Cardiology, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Kexin, Female, lipids (amino acids, peptides, and proteins), Proprotein Convertase 9, Cardiology and Cardiovascular Medicine, business, Lipoprotein
Abstract: International audience; Autosomal dominant hypercholesterolemia results from mutations affecting the low-density lipoprotein receptor pathway, including proprotein convertase subtilisin/kexin type 9 (PCSK9) gain-of-function mutations (GoFm) and apolipoprotein B (APOB) loss-of-function mutations (LoFm). This study examined the long-term efficacy and safety of alirocumab in patients with PCSK9 GoFm and APOB LoFm who participated in the open-label extension to a Phase 2 double-blind study (NCT01604824). Of the 23 patients who completed the 14-week double-blind period and 8-week follow-up, 21 opted to continue in the open-label extension (PCSK9 GoFm, n = 15; APOB LoFm, n = 6). Patients received alirocumab 150 mg every 2 weeks from week 32 up to 3 years for PCSK9 GoFm and 2 years for APOB LoFm. Mean duration of alirocumab exposure was 129 weeks (median: 144 weeks). After initiation of alirocumab treatment, low-density lipoprotein cholesterol (LDL-C) decreased in both groups. At week 80, mean percent reduction in LDL-C from baseline was 58.0% and 47.1% for PCSK9 GoFm and APOB LoFm groups, respectively. Treatment-emergent adverse events were reported in 19 patients (90.5%); no patients discontinued treatment due to treatment-emergent adverse events. In patients with autosomal dominant hypercholesterolemia and elevated LDL-C levels despite receiving maximally tolerated lipid-lowering therapies, alirocumab 150 mg every 2 weeks resulted in clinically meaningful reductions in LDL-C, sustained through to 3 years and 2 years for patients with PCSK9 GoFm and APOB LoFm, respectively. Alirocumab was generally well tolerated with no unexpected safety concerns.
Published: 2020
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8. Roux-en-Y gastric bypass, but not sleeve gastrectomy, decreases plasma PCSK9 levels in morbidly obese patients

Author: Séverine Ledoux, L. Van Gaal, Matthieu Wargny, L. Arnaud, Ann Verhaegen, M. Perrocheau Guillouche, E. Letessier, Michel Krempf, Bertrand Cariou, N. Huten, David Jacobi, M. Le Bras, C. Le May, Claire Blanchard, Matthieu Pichelin, A. Stepanian, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre hospitalier universitaire de Nantes (CHU Nantes), Hopital Louis Mourier - AP-HP [Colombes], Antwerp University Hospital [Edegem] (UZA), Hôpital Lariboisière, Centre Hospitalier Régional Universitaire de Tours (CHRU de Tours), Physiopathologie des Adaptations Nutritionnelles, Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut du Thorax, and Université de Nantes (UN)
Subjects: Blood Glucose, Male, Dyslipidaemia, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, 030204 cardiovascular system & hematology, Gastroenterology, Cohort Studies, PCSK9, 0302 clinical medicine, Endocrinology, Prospective Studies, ComputingMilieux_MISCELLANEOUS, General Medicine, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Roux-en-Y anastomosis, Obesity, Morbid, Treatment Outcome, Kexin, lipids (amino acids, peptides, and proteins), Female, Proprotein Convertase 9, medicine.medical_specialty, Sleeve gastrectomy, bariatric surgery, Gastric bypass, Gastric Bypass, 030209 endocrinology & metabolism, 03 medical and health sciences, RYGB, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Gastrectomy, Internal medicine, Internal Medicine, medicine, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Humans, Obesity, Dyslipidemias, Glycated Hemoglobin, business.industry, Cholesterol, HDL, nutritional and metabolic diseases, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Cholesterol, LDL, medicine.disease, Dyslipidemia, LDL receptor, Human medicine, business, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, Homeostasis
Abstract: Aim. - Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a master regulator of low-density lipoprotein cholesterol (LDL-C) metabolism, acting as an endogenous inhibitor of the LDL receptor. While it has been shown that bariatric surgery differentially affects plasma LDL-C levels, little is known of its effects on plasma PCSK9 concentrations. Therefore, the present study aimed to: (i) investigate the effect of sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) on plasma PCSK9 concentrations; and (ii) correlate baseline or postoperative plasma PCSK9 concentration variations with anthropometric and metabolic parameters. Methods. - Fasting plasma PCSK9 levels were measured by ELISA in morbidly obese patients before and 6 months after bariatric surgery. Patients were recruited from three prospective cohorts (in Nantes and Colombes in France, and Antwerp in Belgium). Results. - A total of 156 patients (34 SG, 122 RYGB) were included. Plasma PCSK9, LDL-C and non-high-density lipoprotein cholesterol (non-HDL-C) levels were significantly reduced after RYGB (-19.6%, -16.6% and -19.5%, respectively; P < 0.0001), but not after SG. In all patients, postoperative PCSK9 change was positively correlated with fasting plasma glucose (FPG; r = 0.22, P = 0.007), HOMA-IR (r = 0.24, P = 0.005), total cholesterol (r = 0.17, P = 0.037) and non-HDL-C (r = 0.17, P = 0.038) variations, but not LDL-C. In contrast to what was observed for glucose parameters (FPG, HOMA-IR), correlation between PCSK9 and non-HDL-C changes after RYGB was independent of total weight loss. Conclusion. - RYGB, but not SG, promotes a significant reduction in plasma PCSK9 levels, and such changes in circulating PCSK9 levels after RYGB appear to be more associated with glucose improvement than with lipid homoeostasis parameters. (C) 2020 Published by Elsevier Masson SAS.
Published: 2020
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9. VLDL (Very-Low-Density Lipoprotein)-Apo E (Apolipoprotein E) May Influence Lp(a) (Lipoprotein [a]) Synthesis or Assembly

Author: Bertrand Cariou, Maud Chétiveaux, Laurent Flet, Audrey Aguesse, Valentin Blanchard, Karine Bernardeau, Gilles Lambert, Cédric Le May, Samy Hadjadj, Thomas Moyon, Estelle Nobécourt-Dupuy, Mikaël Croyal, Léa Cabioch, Michel Krempf, Khadija Ouguerram, Stéphanie Billon-Crossouard, Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Mass Spectrometry Core Facility [Nantes] (CRNH-O ), Diabète athérothrombose et thérapies Réunion Océan Indien (DéTROI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de La Réunion (UR), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Biogenouest-Corsaire platform [Saint Gilles, France], Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Centre hospitalier universitaire de Nantes (CHU Nantes), ELSAN, Partenaires INRAE, Service de Néphrologie [Saint-Pierre, La Réunion], Groupe Hospitalier Sud Réunion (GHSR), ANR-16-RHUS-0007,CHOPIN,CHOPIN(2016), Physiopathologie des Adaptations Nutritionnelles, Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre de recherche en nutrition humaine Ouest, Université de La Réunion (UR), Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme Génomique Santé Biogenouest®, Centre Hospitalier Universitaire Sud Reunion, ANR: ANR-16-RHUS-0007, Le May, Cedric, CHOPIN - - CHOPIN2016 - ANR-16-RHUS-0007 - RHUS - VALID, Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de recherche de l'institut du thorax (ITX-lab), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), and Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, Apolipoprotein E, Very low-density lipoprotein, Apolipoprotein B, Familial hypercholesterolemia, niacin, Lipoproteins, VLDL, 030204 cardiovascular system & hematology, 0302 clinical medicine, ComputingMilieux_MISCELLANEOUS, Randomized Controlled Trials as Topic, apolipoprotein E, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 0303 health sciences, biology, Chemistry, Anticholesteremic Agents, Lipoprotein(a), Middle Aged, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Phenotype, Treatment Outcome, Female, lipids (amino acids, peptides, and proteins), Proprotein Convertase 9, Cardiology and Cardiovascular Medicine, Adult, Heterozygote, medicine.medical_specialty, Adolescent, loss of function mutation, Hyperlipoproteinemia Type II, Young Adult, 03 medical and health sciences, Apolipoproteins E, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], medicine, Humans, Genetic Predisposition to Disease, isotopes, 030304 developmental biology, PCSK9, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, medicine.disease, Endocrinology, Receptors, LDL, kinetics, Case-Control Studies, Delayed-Action Preparations, Mutation, LDL receptor, biology.protein, Biomarkers, Lipoprotein
Abstract: Objective: To clarify the association between PCSK9 (proprotein convertase subtilisin/kexin type 9) and Lp(a) (lipoprotein [a]), we studied Lp(a) kinetics in patients with loss-of-function and gain-of-function PCSK9 mutations and in patients in whom extended-release niacin reduced Lp(a) and PCSK9 concentrations. Approach and Results: Six healthy controls, 9 heterozygous patients with familial hypercholesterolemia (5 with low-density lipoprotein receptor [ LDLR ] mutations and 4 with PCSK9 gain-of-function mutations) and 3 patients with heterozygous dominant-negative PCSK9 loss-of-function mutations were included in the preliminary study. Eight patients were enrolled in a second study assessing the effects of 2 g/day extended-release niacin. Apolipoprotein kinetics in VLDL (very-low-density lipoprotein), LDL (low-density lipoprotein), and Lp(a) were studied using stable isotope techniques. Plasma Lp(a) concentrations were increased in PCSK9 -gain-of-function and familial hypercholesterolemia- LDLR groups compared with controls and PCSK9 -loss-of-function groups (14±12 versus 5±4 mg/dL; P =0.04), but no change was observed in Lp(a) fractional catabolic rate. Subjects with PCSK9 -loss-of-function mutations displayed reduced apoE (apolipoprotein E) concentrations associated with a VLDL-apoE absolute production rate reduction. Lp(a) and VLDL-apoE absolute production rates were correlated ( r =0.50; P r =0.96; P r =0.83; P =0.015). In contrast, PCSK9 reduction (−35%; P =0.008) was only correlated with that of VLDL-apoE absolute production rate ( r =0.79; P =0.028). Conclusions: VLDL-apoE production could determine Lp(a) production and/or assembly. As PCSK9 inhibitors reduce plasma apoE and Lp(a) concentrations, apoE could be the link between PCSK9 and Lp(a).
Published: 2020
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10. 10-year comparative follow up of familial versus multifactorial chylomicronemia syndromes

Author: Hanane Bada, Eric Bruckert, Maeva Nolin, Eric Van Ganse, Manon Belhassen, René Valéro, Marjorie Bérard, Michel Krempf, Philippe Moulin, Vinciane Rebours, PELyon Pharmaco Epidémiologie [Lyon] (Santé Publique et Epidémiologie), Hôpital de la Croix-Rousse [CHU - HCL], Hospices Civils de Lyon (HCL), Health Service and Performance Research (HESPER), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Assistance Publique - Hôpitaux de Marseille (APHM), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and CarMeN, laboratoire
Subjects: Male, Time Factors, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Clinical Biochemistry, DNA Mutational Analysis, pancreatitis, 030204 cardiovascular system & hematology, Biochemistry, 0302 clinical medicine, Endocrinology, Risk Factors, Hyperchylomicronemia, 030212 general & internal medicine, education.field_of_study, diabetes, Incidence (epidemiology), Hazard ratio, Syndrome, Middle Aged, Prognosis, humanities, 3. Good health, ischemic cardiovascular events, [SDV] Life Sciences [q-bio], Acute pancreatitis, Female, Hyperlipoproteinemia Type I, lipids (amino acids, peptides, and proteins), France, Adult, medicine.medical_specialty, Population, Context (language use), 03 medical and health sciences, Young Adult, Internal medicine, Diabetes mellitus, medicine, Humans, Genetic Predisposition to Disease, education, Retrospective Studies, business.industry, Biochemistry (medical), Odds ratio, medicine.disease, Case-Control Studies, Pancreatitis, business, Follow-Up Studies
Abstract: Context The relative incidence of acute pancreatitis, ischemic cardiovascular disease, and diabetes in hyperchylomicronemic patients exhibiting familial chylomicronemia syndrome (FCS) or multifactorial chylomicronemia syndrome (MCS) is unknown. Objective The objective was to study the occurrence of these events in FCS and MCS patients compared with the general population. Methods Twenty-nine FCS and 124 MCS patients, with genetic diagnosis, in 4 lipid clinics were matched with 413 controls. Individual hospital data linked to the national claims database were collected between 2006 and 2016. The occurrence of complications was retrospectively assessed before follow-up and during a median follow-up time of 9.8 years, for 1500 patient years of follow-up. Results Patients with FCS were younger than those with MCS (34.3 ± 13.6 vs 45.2 ± 12.6 years, P Conclusion The incidence of AHP was much higher in FCS than in MCS patients, whereas the incidence of ischemic cardiovascular events was found to be increased in MCS versus FCS patients and a representative matched control group. Differences in both triglyceride-rich lipoproteins metabolism and comorbidities in MCS versus FCS drive the occurrence of different patterns of complications.
Published: 2020
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11. Elevation of Trimethylamine-N-Oxide in Chronic Kidney Disease: Contribution of Decreased Glomerular Filtration Rate

Author: Caroline C. Pelletier, Mikael Croyal, Lavinia Ene, Audrey Aguesse, Stephanie Billon-Crossouard, Michel Krempf, Sandrine Lemoine, Fitsum Guebre-Egziabher, Laurent Juillard, Christophe O. Soulage, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Hospices Civils de Lyon (HCL), Nutrition périnatale [Nantes] (Centres de Recherche en Nutrition Humaine - CRNH), Centre de Recherche en Nutrition Humaine - Ouest, Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes (UN)-Institut National de la Recherche Agronomique (INRA), Mass Spectrometry Core Facility [Nantes] (CRNH-O ), ELSAN Polyclinique Majorelle, Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN), and Croyal, Mikael
Subjects: Adult, Male, Metabolic Clearance Rate, [SDV]Life Sciences [q-bio], lcsh:Medicine, urologic and male genital diseases, Article, Choline, Methylamines, Renal Dialysis, Chronic kidney disease, Humans, Prospective Studies, Renal Insufficiency, Chronic, hemodialysis, lcsh:R, Trimethylamine-N-oxide, Middle Aged, Gastrointestinal Microbiome, Betaine, [SDV] Life Sciences [q-bio], Uremic toxin, Creatinine, Female, Renal clearance, Glomerular Filtration Rate
Abstract: Gut microbiota-dependent Trimethylamine-N-oxide (TMAO) has been reported to be strongly linked to renal function and to increased cardiovascular events in the general population and in Chronic Kidney Disease (CKD) patients. Considering the lack of data assessing renal handling of TMAO, we conducted this study to explore renal excretion and mechanisms of accumulation of TMAO during CKD. We prospectively measured glomerular filtration rate (mGFR) with gold standard methods and plasma concentrations of trimethylamine (TMA), TMAO, choline, betaine, and carnitine by LC-MS/MS in 124 controls, CKD, and hemodialysis (HD) patients. Renal clearance of each metabolite was assessed in a sub-group of 32 patients. Plasma TMAO was inversely correlated with mGFR (r2 = 0.388, p &lt, 0.001), confirming elevation of TMAO plasma levels in CKD. TMAO clearances were not significantly different from mGFR, with a mean &plusmn, SD TMAO fractional excretion of 105% &plusmn, 32%. This suggests a complete renal excretion of TMAO by glomerular filtration with a negligible participation of tubular secretion or reabsorption, during all stages of CKD. Moreover, TMAO was effectively removed within 4 h of hemodiafiltration, showing a higher fractional reduction value than that of urea (84.9% &plusmn, 6.5% vs. 79.2% &plusmn, 5.7%, p = 0.04). This study reports a strong correlation between plasma TMAO levels and mGFR, in CKD, that can be mainly related to a decrease in TMAO glomerular filtration. Clearance data did not support a significant role for tubular secretion in TMAO renal elimination.
Published: 2019
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12. Maternal obesity leads to long-term altered levels of plasma ceramides in the offspring as revealed by a longitudinal lipidomic study in children

Author: Francisco Bolaños-Jiménez, Fengyang Huang, Michel Krempf, Laurence A. Marchat, Mikaël Croyal, Isabelle Romieu, Véronique Ferchaud-Roucher, Khadija Ouguerram, Rosalio Mercado-Camargo, Albino Barraza-Villarreal, Luis Felipe León-Aguilar, Usha Ramakrishnan, Nutrition périnatale [Nantes] (Centres de Recherche en Nutrition Humaine - CRNH), Centre de Recherche en Nutrition Humaine - Ouest, Université de Nantes (UN), Laboratory of Pharmacology and Toxicology, Hospital Infantil de México Federico Gómez, Instituto Politecnico Nacional [Mexico] (IPN), Center for Population Health Research, Insituto Nacional de Salud Publica, INRA: UMR1280 Physiologie des adaptations (UMR1280), Institut National de la Recherche Agronomique (INRA), Physiologie des Adaptations Nutritionnelles [UMR_A1280] (PhAN), Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Hospital Infantil de México Federico Gómez (HIMFG), and Physiopathologie des Adaptations Nutritionnelles (PhAN)
Subjects: Adult, Male, Ceramide, Pediatric Obesity, obesity, Offspring, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Ideal Body Weight, Medicine (miscellaneous), Physiology, 030209 endocrinology & metabolism, Overweight, Ceramides, Umbilical cord, metabolic syndrome, Obesity, Maternal, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Pregnancy, Lipidomics, medicine, Humans, 030212 general & internal medicine, Longitudinal Studies, Risk of obesity, ComputingMilieux_MISCELLANEOUS, 2. Zero hunger, Nutrition and Dietetics, business.industry, Infant, Newborn, Infant, medicine.disease, Obesity, 3. Good health, medicine.anatomical_structure, chemistry, Child, Preschool, symptoms, Female, Disease Susceptibility, medicine.symptom, Metabolic syndrome, business, Biomarkers
Abstract: International audience; Background/objectives Maternal obesity is associated with increased risk of obesity and other symptoms of the metabolic syndrome in the offspring. Nevertheless, the molecular mechanisms and cellular factors underlying this enhanced disease susceptibility remain to be determined. Here, we aimed at identifying changes in plasma lipids in offspring of obese mothers that might underpin, and serve as early biomarkers of, their enhanced metabolic disease risk. Subjects/methods We performed a longitudinal lipidomic profiling in plasma samples from normal weight, overweight, and obese pregnant women and their children that participated in the Prenatal Omega-3 Fatty Acid Supplementation, Growth, and Development trial conducted in Mexico. At recruitment women were aged between 18 and 35 years and in week 18–22 of pregnancy. Blood samples were collected at term delivery by venipuncture from mothers and from the umbilical cord of their newborns and from the same infants at 4 years old under non-fasting conditions. Lipidomic profiling was done using ultra-performance liquid chromatography high-resolution mass spectrometry. Results Analysis of the lipidomic data showed that overweight and obese mothers exhibited a significant reduction in the total abundance of ceramides (Cer) in plasma, mainly of Cer (d18:1/20:0), Cer (d18:1/22:0), Cer (d18:1/23:0), and Cer (d18:1/24:0), compared with mothers of normal body weight. This reduction was confirmed by the direct quantification of these and other ceramide species. Similar quantitative differences in the plasma concentration of Cer (d18:1/22:0), Cer (d18:1/23:0), and Cer (d18:1/24:0), were also found between 4-year-old children of overweight and obese mothers compared with children of mothers of normal body weight. Noteworthy, children exhibited equal daily amounts of energy and food intake independently of the BMI of their mothers. Conclusions Maternal obesity results in long-lasting changes in plasma ceramides in the offspring suggesting that these lipids might be used as early predictors of metabolic disease risk due to maternal obesity.
Published: 2019
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13. Pharmacokinetic and pharmacodynamic assessment of alirocumab in patients with familial hypercholesterolemia associated with proprotein convertase subtilisin/kexin type 9 gain-of-function or apolipoprotein B loss-of-function mutations

Author: Eric Bruckert, Yi Zhang, Paul N. Hopkins, Stephen Donahue, A. Thomas DiCioccio, Feng Yang, Michel Krempf, University of Utah, Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes (UN)-Institut National de la Recherche Agronomique (INRA), and Regeneron Pharmaceuticals Inc.
Subjects: Adult, medicine.medical_specialty, Adolescent, Apolipoprotein B, Endocrinology, Diabetes and Metabolism, Familial hypercholesterolemia, 030204 cardiovascular system & hematology, Antibodies, Monoclonal, Humanized, Placebo, Hyperlipoproteinemia Type II, PCSK9, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Pharmacokinetics, Internal medicine, Internal Medicine, Humans, Medicine, 030212 general & internal medicine, LDL-C, Aged, Apolipoproteins B, Alirocumab, Nutrition and Dietetics, biology, business.industry, Cholesterol, LDL, Middle Aged, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, medicine.disease, 3. Good health, Clinical trial, Endocrinology, Gain of Function Mutation, Pharmacodynamics, biology.protein, Kexin, lipids (amino acids, peptides, and proteins), Proprotein Convertase 9, Cardiology and Cardiovascular Medicine, business, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition
Abstract: Background Familial hypercholesterolemia is characterized by high levels of low-density lipoprotein cholesterol (LDL-C), and causes of familial hypercholesterolemia include apolipoprotein B (APOB) loss-of-function mutations (LOFm) and proprotein convertase subtilisin/kexin type 9 (PCSK9) gain-of-function mutations (GOFm). Objective The aim of this study was to compare the pharmacokinetics and pharmacodynamics of alirocumab between patients with APOB LOFm vs PCSK9 GOFm. Methods Patients (6 APOB LOFm and 17 PCSK9 GOFm carriers) with LDL-C ≥70 mg/dL on maximally tolerated lipid-lowering therapies received alirocumab 150 mg at Weeks 0, 2, 4, and 6, placebo at Week 8, alirocumab at Week 10, placebo at Weeks 12 and 14, then completed a follow-up period at Week 22. Results At Week 8, mean ± standard error (SE) alirocumab concentration was lower in APOB LOFm carriers compared with PCSK9 GOFm carriers (12.12 ± 1.81 vs 16.74 ± 2.53 mg/L). APOB LOFm carriers had higher mean ± SE total PCSK9 (6.56 ± 0.73 mg/L) and lower mean ± SE free PCSK9 (0.025 ± 0.016 mg/L) at Week 8 compared with PCSK9 GOFm carriers (4.21 ± 0.35 and 0.11 ± 0.035 mg/L for total and free PCSK9, respectively). Despite this observed greater PCSK9 suppression, mean ± SE percent LDL-C reduction was lower in APOB LOFm (55.3 ± 1.0%) compared with PCSK9 GOFm carriers (73.1 ± 0.9%). Treatment-emergent adverse events occurred in 16 patients (94.1%) in the PCSK9 GOFm group and 5 patients (83.3%) in the APOB LOFm group. Conclusions Overall, PCSK9 inhibition with alirocumab results in clinically meaningful reductions in LDL-C in both APOB LOFm and PCSK9 GOFm carriers, although reductions were greater in the PCSK9 GOFm carriers. The results indicate a possible underlying contributor to hypercholesterolemia other than PCSK9 in patients with APOB LOFm. Clinical Trial Registration NCT01604824; clinicaltrials.gov.
Published: 2019
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14. The SURCOUF study: Design and baseline characteristics of a prospective population-based cohort on diabetes care in France

Author: Maja Velkovski-Rouyer, Matthieu Wargny, Brice Leclère, E. Nobecourt, Emeric Scharbarg, Sophie de Visme, Matthieu Hanf, Michel Krempf, Patrick Plunian, Service d'Endocrinologie, Maladies Métaboliques et de la Nutrition, Hôpital Nord [CHU - APHM], Centre de Recherche en Nutrition Humaine, Hôpital Hôtel-Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), MSD France, and Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Adult, Male, Pediatrics, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, MEDLINE, Cohort Studies, Diabetes Complications, Population based cohort, Endocrinology, Diabetes mellitus, Medicine, Humans, Prospective Studies, Prospective cohort study, ComputingMilieux_MISCELLANEOUS, Aged, business.industry, General Medicine, Middle Aged, medicine.disease, Diabetes Mellitus, Type 1, Diabetes Mellitus, Type 2, Baseline characteristics, Female, France, business, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Cohort study
Abstract: Annales d'Endocrinologie - In Press.Proof corrected by the author Available online since dimanche 3 mars 2019
Published: 2019
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15. Residual vascular risk in diabetes - Will the SPPARM alpha concept hold the key?

Author: Jean-Charles Fruchart, Raul D. Santos, Shizuya Yamashita, Peter Libby, Masanori Aikawa, Jorge Plutzky, Aruna Pradhan, Paul Ridker, Carlos Aguilar-Salinas, Khalid Al Rasadi, Pierre Amarenco, Philip J. Barter, Richard Ceska, Alberto Corsini, Massimiliano Ruscica, Jean-Pierre Després, Patrick Duriez, Robert H. Eckel, Marat V. Ezhov, Michel Farnier, Henry N. Ginsberg, Michel P. Hermans, Shun Ishibashi, Fredrik Karpe, Tatsuhiko Kodama, Wolfgang Koenig, Michel Krempf, Soo Lim, Alberto J. Lorenzatti, Ruth McPherson, Jesus Millan Nuñez-Cortes, Børge G. Nordestgaard, Hisao Ogawa, Chris J. Packard, Carlos I. Ponte-Negretti, Željko Reiner, Shaukat Sadikot, Hitoshi Shimano, Piyamitr Sritara, Jane K. Stock, Ta-Chen Su, Andrey V. Susekov, André Tartar, Marja-Riitta Taskinen, Alexander Tenenbaum, Lale S. Tokgözoğlu, Brian Tomlinson, Anne Tybjærg-Hansen, Paul Valensi, Michal Vrablík, Walter Wahli, Gerald F. Watts, Koutaro Yokote, Alberto Zambon, R3i Foundation, Partenaires INRAE, University of São Paulo, Medical Center, University Graduate School of Medicine, Brigham and Women's Hospital [Boston], Physiopathologie des Adaptations Nutritionnelles (PhAN), and Université de Nantes (UN)-Institut National de la Recherche Agronomique (INRA)
Subjects: medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Alpha (ethology), Review, 030204 cardiovascular system & hematology, Vascular risk, Residual, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, SPPARM, Diabetes mellitus, Journal Article, Internal Medicine, medicine, Humans, Residual cardiovascular risk, diabetes, SPPARM, PPAR alpha, 030212 general & internal medicine, Intensive care medicine, ComputingMilieux_MISCELLANEOUS, risk, diabetes, PPAR-alpha Agonists, business.industry, cardiovascular, General Medicine, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Prognosis, medicine.disease, Diabetes Mellitus, Type 2, Residual cardiovascular risk, Key (cryptography), Blood pressure, business, Diabetic Angiopathies, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: No abstract available.
Published: 2019
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16. Long-term complications of open mason's vertical banded gastroplasty at a single tertiary center and literature review

Author: Eric Mirallié, Bertrand Cariou, David Jacobi, Guillaume Boulanger, Michel Krempf, Claire Blanchard, Tristan Greilsamer, Marie Guillouche, Clinique de chirurgie digestive et endocrinienne, IMAD, Centre hospitalier universitaire de Nantes (CHU Nantes), Physiopathologie des Adaptations Nutritionnelles (PhAN), and Université de Nantes (UN)-Institut National de la Recherche Agronomique (INRA)
Subjects: Reoperation, Long term complications, medicine.medical_specialty, Gastroplasty, 030209 endocrinology & metabolism, 03 medical and health sciences, Postoperative Complications, 0302 clinical medicine, Weight loss, Weight Loss, medicine, Humans, Laparoscopy, 2. Zero hunger, medicine.diagnostic_test, business.industry, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, General Medicine, Esophageal cancer, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, University hospital, medicine.disease, Obesity, Morbid, 3. Good health, Surgery, Banded gastroplasty, 030211 gastroenterology & hepatology, medicine.symptom, Complication, business, Body mass index, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition
Abstract: International audience; Vertical banded gastroplasty (VBG), introduced by Mason in 1982, is now discarded because of important long-term complications and technical difficulties to do revisional surgery. We investigated the long-term complications of VBG in our center and compared it with the literature data. Patients who underwent an open VBG at the University Hospital of Nantes between October 1991 and May 2006 were included. We reviewed preoperative clinical data, long-term outcome in weight loss, complications, and revisional surgeries with a long follow-up. Sixty-three patients (52 women and 11 men) were included, with a mean age of 43 ± 10 years and a body mass index of 46.7 ± 8.3 kg/m². The mean follow-up was 8.2 ± 4.2 years. At the end of follow-up, the mean excess weight loss (EWL) was 29.8%. Long-term success (excess weight loss > 50%) of the procedure was observed in 25 patients (39.7%). A second intervention was performed in 15 patients (23.8%), and three needed a third redo procedure. Six patients (40%) had this new intervention for late complications, and nine (60%) for weight regain. Weight loss is satisfying in the long term although the rate of reintervention is high. Long-term complication can be severe, especially with gastric stenosis that could lead to esophageal cancer. A second reintervention could be technically demanding, especially by laparoscopy, and the patients should be referred to a specialized center.
Published: 2019

17. In vivo evidence for transintestinal cholesterol efflux in patients with complete common bile duct obstruction

Author: Audrey Aguesse, Laurent Flet, Bertrand Cariou, Mikaël Croyal, Eric Frampas, Claire Blanchard, Xavier Prieur, François Moreau, Christophe Perret, Cédric Le May, Eric Mirallié, Michel Krempf, Frédéric Douane, Matthieu Pichelin, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Pharmacie, Hôtel-Dieu-Centre hospitalier universitaire de Nantes (CHU Nantes), Service de Radiologie Centrale [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Service de Chirurgie Digestive et Endocrinienne [Nantes], Nutrition périnatale [Nantes] (Centres de Recherche en Nutrition Humaine - CRNH), Centre de Recherche en Nutrition Humaine - Ouest, Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes (UN)-Institut National de la Recherche Agronomique (INRA), INRA: UMR1280 Physiologie des adaptations (UMR1280), Institut National de la Recherche Agronomique (INRA), Centre de Recherche en Cancérologie / Nantes - Angers (CRCNA), Physiologie des Adaptations Nutritionnelles [UMR_A1280] (PhAN), and Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN)
Subjects: Male, Trans Intestinal Cholesterol Efflux, Endocrinology, Diabetes and Metabolism, Common bile duct obstruction, [SDV]Life Sciences [q-bio], Bile duct obstruction, 030204 cardiovascular system & hematology, Gastroenterology, Cholangiocarcinoma, chemistry.chemical_compound, Feces, Plasma, 0302 clinical medicine, Trans Intestinal Cholesterol Efflux Cholesterol, Medicine, Bile, TICE, 030212 general & internal medicine, Prospective Studies, ComputingMilieux_MISCELLANEOUS, Aged, 80 and over, Nutrition and Dietetics, Cholestasis, Bile duct, Reverse cholesterol transport, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Magnetic Resonance Imaging, Non-detectable, 3. Good health, Hepatobiliary Elimination, Intestines, medicine.anatomical_structure, Cholesterol, Female, Efflux, Cardiology and Cardiovascular Medicine, MRI, medicine.medical_specialty, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, In vivo, Internal medicine, Intestinal Elimination, Internal Medicine, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Humans, In patient, Aged, business.industry, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, chemistry, ND, business
Abstract: International audience; Background: Beyond the hepatobiliary pathway, studies have demonstrated that direct TransIntestinal Cholesterol Efflux (TICE) of plasma-derived cholesterol may contribute to reverse cholesterol transport. The clinical evidence of TICE in human remains challenged due to the difficulty to discriminate the hepatobiliary and transintestinal routes in vivo. Objective: To provide the first proof of concept that TICE exists in vivo in humans by demonstrating that plasma labeled cholesterol can be excreted in the feces of patients with complete bile duct obstruction. Methods: Plasma, bile and fecal cholesterol excretion was measured by mass spectrometry 24, 48 and 72h after intravenous injection of D7-cholesterol in two patients presenting cholangiocarcinomas with a total obstruction of their primary bile duct. Results: No trace of bile acids was detected in the feces of the two patients. Despite this, a significant amount of plasma D7-cholesterol was quantified in the feces of the two patients 48h and 72h after the intravenous injection. Conclusion: our data bring a direct proof that TICE is an active pathway in humans. ClinicalTrials.gov Registration number: NCT01958216 Highlights: The transintestinal (TICE) route is crucial for plasma cholesterol excretion in rodent To date, the physiological relevance of TICE in humans remains questioned Patients with obstructed biliary route can excrete plasma cholesterol in their feces TICE is an active pathway in humans
Published: 2019
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18. Fenofibrate decreases plasma ceramides in type 2 diabetic patients: a novel marker for CVD?

Author: Gilles Lambert, Thomas Baty, Stéphanie Billon-Crossouard, Zied Kaabia, Stéphane Ramin-Mangata, Tim Hollstein, Michel Krempf, Audrey Aguesse, Mikaël Croyal, Fanta Fall, David R. Sullivan, Luis León, E. Nobecourt, Nutrition périnatale [Nantes] (Centres de Recherche en Nutrition Humaine - CRNH), Centre de Recherche en Nutrition Humaine - Ouest, Diabète athérothrombose et thérapies Réunion Océan Indien (DéTROI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de La Réunion (UR), Centre Hospitalier Universitaire de l'Hôtel Dieu (CHU Hôtel Dieu), Physiologie des Adaptations Nutritionnelles [UMR_A1280] (PhAN), Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN), Hôpital Guillaume et René Laennec - Centre Hospitalier Universitaire de Nantes, Laboratoire d'optique appliquée (LOA), Centre National de la Recherche Scientifique (CNRS)-École polytechnique (X)-École Nationale Supérieure de Techniques Avancées (ENSTA Paris), Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes (UN)-Institut National de la Recherche Agronomique (INRA), École Nationale Supérieure de Techniques Avancées (ENSTA Paris)-École polytechnique (X)-Centre National de la Recherche Scientifique (CNRS), Biogenouest CORSAIRE core facility, Allocation de recherche chaire mixte (INSERM-Universite de La Reunion), and Programme de recherche hospitaliere en sante ANR-16-RHUS-0007
Subjects: 0301 basic medicine, Male, medicine.medical_specialty, Ceramide, Apolipoprotein B, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Type 2 diabetes, Ceramides, 03 medical and health sciences, chemistry.chemical_compound, Endocrinology, Fenofibrate, Diabetes mellitus, Internal medicine, Lipidomics, Internal Medicine, medicine, Humans, ComputingMilieux_MISCELLANEOUS, Aged, biology, business.industry, General Medicine, Middle Aged, medicine.disease, Lipid Metabolism, Sphingolipid, Apolipoprotein, 3. Good health, 030104 developmental biology, chemistry, Diabetes Mellitus, Type 2, Cardiovascular Diseases, biology.protein, lipids (amino acids, peptides, and proteins), Female, Sphingomyelin, business, Biomarkers, medicine.drug
Abstract: International audience; AimThe benefit of the lipid-lowering drug fenofibrate on cardiovascular outcomes is controversial. Our aim was to find new circulating markers to identify those patients most likely to benefit from fenofibrate prescription.MethodsAnalyses were conducted of plasma samples collected from 102 patients with type 2 diabetes, enrolled in the FIELD trial, before and after fenofibrate treatment (200 mg/day). Non-targeted and targeted lipid analyses and apolipoprotein measurements were made using mass spectrometry methods.ResultsLipidomics revealed a global decrease in ceramide after fenofibrate treatment confirmed by quantitative analysis (−18.2%, P < 0.001). These changes were strongly associated with those found for plasma sphingomyelin (r = 0.80, P < 0.001) and, to a lesser extent, for sphingosine-1-phosphate (r = 0.34, P < 0.001). Ceramide levels decreased in 73.5% of patients. In addition to the expected lipid changes (decreases in triglycerides, total cholesterol and LDL cholesterol, and increase in HDL cholesterol), fenofibrate also lowered plasma apoC-II (−11.1%, P < 0.01), apoC-III (−24.6%; P < 0.001), apoB100 (−27.0%, P < 0.01) and sphingomyelinase (−7.6%, P < 0.001), and increased plasma apoA-II (22.4%, P < 0.001) as well as adiponectin (11.4%, P < 0.001). No significant association was found between ceramide decrease and these modulations except for total cholesterol (r = 0.20, P = 0.047) and HDL protein components. At baseline, only elevated sphingolipid levels were significantly associated with ceramide reduction after fenofibrate treatment.ConclusionFenofibrate lowers plasma ceramide independently of the usual lipid parameters. As ceramide is a strong marker of atherosclerosis, our study underpins the need to further evaluate its contribution to cardiovascular events in fenofibrate-treated patients.AimThe benefit of the lipid-lowering drug fenofibrate on cardiovascular outcomes is controversial. Our aim was to find new circulating markers to identify those patients most likely to benefit from fenofibrate prescription.MethodsAnalyses were conducted of plasma samples collected from 102 patients with type 2 diabetes, enrolled in the FIELD trial, before and after fenofibrate treatment (200 mg/day). Non-targeted and targeted lipid analyses and apolipoprotein measurements were made using mass spectrometry methods.ResultsLipidomics revealed a global decrease in ceramide after fenofibrate treatment confirmed by quantitative analysis (−18.2%, P < 0.001). These changes were strongly associated with those found for plasma sphingomyelin (r = 0.80, P < 0.001) and, to a lesser extent, for sphingosine-1-phosphate (r = 0.34, P < 0.001). Ceramide levels decreased in 73.5% of patients. In addition to the expected lipid changes (decreases in triglycerides, total cholesterol and LDL cholesterol, and increase in HDL cholesterol), fenofibrate also lowered plasma apoC-II (−11.1%, P < 0.01), apoC-III (−24.6%; P < 0.001), apoB100 (−27.0%, P < 0.01) and sphingomyelinase (−7.6%, P < 0.001), and increased plasma apoA-II (22.4%, P < 0.001) as well as adiponectin (11.4%, P < 0.001). No significant association was found between ceramide decrease and these modulations except for total cholesterol (r = 0.20, P = 0.047) and HDL protein components. At baseline, only elevated sphingolipid levels were significantly associated with ceramide reduction after fenofibrate treatment.ConclusionFenofibrate lowers plasma ceramide independently of the usual lipid parameters. As ceramide is a strong marker of atherosclerosis, our study underpins the need to further evaluate its contribution to cardiovascular events in fenofibrate-treated patients.
Published: 2018
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19. Roux-en-Y gastric bypass reduces plasma cholesterol in diet-induced obese mice by affecting trans-intestinal cholesterol excretion and intestinal cholesterol absorption

Author: Michel Krempf, Frédéric Borel, Claire Blanchard, Bertrand Cariou, C. Le May, Mikaël Croyal, Michel Neunlist, L. Toque, Audrey Aguesse, François Moreau, Xavier Prieur, L. Arnaud, Audrey Ayer, Damien Garçon, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Guillaume et René Laennec - Centre Hospitalier Universitaire de Nantes, U913, and Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, 0301 basic medicine, medicine.medical_specialty, Sleeve gastrectomy, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Gastric Bypass, Mice, Obese, Medicine (miscellaneous), Blood lipids, Intestinal absorption, Metabolic symdrome, Mice, 03 medical and health sciences, chemistry.chemical_compound, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Weight loss, Internal medicine, medicine, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Animals, Obesity, ComputingMilieux_MISCELLANEOUS, 2. Zero hunger, Nutrition and Dietetics, Cholesterol, business.industry, nutritional and metabolic diseases, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, medicine.disease, Obesity, Morbid, 3. Good health, Mice, Inbred C57BL, 030104 developmental biology, Endocrinology, Cardiovascular diseases, Intestinal Absorption, chemistry, Intestinal cholesterol absorption, lipids (amino acids, peptides, and proteins), medicine.symptom, business, Fat metabolism, Diet-induced obese, Dyslipidemia
Abstract: International audience; OBJECTIVE: Bariatric surgery appears as the most efficient therapeutic alternative in morbidly obese patients. In addition to its efficiency to decrease body weight, it also improves metabolic complications associated to morbid obesity, including dyslipidemia. Although the cholesterol-lowering effect varies with the bariatric procedures, the underlying molecular mechanisms remain poorly defined. This study aims to assess the consequence of both restrictive (sleeve gastrectomy; SG) and malabsorptive (Roux-en-Y gastric bypass; RYGB) procedures on cholesterol metabolism in mice. SUBJECTS: Ten-week-old C57BL6/J males were fed with a high-fat diet for 8-14 weeks before sleeve or RYGB surgery. RESULTS: SG has a modest and transient effect on plasma cholesterol levels, linked to a reduction in food intake. In contrast, modified RYGB led to a sustained ≈35% reduction in plasma cholesterol concentrations with a drastic increase in fecal cholesterol output. Mechanistically, RYGB exerts a synergystic effect on cholesterol metabolism by inducing the trans-intestinal cholesterol efflux and reducing the intestinal cholesterol absorption. CONCLUSIONS: In mice, RYGB, but not sleeve, strongly favors plasma cholesterol elimination by concomitantly increasing trans-intestinal cholesterol excretion and by decreasing intestinal cholesterol absorption. Our models open new perspective for deciphering the hypocholesterolemic effects of bariatric procedures.
Published: 2018
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20. Stable Isotope Kinetic Study of ApoM (Apolipoprotein M)

Author: Luis León, Khadija Ouguerram, Mikaël Croyal, Thomas Moyon, Michel Krempf, Maud Chétiveaux, Stéphanie Billon-Crossouard, Sophie Goulitquer, Valentin Blanchard, Audrey Aguesse, Fanta Fall, Gilles Lambert, E. Nobecourt, Nutrition périnatale [Nantes] (Centres de Recherche en Nutrition Humaine - CRNH), Centre de Recherche en Nutrition Humaine - Ouest, Génétique moléculaire et génétique épidémiologique, Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiologie des Adaptations Nutritionnelles [UMR_A1280] (PhAN), Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN), Centre Hospitalier Universitaire de l'Hôtel Dieu (CHU Hôtel Dieu), Institut du thorax, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), Bureau d'Économie Théorique et Appliquée (BETA), Institut National de la Recherche Agronomique (INRA)-Université de Strasbourg (UNISTRA)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), West Human Nutrition Research Center, INRA: UMR1280 Physiologie des adaptations (UMR1280), Institut National de la Recherche Agronomique (INRA), Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes (UN)-Institut National de la Recherche Agronomique (INRA), Université de La Réunion (UR), and Biogenouest CORSAIRE core facility
Subjects: Adult, Male, 0301 basic medicine, medicine.medical_specialty, Adolescent, Apolipoprotein B, [SDV]Life Sciences [q-bio], Kinetics, Apolipoproteins M, 030204 cardiovascular system & hematology, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Leucine, Sphingosine, Internal medicine, lipid metabolism, medicine, Humans, Secretion, Infusions, Intravenous, triglycerides, Chromatography, High Pressure Liquid, ComputingMilieux_MISCELLANEOUS, biology, Catabolism, Chemistry, Lipid metabolism, Middle Aged, Deuterium, Lipoproteins, LDL, lipoproteins, 030104 developmental biology, Endocrinology, APOM, Proteolysis, sphingosine-1-phosphate, biology.protein, lipids (amino acids, peptides, and proteins), Lysophospholipids, Lipoproteins, HDL, Cardiology and Cardiovascular Medicine, apolipoproteins, Chromatography, Liquid, Protein Binding, Lipoprotein
Abstract: Objective— ApoM (apolipoprotein M) binds primarily to high-density lipoprotein before to be exchanged with apoB (apolipoprotein B)–containing lipoproteins. Low-density lipoprotein (LDL) receptor–mediated clearance of apoB-containing particles could influence plasma apoM kinetics and decrease its antiatherogenic properties. In humans, we aimed to describe the interaction of apoM kinetics with other components of lipid metabolism to better define its potential benefit on atherosclerosis. Approach and Results— Fourteen male subjects received a primed infusion of 2 H 3 -leucine for 14 hours, and analyses were performed by liquid chromatography–tandem mass spectrometry from the hourly plasma samples. Fractional catabolic rates and production rates within lipoproteins were calculated using compartmental models. ApoM was found not only in high-density lipoprotein (59%) and LDL (4%) but also in a non–lipoprotein-related compartment (37%). The apoM distribution was heterogeneous within LDL and non–lipoprotein-related compartments according to plasma triglycerides ( r =0.86; P r range, 0.55–0.89; P r =0.55; P =0.042). Significant correlations were found between triglycerides and production rates of LDL-apoM ( r =0.73; P Conclusions— In humans, LDL kinetics play a key role in apoM turnover. Plasma triglycerides act on both apoM and sphingosine-1-phosphate distributions between lipoproteins. These results confirmed that apoM could be bound to high-density lipoprotein after secretion and then quickly exchanged with a non–lipoprotein-related compartment and to LDL to be slowly catabolized.
Published: 2018
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21. Consequences of blunting the mevalonate pathway in cancer identified by a pluriomics approach

Author: Julie Lalande, Véronique Ferchaud-Roucher, Mikaël Croyal, Alain Bouchereau, Sophie Goulitquer, Catherine Le Jossic-Corcos, Jean-Philippe Antignac, Serge Akoka, Michel Krempf, Stéphanie Durand, Yann Guitton, Philippe Potin, Danielle Arzur, Patrick Giraudeau, Anne-Lise Royer, Laurent Corcos, Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Laboratoire Universitaire de Biodiversité et Ecologie Microbienne (LUBEM), Nutrition périnatale [Nantes] (Centres de Recherche en Nutrition Humaine - CRNH), Centre de Recherche en Nutrition Humaine - Ouest, École supérieure du professorat et de l'éducation - Académie de Nantes (ESPE Nantes), Université de Nantes (UN), Laboratoire d'étude des Résidus et Contaminants dans les Aliments (LABERCA), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Unité de Nutrition Humaine - Clermont Auvergne (UNH), Institut National de la Recherche Agronomique (INRA)-Université Clermont Auvergne (UCA), Institut de Génétique, Environnement et Protection des Plantes (IGEPP), Institut National de la Recherche Agronomique (INRA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-AGROCAMPUS OUEST, Station biologique de Roscoff (SBR), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biologie Intégrative des Modèles Marins (LBI2M), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Station biologique de Roscoff (SBR), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'analyse isotopique et électrochimique de metabolismes (LAIEM), Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS), PRES Université Nantes Angers Le Mans (UNAM), Centre de Recherche en Nutrition Humaine Ouest (CRNH Ouest), UMR 1280 Physiologie des Adaptations Nutritionnelles, Institut National de la Recherche Agronomique (INRA), Chimie Et Interdisciplinarité : Synthèse, Analyse, Modélisation (CEISAM), Université de Nantes - Faculté des Sciences et des Techniques, Université de Nantes (UN)-Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS), Id2 Santé, Région Bretagne Pays de Loire, INSERM, Université de Brest, IDEALG, Végétaux marins et biomolécules (UMR7139), Station biologique de Roscoff [Roscoff] (SBR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-GOEMAR-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biotechnologies Végétales appliquées aux Plantes Aromatiques et Médicinales (LBVPAM), Université Jean Monnet [Saint-Étienne] (UJM), Virologie humaine, École normale supérieure - Lyon (ENS Lyon)-IFR128-Institut National de la Santé et de la Recherche Médicale (INSERM), Interactions cellulaires et moléculaires (ICM), Centre National de la Recherche Scientifique (CNRS)-IFR140-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), APBV, Amélioration des Plantes et Biotechnologies Végétales (APBV), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-AGROCAMPUS OUEST-Institut National de la Recherche Agronomique (INRA)-Université de Rennes 1 (UR1), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Nutrition Humaine (UNH), Institut National de la Recherche Agronomique (INRA)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes (UN)-Institut National de la Recherche Agronomique (INRA), Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Institut National de la Recherche Agronomique (INRA)-École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Institut National de la Recherche Agronomique (INRA)-Université de Rennes (UR)-AGROCAMPUS OUEST, Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN), Université de Nantes (UN)-Université de Nantes (UN)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Bouler, Jean Michel, and Corcos, Laurent
Subjects: 0301 basic medicine, Cancer Research, Magnetic Resonance Spectroscopy, Immunology, Médecine humaine et pathologie, Mevalonic Acid, (lovastatin + docetaxel) combination, Computational biology, Biology, Gas Chromatography-Mass Spectrometry, Article, Transcriptome, 03 medical and health sciences, Cellular and Molecular Neuroscience, metabolomics and lipidomics alterations, Metabolomics, Tandem Mass Spectrometry, gastric cancer cells, [CHIM] Chemical Sciences, Lipidomics, Food and Nutrition, Animals, Humans, [CHIM]Chemical Sciences, lcsh:QH573-671, KEGG, ComputingMilieux_MISCELLANEOUS, Cancer, lcsh:Cytology, Cell Biology, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], 3. Good health, Metabolic pathway, 030104 developmental biology, Alimentation et Nutrition, Cancer cell, OGDH, Human health and pathology, Mevalonate pathway, Metabolic Networks and Pathways, Chromatography, Liquid
Abstract: We have previously shown that the combination of statins and taxanes was a powerful trigger of HGT-1 human gastric cancer cells’ apoptosis1. Importantly, several genes involved in the “Central carbon metabolism pathway in cancer”, as reported in the Kyoto Encyclopedia of Genes and Genomes, were either up- (ACLY, ERBB2, GCK, MYC, PGM, PKFB2, SLC1A5, SLC7A5, SLC16A3,) or down- (IDH, MDH1, OGDH, P53, PDK) regulated in response to the drug association. In the present study, we conducted non-targeted metabolomics and lipidomics analyses by complementary methods and cross-platform initiatives, namely mass spectrometry (GC-MS, LC-MS) and nuclear magnetic resonance (NMR), to analyze the changes resulting from these treatments. We identified several altered biochemical pathways involved in the anabolism and disposition of amino acids, sugars, and lipids. Using the Cytoscape environment with, as an input, the identified biochemical marker changes, we distinguished the functional links between pathways. Finally, looking at the overlap between metabolomics/lipidomics and transcriptome changes, we identified correlations between gene expression modifications and changes in metabolites/lipids. Among the metabolites commonly detected by all types of platforms, glutamine was the most induced (6–7-fold), pointing to an important metabolic adaptation of cancer cells. Taken together, our results demonstrated that combining robust biochemical and molecular approaches was efficient to identify both altered metabolic pathways and overlapping gene expression alterations in human gastric cancer cells engaging into apoptosis following blunting the cholesterol synthesis pathway.
Published: 2018
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22. Model Free iPID Control for Glycemia Regulation of Type-1 Diabetes

Author: Jean-Yves Poirier, Lucy Chaillous, Taghreed Mohammadridha, Mourad Ait-Ahmed, Michel Krempf, Claude H. Moog, Isabelle Guilhem, Laboratoire des Sciences du Numérique de Nantes (LS2N), IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN)-École Centrale de Nantes (ECN)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche en Electrotechnique et Electronique de Nantes Atlantique EA4642 (IREENA), Institut Universitaire de Technologie Saint-Nazaire (IUT Saint-Nazaire), Université de Nantes (UN)-Université de Nantes (UN)-Ecole Polytechnique de l'Université de Nantes (EPUN), Université de Nantes (UN)-Institut Universitaire de Technologie - La Roche-sur-Yon (IUT La Roche-sur-Yon), Université de Nantes (UN)-Université de Nantes (UN), Institut du thorax, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), CHU Pontchaillou [Rennes], Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Université de Nantes (UN)-Université de Nantes (UN)-École Centrale de Nantes (ECN)-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique Bretagne-Pays de la Loire (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Blood Glucose, Pancreas, Artificial, 0209 industrial biotechnology, Engineering, Biomedical Engineering, PID controller, 030209 endocrinology & metabolism, 02 engineering and technology, 03 medical and health sciences, 020901 industrial engineering & automation, 0302 clinical medicine, Insulin Infusion Systems, glycemia regulation, Control theory, Robustness (computer science), Biomedical measurement, [INFO.INFO-AU]Computer Science [cs]/Automatic Control Engineering, Humans, Overall performance, Insulin, Noise measurement, business.industry, Biological system modeling, Signal Processing, Computer-Assisted, Model free, Noise, Diabetes Mellitus, Type 1, type-1 diabetes, Normal pancreatic secretion, business, Algorithms
Abstract: Objective: The objective is to design a fully automated glycemia controller of Type-1 Diabetes (T1D) in both fasting and postprandial phases on a large number of virtual patients. Methods: A model-free intelligent proportional-integral-derivative (iPID) is used to infuse insulin. The feasibility of iPID is tested in silico on two simulators with and without measurement noise. The first simulator is derived from a long-term linear time-invariant model. The controller is also validated on the UVa/Padova metabolic simulator on 10 adults under 25 runs/subject for noise robustness test. Results: It was shown that without measurement noise, iPID mimicked the normal pancreatic secretion with a relatively fast reaction to meals as compared to a standard PID. With the UVa/Padova simulator, the robustness against CGM noise was tested. A higher percentage of time in target was obtained with iPID as compared to standard PID with reduced time spent in hyperglycemia. Conclusion: Two different T1D simulators tests showed that iPID detects meals and reacts faster to meal perturbations as compared to a classic PID. The intelligent part turns the controller to be more aggressive immediately after meals without neglecting safety. Further research is suggested to improve the computation of the intelligent part of iPID for such systems under actuator constraints. Any improvement can impact the overall performance of the model-free controller. Significance: The simple structure iPID is a step for PID-like controllers since it combines the classic PID nice properties with new adaptive features.
Published: 2018
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23. Perinatal Hypercholesterolemia Exacerbates Atherosclerosis Lesions in Offspring by Altering Metabolism of Trimethylamine-N-Oxide and Bile Acids

Author: Ramaroson Andriantsitohaina, Khadija Ouguerram, Estelle Nobécourt-Dupuy, Audrey Aguesse, Valérie Amarger, Michel Krempf, Pierre de Coppet, Charlotte Trenteseaux, Anh-Thu Gaston, Guillaume Poupeau, Jamila Laschet, Hémostase, bio-ingénierie et remodelage cardiovasculaires (LBPC), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Institut Galilée-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiologie des Adaptations Nutritionnelles [UMR_A1280] (PhAN), Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN), UMR 1280 Physiologie des Adaptations Nutritionnelles, Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN)-Alimentation Humaine (ALIM.H), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Physiologie des Adaptations Nutritionnelles (PhAN), Stress Oxydant et Pathologies Métaboliques (SOPAM), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Génétique Moléculaire Animale (UGMA), Université de Limoges (UNILIM)-Institut National de la Recherche Agronomique (INRA), INRA: UMR1280 Physiologie des adaptations (UMR1280), Institut National de la Recherche Agronomique (INRA), Centre hospitalier universitaire de Nantes (CHU Nantes), Université Paris Diderot - Paris 7 (UPD7)-Université Paris 13 (UP13)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Galilée, Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes (UN)-Institut National de la Recherche Agronomique (INRA), Unité de Génétique Moléculaire Animale (UMR GMA), Institut National de la Recherche Agronomique (INRA)-Université de Limoges (UNILIM), Centre de Recherche en Nutrition Humaine Ouest, Nantes, and region Pays de la Loire
Subjects: Male, 0301 basic medicine, Apolipoprotein B, [SDV]Life Sciences [q-bio], Receptors, Cytoplasmic and Nuclear, Trimethylamine N-oxide, 030204 cardiovascular system & hematology, chemistry.chemical_compound, 0302 clinical medicine, Pregnancy, Cholesterol 7-alpha-Hydroxylase, Promoter Regions, Genetic, Aorta, ComputingMilieux_MISCELLANEOUS, Mice, Knockout, biology, Age Factors, Gallbladder, Scavenger Receptors, Class B, Plaque, Atherosclerotic, Cholesterol, Phenotype, Liver, Prenatal Exposure Delayed Effects, Oxygenases, Female, Cardiology and Cardiovascular Medicine, medicine.medical_specialty, Offspring, Hypercholesterolemia, Aortic Diseases, bile, Cholesterol 7 alpha-hydroxylase, trimethylamine-N-oxide, Bile Acids and Salts, Methylamines, 03 medical and health sciences, Apolipoproteins E, medicine.artery, Internal medicine, medicine, Animals, Genetic Predisposition to Disease, DNA Methylation, Atherosclerosis, SCARB1, Disease Models, Animal, 030104 developmental biology, Endocrinology, Animals, Newborn, Receptors, LDL, chemistry, LDL receptor, biology.protein, NR1H4 Gene
Abstract: Objective— Experimental studies suggest that maternal hypercholesterolemia may be relevant for the early onset of cardiovascular disease in offspring. We investigated the effect of perinatal hypercholesterolemia on the atherosclerosis development in the offspring of apolipoprotein E–deficient mice and the underlying mechanism. Approach and Results— Atherosclerosis and related parameters were studied in adult male or female apolipoprotein E–deficient mice offspring from either normocholesterolemic or hypercholesterolemic mothers and normocholesterolemic fathers. Female born to hypercholesterolemic mothers had more aortic root lesions than female born to normocholesterolemic mothers. Lesions in whole aorta did not differ between groups. Higher trimethylamine-N-oxide levels and Fmo3 hepatic gene expression were higher in female born to hypercholesterolemic mothers offspring compared with female born to normocholesterolemic mothers and male. Trimethylamine-N-oxide levels were correlated with the size of atherosclerotic root lesions. Levels of hepatic cholesterol and gallbladder bile acid were greater in male born to hypercholesterolemic mothers compared with male born to normocholesterolemic mothers. At 18 weeks of age, female born to hypercholesterolemic mothers showed lower hepatic Scarb1 and Cyp7a1 but higher Nr1h4 gene expression compared with female born to normocholesterolemic mothers. Male born to hypercholesterolemic mothers showed an increase in Scarb1 and Ldlr gene expression compared with male born to normocholesterolemic mothers. At 25 weeks of age, female born to hypercholesterolemic mothers had lower Cyp7a1 gene expression compared with female born to normocholesterolemic mothers. DNA methylation of Fmo3, Scarb1 , and Ldlr promoter regions was slightly modified and may explain the mRNA expression modulation. Conclusions— Our findings suggest that maternal hypercholesterolemia may exacerbate the development of atherosclerosis in female offspring by affecting metabolism of trimethylamine-N-oxide and bile acids. These data could be explained by epigenetic alterations.
Published: 2017
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24. Plasma cholesterol is excreted in the feces of patients with complete common bile duct obstruction : in vivo evidence for tice pathway in humans

Author: Eric Frampas, Audrey Aguesse, Frédéric Douane, Xavier Prieur, François Moreau, Claire Blanchard, Cédric Le May, Bertrand Cariou, Michel Krempf, Matthieu Pichelin, Christophe Perret, Khadija Ouguerram, Laurent Flet, Eric Miraillé, Université de Nantes (UN), Hôpital Hôtel-Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes (UN)-Institut National de la Recherche Agronomique (INRA), Institut National de la Santé et de la Recherche Médicale (INSERM), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre National de la Recherche Scientifique (CNRS), and European Atherosclerosis Society. SWE.
Subjects: medicine.medical_specialty, business.industry, Common bile duct obstruction, [SDV]Life Sciences [q-bio], 030209 endocrinology & metabolism, 030204 cardiovascular system & hematology, Gastroenterology, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Plasma cholesterol, In vivo, Internal medicine, Medicine, Cardiology and Cardiovascular Medicine, business, Feces, ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2017

25. Alirocumab efficiently reduces LP(A) levels by lowering Apolipoprotein (A) [APO(A)] production rate in Non-Human primates (NHP)

Author: Bruno Poirier, Rose-Hélène Blanchard, Thi-Thu-Trang Tran, Etienne Guillot, Jean-Chistophe Le Bail, Mikaël Croyal, Michel Krempf, Christophe Boixel, Gilles Lambert, Aurélie Thedrez, Elise F. Villard, Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes (UN)-Institut National de la Recherche Agronomique (INRA), Sanofi, Université de La Réunion (UR), and European Atherosclerosis Society. SWE.
Subjects: medicine.medical_specialty, Endocrinology, Biochemistry, Apolipoprotein B, biology, Internal medicine, [SDV]Life Sciences [q-bio], medicine, biology.protein, Cardiology and Cardiovascular Medicine, ComputingMilieux_MISCELLANEOUS, Production rate, Alirocumab
Abstract: International audience
Published: 2017

26. Plasma PCSK9 measurement by liquid chromatography-Tandem mass spectrometry and comparison with conventional ELISA

Author: Pedro Mata, Aurélie Thedrez, Gilles Lambert, Rodrigo Alonso, Fanta Fall, Véronique Ferchaud-Roucher, Mickael Croyal, Audrey Aguesse, Stéphanie Billon-Crossouard, Michel Krempf, Khadija Ouguerram, Estelle Nobecourt, Physiologie des Adaptations Nutritionnelles [UMR_A1280] (PhAN), Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN), West Human Nutrition Research Center, Centre Hospitalier Universitaire de l'Hôtel Dieu (CHU Hôtel Dieu), UMR1280, Physiologie des Adaptations Nutritionnelles, Institut National de la Recherche Agronomique (INRA), Department of Endocrinology, Metabolic Diseases and Nutrition, Hôpital Guillaume et René Laennec - Centre Hospitalier Universitaire de Nantes, Spanish Familial Hypercholesterolemia Foundation, Department of Nutrition [Oslo], Institute of Basic Medical Sciences [Oslo], Faculty of Medicine [Oslo], University of Oslo (UiO)-University of Oslo (UiO)-Faculty of Medicine [Oslo], University of Oslo (UiO)-University of Oslo (UiO), 1188, Diabète, Athérothrombose, Thérapies Réunion, Institut National de la Santé et de la Recherche Médicale (INSERM), Faculté de Médecine, Université de Ngozi, Centre Hospitalier Universitaire de la Réunion (CHU de la Réunion), Biogenouest CORSAIRE core facility, Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes (UN)-Institut National de la Recherche Agronomique (INRA), Diabète athérothrombose et thérapies Réunion Océan Indien (DéTROI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de La Réunion (UR), and Centre Hospitalier Universitaire de La Réunion (CHU La Réunion)
Subjects: Adult, Male, 0301 basic medicine, [SDV]Life Sciences [q-bio], Clinical Biochemistry, Enzyme-Linked Immunosorbent Assay, Mass spectrometry, Tandem mass spectrometry, Sensitivity and Specificity, Biochemistry, Analytical Chemistry, PCSK9, 03 medical and health sciences, Tandem Mass Spectrometry, Liquid chromatography–mass spectrometry, medicine, Humans, Trypsin, Solid phase extraction, LC-MS/MS, Solid-phase extraction, Chromatography, Chemistry, Proteotypic peptide analysis, Solid Phase Extraction, Subtilisin, Reproducibility of Results, Cell Biology, General Medicine, Middle Aged, Blood proteins, Peptide Fragments, 030104 developmental biology, Linear Models, Kexin, Female, Proprotein Convertase 9, Chromatography, Liquid, medicine.drug
Abstract: The combination of liquid chromatography-tandem mass spectrometry (LC-MS/MS) and trypsin proteolysis is an effective tool for accurate quantitation of multiple proteins in a single run. However, expensive samples pre-treatment as immunoenrichment are often required to analyze low abundant proteins. Plasma proprotein convertase subtilisin/kexin type 9 (PCSK9), a circulating regulator of low-density lipoprotein metabolism, was studied as an example of a low abundant plasma protein. We investigated post-proteolysis solid-phase extraction (SPE) as an alternative strategy to improve its detection. After optimization of pretreatment, including denaturation, reduction, alkylation, tryptic digestion and selective SPE concentration, 91 +/- 7% of PCSK9 was recovered from human plasma samples and coefficients of variation were less than 13.2% with a lower limit of quantification of 37.5 ng/ml. This LC-MS/MS method was compared with standard enzyme-linked immunosorbent assay in 30 human plasma samples with a broad range of PCSK9 concentrations. Both methods were significantly correlated (r =0.936, p < 0.001) with less than 7% of the values out of the 95% confidence interval and similar concentrations were measured using either LC-MS/MS or ELISA methods (514.2 +/- 217.2 vs. 504.2 +/- 231.0 ng/ml, respectively p = NS). This method involving SPE is an effective measurement tool for low abundant plasma protein analysis that could be easily included in multiplexed assays.
Published: 2017
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27. Severe decrease in high-density lipoprotein cholesterol with the combination of fibrates and ezetimibe: A case series

Author: Bertrand Cariou, Gilles Lambert, Michel Krempf, Estelle Nobecourt, Department of Endocrinology, Metabolic diseases and Nutrition, l’institut du thorax, Centre hospitalier universitaire de Nantes (CHU Nantes), UMR 1280 Physiologie des Adaptations Nutritionnelles, Institut National de la Recherche Agronomique (INRA), Centre de Recherche en Nutrition Humaine (CRNH), Physiologie des Adaptations Nutritionnelles, Human Nutrition Research Center (CRNH), Diabète athérothrombose et thérapies Réunion Océan Indien (DéTROI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de La Réunion (UR), Centre Hospitalier Universitaire de la Réunion (CHU de la Réunion), Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes (UN)-Institut National de la Recherche Agronomique (INRA), and Centre Hospitalier Universitaire de La Réunion (CHU La Réunion)
Subjects: Male, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Familial hypercholesterolemia, 030204 cardiovascular system & hematology, Gastroenterology, Hyperlipoproteinemia Type II, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, High-density lipoprotein, Ezetimibe, Internal medicine, Internal Medicine, medicine, Humans, Drug Interactions, In patient, 030212 general & internal medicine, Lipoprotein cholesterol, Nutrition and Dietetics, Cholesterol, business.industry, Cholesterol, HDL, Fibric Acids, nutritional and metabolic diseases, Middle Aged, medicine.disease, Cardiovascular disease, 3. Good health, Discontinuation, Treatment Outcome, Endocrinology, chemistry, lipids (amino acids, peptides, and proteins), Cardiology and Cardiovascular Medicine, business, Fibrates, Dyslipidemia, medicine.drug
Abstract: A sudden and severe drug-induced decrease in plasma high-density lipoprotein cholesterol (HDL-C) is a rare condition. We report 2 patients with familial hypercholesterolemia treated with statins and fibrates and 2 others with mixed dyslipidemia treated with fibrates, who presented with a sudden and severe decrease in HDL-C (from -44% to -95%, compared with baseline). Three of the patients were treated with fibrates and had a sudden decrease in HDL-C after the adjunction of ezetimibe. HDL-C returned to normal levels after discontinuation of the offending therapies. In 2 of these patients, the reintroduction of ezetimibe with no fibrates did not affect HDL-C. In conclusion, we report a new profile of patients who are at risk for a sudden drop of HDL-C related to treatment with a combination of fibrates and ezetimibe. Although a sudden drop of HDL-C is a rare event, we recommend to carefully monitor plasma HDL-C in patients submitted to both drugs.
Published: 2017
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28. The complexity of lipoprotein (a) lowering by PCSK9 monoclonal antibodies

Author: Etienne Guillot, Jean Christophe LeBail, Stéphane Ramin-Mangata, Michel Krempf, David Couret, Mikaël Croyal, Estelle Nobécourt-Dupuy, Jorg Blankenstein, Gilles Lambert, Elise F. Villard, Aurélie Thedrez, Nicolas Diotel, Bruno Poirier, Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes (UN)-Institut National de la Recherche Agronomique (INRA), Université de La Réunion (UR), Diabète athérothrombose et thérapies Réunion Océan Indien (DéTROI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de La Réunion (UR), Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), Service Endocrinologue, Centre hospitalier universitaire de Nantes (CHU Nantes), Sanofi-Aventis R&D, SANOFI Recherche, Physiologie des Adaptations Nutritionnelles [UMR_A1280] (PhAN), Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN), Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), and ProdInra, Archive Ouverte
Subjects: 0301 basic medicine, medicine.drug_class, [SDV]Life Sciences [q-bio], Hyperlipidemias, 030204 cardiovascular system & hematology, Pharmacology, Antibodies, Monoclonal, Humanized, Monoclonal antibody, statins, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, medicine, Humans, Hypolipidemic Agents, proprotein convertase subtilisin kexin type 9 (PCSK9), biology, Cholesterol, PCSK9, PCSK9 Inhibitors, lipoprotein (a), Antibodies, Monoclonal, General Medicine, Lipoprotein(a), Proprotein convertase, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, low-density lipoprotein (LDL) receptor, Receptors, LDL, chemistry, Research Design, LDL receptor, Immunology, biology.protein, Kexin, lipids (amino acids, peptides, and proteins), Proprotein Convertase 9, Lipoprotein
Abstract: Since 2012, clinical trials dedicated to proprotein convertase subtilisin kexin type 9 (PCSK9) inhibition with monoclonal antibodies (mAbs) have unambiguously demonstrated robust reductions not only in low-density lipoprotein (LDL) cholesterol (LDL-C) but also in lipoprotein (a) [Lp(a)] levels. The scientific literature published prior to those studies did not provide any evidence for a link between PCSK9 and Lp(a) metabolism. More recent investigations, either in vitro or in vivo, have attempted to unravel the mechanism(s) by which PCSK9 mAbs reduce circulating Lp(a) levels, with some showing a specific implication of the LDL receptor (LDLR) in Lp(a) clearance whereas others found no significant role for the LDLR in that process. This elusive pathway appears clearly distinct from that of the widely prescribed statins that also enhance LDLR function but do not lower circulating Lp (a) levels in humans. So how does PCSK9 inhibition with mAbs reduce Lp(a)? This still remains to be established.
Published: 2017
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29. Antibiotic exposure and bacterial resistance in human and veterinary medicine: a problem-based learning topic for Master's students

Author: Nathalie Ruvoen, Sébastien Couvreur, Matthieu Eveillard, Hervé Pouliquen, Didier Lepelletier, Michel Krempf, C. Magras, Université Bretagne Loire (COMUE) (UBL), Biologie, Epidémiologie et analyse de risque en Santé Animale (BIOEPAR), Institut National de la Recherche Agronomique (INRA), Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Ecole Supérieure d'Agriculture (Groupe ESA), Physiopathologie des Adaptations Nutritionnelles (PhAN), and Université de Nantes (UN)-Institut National de la Recherche Agronomique (INRA)
Subjects: 0301 basic medicine, Veterinary medicine, education, Interpersonal communication, Microbiology, 03 medical and health sciences, Antibiotic resistance, Drug Resistance, Bacterial, Genetics, Students, Premedical, Animals, Humans, Group work, Students, problem-based learning, Molecular Biology, student-centred, 4. Education, 05 social sciences, Antibiotic exposure, 050301 education, Student centred, Bacterial Infections, innovation, 3. Good health, Test (assessment), Anti-Bacterial Agents, 030104 developmental biology, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Problem-based learning, Master s, Curriculum, Psychology, 0503 education, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; This report describes a problem-based learning activity concerning antibiotic exposure and bacterial resistance in humanand veterinary medicine. In addition, learning outcomes and satisfaction of students were recorded by the supervisors ofthe activity. The students all participated actively in the group work and considered that the small size of the groupfacilitated interpersonal communication. They believed that working in an interdisciplinary group helped them learn betterthan if they were following specific courses. They also reported that their mid-term meeting with one of the supervisorswas a catalyst for the initiation of a real work group. Concerning the evaluation of the activity itself, the supervisorsconsidered that the group provided a relevant analysis of the issue. These characteristics should encourage teachers to testthis method of learning certain aspects of microbiology and infectious diseases with their students.This report describes a problem-based learning activity concerning antibiotic exposure and bacterial resistance in humanand veterinary medicine. In addition, learning outcomes and satisfaction of students were recorded by the supervisors ofthe activity. The students all participated actively in the group work and considered that the small size of the groupfacilitated interpersonal communication. They believed that working in an interdisciplinary group helped them learn betterthan if they were following specific courses. They also reported that their mid-term meeting with one of the supervisorswas a catalyst for the initiation of a real work group. Concerning the evaluation of the activity itself, the supervisorsconsidered that the group provided a relevant analysis of the issue. These characteristics should encourage teachers to testthis method of learning certain aspects of microbiology and infectious diseases with their students.
Published: 2017
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30. Identification of novel APOB mutations by targeted next-generation sequencing for the molecular diagnosis of familial hypobetalipoproteinemia

Author: Mikaël Croyal, Jean-Jacques Schott, Simon Lecointe, Solena Le Scouarnec, Hervé Le Marec, Jocelyne Magré, Elias Barrak, Marie Marrec, Richard Redon, Bertrand Cariou, Michel Krempf, Matthieu Pichelin, Antoine Rimbert, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), CHU de Nantes, l'Institut du Thorax, CIC, Fondation Leducq-13CVD03 / Fundazione Cariplo 2012-0549 /Fondation de France 2015-00047967, Nutrition périnatale [Nantes] (Centres de Recherche en Nutrition Humaine - CRNH), Centre de Recherche en Nutrition Humaine - Ouest, Institut du thorax, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), CHATEL, Stephanie, and Unité de recherche de l'institut du thorax (ITX-lab)
Subjects: 0301 basic medicine, Apolipoprotein B, [SDV]Life Sciences [q-bio], 030204 cardiovascular system & hematology, medicine.disease_cause, Hypobetalipoproteinemias, PCSK9, 0302 clinical medicine, Filamin-A, Dachsous, Familial hypobetalipoproteinemia, Aged, 80 and over, Genetics, Sanger sequencing, Mutation, biology, High-Throughput Nucleotide Sequencing, SAR1B, Middle Aged, Abetalipoproteinemia, Pedigree, 3. Good health, [SDV] Life Sciences [q-bio], Phenotype, Codon, Nonsense, Apolipoprotein B-100, symbols, lipids (amino acids, peptides, and proteins), Molecular diagnosis, Proprotein Convertase 9, APOB, Cardiology and Cardiovascular Medicine, Adult, myxomatous disease, Heterozygote, Target next generation sequencing, Adolescent, Nonsense mutation, digestive system, DNA sequencing, Young Adult, 03 medical and health sciences, symbols.namesake, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Genetic variation, medicine, Humans, Aged, Gene Library, animal model, Genetic Variation, Reproducibility of Results, nutritional and metabolic diseases, Cholesterol, LDL, Sequence Analysis, DNA, Minor allele frequency, 030104 developmental biology, biology.protein, genetic, mitral valve prolapse
Abstract: International audience; BACKGROUND AND AIMS: Familial hypobetalipoproteinemia (FHBL) is a co-dominant disorder characterized by decreased plasma levels of LDL-cholesterol and apolipoprotein B (ApoB). Currently, genetic diagnosis in FHBL relies largely on Sanger sequencing to identify APOB and PCSK9 gene mutations and on western blotting to detect truncated ApoB species. METHODS: Here, we applied targeted enrichment and next-generation sequencing (NGS) on a panel of three FHBL genes and two abetalipoproteinemia genes (APOB, PCSK9, ANGPTL3, MTTP and SAR1B). RESULTS: In this study, we identified five likely pathogenic heterozygous rare variants. These include four novel nonsense mutations in APOB (p.Gln845*, p.Gln2571*, p.Cys2933* and p.Ser3718*) and a rare variant in PCSK9 (Minor Allele Frequency \textless0.1%). The affected family members tested were shown to be carriers, suggesting co-segregation with low LDL-C. CONCLUSIONS: Our study further demonstrates that NGS is a reliable and practical approach for the molecular screening of FHBL-causative genes that may provide a mean for deciphering the genetic basis in FHBL.
Published: 2016
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31. Multiplexed peptide analysis for kinetic measurements of major human apolipoproteins by LC/MS/MS

Author: Mikaël Croyal, Fanta Fall, Estelle Nobecourt, Yassine Zair, Maud Chétiveaux, Véronique Ferchaud-Roucher, Michel Krempf, Khadija Ouguerram, Nutrition périnatale [Nantes] (Centres de Recherche en Nutrition Humaine - CRNH), Centre de Recherche en Nutrition Humaine - Ouest, Centre Hospitalier Universitaire de l'Hôtel Dieu (CHU Hôtel Dieu), Université de Nantes (UN), Institut du thorax, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Physiologie des Adaptations Nutritionnelles [UMR_A1280] (PhAN), Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN), West Human Nutrition Research Center, Physiologie des Adaptations Nutritionnelles (PhAN), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, 0301 basic medicine, Peptide analysis, [SDV]Life Sciences [q-bio], Analytical chemistry, QD415-436, Tandem mass spectrometry, Kinetic energy, Biochemistry, Gas Chromatography-Mass Spectrometry, 03 medical and health sciences, Endocrinology, Tandem Mass Spectrometry, lipoproteins/metabolism, In vivo, Liquid chromatography–mass spectrometry, Lc ms ms, Methods, stable isotope, medicine, Humans, nutrition protein, liquid chromatography-tandem mass spectrometry, multiplexed assay, lipoproteins/kinetics, ComputingMilieux_MISCELLANEOUS, Chromatography, Chemistry, Cell Biology, Middle Aged, Trypsin, Peptide Fragments, Apolipoproteins, 030104 developmental biology, lipids (amino acids, peptides, and proteins), Gas chromatography–mass spectrometry, Chromatography, Liquid, medicine.drug
Abstract: This work was supported by the Biogenouest CORSAIRE core facility; International audience; A multiplexed assay was developed by MS to analyze, in a single run, six major human Apos involved in lipoprotein metabolism: ApoA-I, ApoA-II, ApoB100, ApoC-II, ApoC-III, and ApoE. This method was validated in vivo in six subjects who received a 14 h constant infusion of [5,5,5-H-2(3)] L-leucine at 10 mu M/kg/h. Plasma lipoprotein fractions were isolated from collected blood samples and were digested with trypsin. Proteotypic peptides were subsequently analyzed by LC/MS/MS. Enrichment measurement data were compared with those obtained by the standard method using GC/MS. The required time to obtain the LC/MS/MS data was less than that needed for GC/MS. The enrichments from both methods were correlated for ApoA-I (r = 0.994; P < 0.0001) and ApoB100 (r = 0.999; P < 0.0001), and the Bland-Altman plot confirmed the similarity of the two methods. Intra-and inter-assay variability calculated for the six Apos of interest did not exceed 10.7 and 12.5%, respectively, and kinetic parameters were similar and/or in agreement with previously reported data. Therefore, LC/MS/MS can be considered as a useful tool for human Apo kinetic studies using stable isotopes.
Published: 2016
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32. The very high cardiovascular risk in heterozygous familial hypercholesterolemia: Analysis of 734 French patients

Author: Olivier Ziegler, Philippe Moulin, J.D. Lalau, Franck Boccara, Michel Farnier, B. Vergès, Michel Krempf, Sophie Béliard, Mondher Toumi, Noël Peretti, Régis Hankard, Valérie Carreau, V. Durlach, Alain Carrié, David Rosenbaum, Gérald Luc, F. Paillard, P. Moulin, Patrick Tounian, Aurélie Millier, Denis Angoulvant, Jean Ferrières, G. Luc, E. Bruckert, Eric Bruckert, A. Pradignac, S. Béliard, Y. Pucheu, Alexandre Fredenrich, Nutrition, obésité et risque thrombotique (NORT), Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), and W.V. Brown
Subjects: Male, Endocrinology, Diabetes and Metabolism, Disease, Familial hypercholesterolemia, 030204 cardiovascular system & hematology, Body Mass Index, 0302 clinical medicine, Risk Factors, Hyperlipidemia, 030212 general & internal medicine, ComputingMilieux_MISCELLANEOUS, 2. Zero hunger, education.field_of_study, Nutrition and Dietetics, Anticholesteremic Agents, Middle Aged, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Plaque, Atherosclerotic, 3. Good health, Carotid Arteries, Cholesterol, Cardiovascular Diseases, LDL cholesterol, Female, France, Cardiology and Cardiovascular Medicine, Adult, medicine.medical_specialty, Population, Hypercholesterolemia, Hyperlipoproteinemia Type II, 03 medical and health sciences, Internal medicine, Internal Medicine, medicine, Humans, Risk factor, education, Aged, Retrospective Studies, business.industry, Maximum level, Cholesterol, LDL, medicine.disease, Cardiovascular risk, Cross-Sectional Studies, Physical therapy, Heterozygous familial hypercholesterolemia, business, Very high risk, Body mass index
Abstract: International audience; BACKGROUND: Heterozygous familial hypercholesterolemia (heFH) is a genetic disease causing high levels of low-density lipoprotein cholesterol (LDL-C). Although this population is at high cardiovascular (CV) risk, the risk is variable within patients depending on additional risk factors. CV disease risk groups have been defined by the Nouvelle Societe Francophone d'Atherosclerose (NSFA) and by the National Lipid Association recommendations. OBJECTIVES: The study aimed to describe a sample of French heFH patients, comparing patients at very high risk (VHR) and patients at high risk in terms of demographic and clinical characteristics as well as biological measurements and disease management. METHODS: Cross-sectional retrospective analysis on 734 patients hospitalized after 2005 in 5 academic centers. RESULTS: When considering NSFA classification, 550 (74.9%) patients belonged to the VHR group. Most patients in the VHR group presented more than 1 risk factor, the most prevalent ones being Lp(a) > 50 mg/dL and smoking. Patients in the VHR group were older (50.6 vs 45.0 years old, P =.0002), and presented a higher body mass index (25.5 kg/m(2) vs 23.3 kg/m(2), P
Published: 2016
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33. IRES-dependent translation of the long non coding RNA meloe in melanoma cells produces the most immunogenic MELOE antigens

Author: Delphine Carbonnelle, Michel Krempf, Nathalie Labarrière, François Lang, Maud Charpentier, Laetitia Florenceau, Agnès Fortun, Mikaël Croyal, Catherine Rabu, Centre de Recherche en Cancérologie / Nantes - Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Nutrition périnatale [Nantes] (Centres de Recherche en Nutrition Humaine - CRNH), Centre de Recherche en Nutrition Humaine - Ouest, INRA: UMR1280 Physiologie des adaptations (UMR1280), Institut National de la Recherche Agronomique (INRA), Centre hospitalier universitaire de Nantes (CHU Nantes), ANR-11-LABX-0016/11-LABX-0016,IGO,Immunothérapies Grand Ouest(2011), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), ANR-11-LABX-0016,IGO,Immunothérapies Grand Ouest(2011), Bernardo, Elizabeth, Laboratoires d'excellence - Immunothérapies Grand Ouest - - IGO2011 - ANR-11-LABX-0016 - LABX - VALID, Physiopathologie des Adaptations Nutritionnelles (PhAN), Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN), and Lang, François
Subjects: mélanome, 0301 basic medicine, 0302 clinical medicine, spectrométrie de masse, IRES, Cells, Cultured, 2. Zero hunger, acide ribonucléique, Melanoma, Immunogenicity, Neoplasm Proteins, 3. Good health, medicine.anatomical_structure, Oncology, tumor antigens, 030220 oncology & carcinogenesis, long non coding RNA, Melanocytes, [SDV.IMM]Life Sciences [q-bio]/Immunology, RNA, Long Noncoding, immunotherapy, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, Research Paper, [SDV.IMM] Life Sciences [q-bio]/Immunology, T cell, mélanocyte, [SDV.CAN]Life Sciences [q-bio]/Cancer, Internal Ribosome Entry Sites, Biology, Open Reading Frames, 03 medical and health sciences, immunogénétique, Antigen, [SDV.CAN] Life Sciences [q-bio]/Cancer, Antigens, Neoplasm, Cell Line, Tumor, medicine, melanoma, Humans, Amino Acid Sequence, antigène, Melanoma-associated antigen, Base Sequence, RNA, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, medicine.disease, biology.organism_classification, Virology, Internal ribosome entry site, 030104 developmental biology, Meloe, Protein Biosynthesis, Leukocytes, Mononuclear
Abstract: // Maud Charpentier 1 , Mikael Croyal 2, 3 , Delphine Carbonnelle 1 , Agnes Fortun 1 , Laetitia Florenceau 1, 4 , Catherine Rabu 1 , Michel Krempf 2, 3, 4 , Nathalie Labarriere 1, 4 , Francois Lang 1 1 CRCNA, INSERM, CNRS, Universite d’Angers, Universite de Nantes, Nantes, France 2 UMR INRA 1280, CHU, Nantes, France 3 West Human Nutrition Research Center, CHU, Nantes, France 4 CHU, Nantes, France Correspondence to: Francois Lang, email: francois.lang@univ-nantes.fr Keywords: melanoma, IRES, long non coding RNA, tumor antigens, immunotherapy Received: June 07, 2016 Accepted: July 20, 2016 Published: July 29, 2016 ABSTRACT MELOE-1 and MELOE-2, two highly specific melanoma antigens involved in T cell immunosurveillance are produced by IRES-dependent translation of the long « non coding » and polycistronic RNA, meloe . In the present study, we document the expression of an additional ORF, MELOE-3, located in the 5′ region of meloe . Data from in vitro translation experiments and transfection of melanoma cells with bicistronic vectors documented that MELOE-3 is exclusively translated by the classical cap-dependent pathway. Using a sensitive tandem mass spectrometry technique, we detected the presence of MELOE-3 in total lysates of both melanoma cells and normal melanocytes. This contrasts with our previous observation of the melanoma-restricted expression of MELOE-1 and MELOE-2. Furthermore, in vitro stimulation of PBMC from 6 healthy donors with overlapping peptides from MELOE-1 or MELOE-3 revealed a very scarce MELOE-3 specific T cell repertoire as compared to the abundant repertoire observed against MELOE-1. The poor immunogenicity of MELOE-3 and its expression in melanocytes is consistent with an immune tolerance towards a physiologically expressed protein. In contrast, melanoma-restricted expression of IRES-dependent MELOE-1 may explain its high immunogenicity. In conclusion, within the MELOE family, IRES-dependent antigens represent the best T cell targets for immunotherapy of melanoma.
Published: 2016
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34. Direct and maternal n-3 long-chain polyunsaturated fatty acid supplementation improved triglyceridemia and glycemia through the regulation of hepatic and muscle sphingolipid synthesis in offspring hamsters fed a high-fat diet

Author: Fatima Kasbi-Chadli, Véronique Ferchaud-Roucher, Khadija Ouguerram, Michel Krempf, Centre hospitalier universitaire de Nantes (CHU Nantes), Physiologie des Adaptations Nutritionnelles (PhAN), and Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN)
Subjects: Blood Glucose, Male, 0301 basic medicine, Medicine (miscellaneous), n-3 PUFA, chemistry.chemical_compound, Sphingosine, Cricetinae, [SDV.IDA]Life Sciences [q-bio]/Food engineering, Hypertriglyceridemia, 2. Zero hunger, chemistry.chemical_classification, Nutrition and Dietetics, music.instrument, biology, Metabolic syndrome, 3. Good health, Fatty acid synthase, Adipose Tissue, Liver, Lipogenesis, Female, lipids (amino acids, peptides, and proteins), Sterol Regulatory Element Binding Protein 1, Stearoyl-CoA Desaturase, Polyunsaturated fatty acid, medicine.medical_specialty, Ceramide, Lactosylceramides, Carbohydrate metabolism, Ceramides, Diet, High-Fat, 03 medical and health sciences, Lactosylceramide, Antigens, CD, Internal medicine, Fatty Acids, Omega-3, medicine, Hamster, Animals, Diacylglycerol O-Acyltransferase, RNA, Messenger, Maternal nutrition, Muscle, Skeletal, music, Triglycerides, Sphingolipids, Tumor Necrosis Factor-alpha, Cholesterol, HDL, Cholesterol, LDL, Maternal Nutritional Physiological Phenomena, Sphingolipid, 030104 developmental biology, Endocrinology, chemistry, Dietary Supplements, biology.protein, Fatty Acid Synthases, Lysophospholipids
Abstract: International audience; We recently reported that direct and maternal supplementation with n-3 long-chain polyunsaturated fatty acids (n-3 LC-PUFA) alleviates the metabolic disturbances in adult hamster pups fed with a high-fat diet (HFD). In this study, we hypothesized that these results involved a perinatal modulating effect of sphingolipids by n-3 LC-PUFA. We studied the effect of direct and maternal n-3 LC-PUFA supplementation on sphingolipid contents in liver and muscle, hepatic triglycerides (TG) secretion and glucose tolerance. Offspring male hamsters born from supplemented (C omega) or unsupplemented (C) mothers were subjected after weaning to a HFD during 16 weeks, without (C omega-HF or C-HF) or with direct supplementation with n-3 LC-PUFA (C-HF omega). Direct supplementation decreased sphingosine, sphinganine and ceramides in liver and decreased sphingosine, sphinganine, sphingosine-1-phosphate (S1P) and ceramides in muscle in C-HF omega compared to C-HF (p < 0.05). Maternal supplementation decreased C20 ceramide and lactosylceramide in liver and sphinganine, S1P and lactosylceramide in muscle (p < 0.05). This supplementation tended to decrease glucosylceramide in liver (p < 0.06) and muscle (p < 0.07) in C omega-HF compared to C-HF. Direct supplementation increased glucose tolerance and decreased hepatic TG secretion and hepatic gene expression levels of diacylglycerol O-acyltransferase 2 (DGAT2), sterol regulatory element-binding protein-1c (SREBP-1c), fatty acid synthase, stearoyl-CoA desaturase-1 (SCD1) and tumor necrosis factor alpha (TNF alpha). Maternal supplementation decreased basal glycemia and hepatic TG secretion. We observed a positive correlation between hepatic TG secretion and hepatic ceramide (p = 0.0059), and between basal glycemia and hepatic ceramide (p = 0.04) or muscle lactosylceramide contents (p = 0.001). We observed an improvement of lipids and glucose metabolism in hamster with n-3 LC-PUFA direct supplementation and a decrease in glycemia and hepatic TG secretion with maternal supplementation. These results are probably related to a decrease in both lipogenesis and sphingolipid contents in liver and muscle.
Published: 2016
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35. Effet des chirurgies bariatriques sur le métabolisme du cholestérol chez la souris

Author: Claire Blanchard, François Moreau, V. Ferchaud, Michel Krempf, Audrey Ayer, F. Borel, C. Le May, Bertrand Cariou, Physiologie des Adaptations Nutritionnelles (PhAN), and Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN)
Subjects: 0303 health sciences, 03 medical and health sciences, 0302 clinical medicine, Nutrition and Dietetics, 030309 nutrition & dietetics, Endocrinology, Diabetes and Metabolism, Internal Medicine, 030209 endocrinology & metabolism, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, ComputingMilieux_MISCELLANEOUS, 3. Good health
Abstract: Introduction et but de l’etude Les chirurgies bariatriques representent une alternative therapeutique de choix chez les patients obeses morbides. Outre la perte de poids, ces chirurgies induisent une reduction significative des complications metaboliques associees, notamment les dyslipidemies. Cette etude vise a determiner chez la souris les consequences de 2 methodes de chirurgies bariatriques, i.e. la gastrectomie de type sleeve (sleeve) et de type bypass roux en Y (RYGB), sur les voies regulant le metabolisme du cholesterol. Materiel et methodes Des souris mâles C57BL6/J âgees de 10 semaines ont recu un regime hyperlipidique pendant 8 (sleeve) a 12 semaines (RYGB) avant les chirurgies. Les souris ont ete randomisees sur le poids et la cholesterolemie puis ont beneficie d’une chirurgie de type sham (laparotomie), sleeve ou d’un RYGB. Nous avons mesure les consequences des chirurgies sur le poids et le metabolisme glucidique et lipidique. L’analyse de l’excretion biliaire, transintestinale et fecale de cholesterol a ete determinee in vivo par spectrometrie de masse (GC-MS). Resultats et analyse statistique La duree operatoire moyenne mesuree a ete de 49,33 ± 5,1 minutes pour le groupe sleeve et de 93,63 ± 1,7 minutes pour le groupe RYGB. Quatorze jours apres chirurgie (j+14), la chirurgie de type sleeve et RYGB ont induit une reduction significative du poids corporel (respectivement −15,63 % et −25 % par rapport a la valeur mesuree avant la chirurgie [p Conclusion En conclusion, nous avons mis en place, avec succes, deux modeles de chirurgie bariatrique chez la souris. L’effet hypocholesterolemiant observe apres chirurgie de type sleeve est modeste et semble etre principalement lie a des modifications de la prise alimentaire. En revanche, la chirurgie de type RYGB induit une hypocholesterolemie marquee et une forte induction de l’excretion fecale de cholesterol.
Published: 2015

36. Characterization of Autosomal Dominant Hypercholesterolemia Caused by PCSK9 Gain of Function Mutations and Its Specific Treatment With Alirocumab, a PCSK9 Monoclonal Antibody

Author: Bertrand Cariou, Yassine Zair, Hisashi Makino, Paul N. Hopkins, Alain Carrié, Sara Hamon, Bernard Chanu, Michel Farnier, Kunimasa Yagi, Hiroshi Mabuchi, Yee P. Teoh, Michel Krempf, Matthieu Pichelin, Neil Stahl, Johanna Mendoza, George D. Yancopoulos, Masakazu Yamagishi, Charles van Heyningen, Catherine Boileau, Marianne Abifadel, A. David Marais, Sigrid W. Fouchier, Barbara Sjouke, Valérie Carreau, Masa-aki Kawashiri, Eric Bruckert, Scott Mellis, Mafalda Bourbon, Hayato Tada, Yoshihiro Miyamoto, Yunling Du, Jean-Pierre Rabès, Gary Swergold, Joep C. Defesche, Mariko Harada-Shiba, Ichiro Kishimoto, Shoji Katsuda, Trond P. Leren, Handrean Soran, Atsushi Nohara, Gérald Luc, Gilles Lambert, Cardiovascular Genetics Division, University of Utah School of Medicine [Salt Lake City], Service d'endocrinologie-métabolisme [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Institut E3M [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [APHP], Service de Médecine Interne, PRES Université Lille Nord de France-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Department of Vascular Medicine, Emma Children’s Hospital Academic Medical Centre, National cerebral and cardiovascular center research institute, Hémostase, bio-ingénierie et remodelage cardiovasculaires (LBPC), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Institut Galilée-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Biochimie et de Génétique Moléculaire, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Ambroise Paré-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Service de Biochimie Endocrinienne et Oncologique [CHU Pitié-Salpêtrière], Point médical (Dijon), Laboratoire de Recherche Vasculaire Translationnelle (LVTS (UMR_S_1148 / U1148)), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Saint-Joseph de Beyrouth (USJ), Service de cardiologie, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 (UPD7), Service d'endocrinologie, diabétologie et nutrition, Centre de Recherche en Nutrition Humaine - Ile de France (CRNH - IDF)-Hôpital Jean Verdier [Bondy], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Sorbonne Paris Cité (USPC)-Université Paris 13 (UP13), Bureau d'Économie Théorique et Appliquée (BETA), Institut National de la Recherche Agronomique (INRA)-Université de Strasbourg (UNISTRA)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Diderot - Paris 7 (UPD7)-Université Paris 13 (UP13)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Service d’Endocrinologie, Métabolisme et Prévention des Risques Cardio-Vasculaires [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Paris Diderot - Paris 7 (UPD7)-Université Paris 13 (UP13)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Galilée, Service de biochimie, d'hormonologie et de génétique moléculaire [CHU Amrboise Paré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], Service de Biochimie Endocrinienne et Oncologie [CHU Pitié-Salpêtrière], Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche en Nutrition Humaine - Ile de France (CRNH - IDF)-Hôpital Jean Verdier [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Sorbonne Paris Cité (USPC)-Université Paris 13 (UP13), Université de Lorraine (UL)-Université de Strasbourg (UNISTRA)-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS), ACS - Amsterdam Cardiovascular Sciences, Experimental Vascular Medicine, Medical Biochemistry, Graduate School, and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: Male, Apolipoprotein B, [SDV]Life Sciences [q-bio], alirocumab, Coronary Artery Disease, Bioinformatics, Gastroenterology, Doenças Cardio e Cérebro-vasculares, PCSK9, Hypercapnia, Coronary artery disease, Cardiovascular Disease, Clinical endpoint, Genetics (clinical), education.field_of_study, biology, Serine Endopeptidases, Antibodies, Monoclonal, PCSK9 protein, cardiovascular diseases, clinical trial, genetics, human, hypercholesterolemia, Middle Aged, Clinical Trial, 3. Good health, Cardiovascular Diseases, Alimentation et Nutrition, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Original Article, Female, Proprotein Convertases, Proprotein Convertase 9, Cardiology and Cardiovascular Medicine, Adult, medicine.medical_specialty, Heterozygote, Adolescent, Population, Hypercholesterolemia, Antibodies, Monoclonal, Humanized, Hyperlipoproteinemia Type II, Double-Blind Method, Internal medicine, medicine, Genetics, Food and Nutrition, Humans, education, Alirocumab, Aged, business.industry, Cholesterol, LDL, medicine.disease, Clinical trial, Receptors, LDL, Mutation, biology.protein, Age of onset, business
Abstract: Supplemental Digital Content is available in the text., Background— Patients with PCSK9 gene gain of function (GOF) mutations have a rare form of autosomal dominant hypercholesterolemia. However, data examining their clinical characteristics and geographic distribution are lacking. Furthermore, no randomized treatment study in this population has been reported. Methods and Results— We compiled clinical characteristics of PCSK9 GOF mutation carriers in a multinational retrospective, cross-sectional, observational study. We then performed a randomized placebo-phase, double-blind study of alirocumab 150 mg administered subcutaneously every 2 weeks to 13 patients representing 4 different PCSK9 GOF mutations with low-density lipoprotein cholesterol (LDL-C) ≥70 mg/dL on their current lipid-lowering therapies at baseline. Observational study: among 164 patients, 16 different PCSK9 GOF mutations distributed throughout the gene were associated with varying severity of untreated LDL-C levels. Coronary artery disease was common (33%; average age of onset, 49.4 years), and untreated LDL-C concentrations were higher compared with matched carriers of mutations in the LDLR (n=2126) or apolipoprotein B (n=470) genes. Intervention study: in PCSK9 GOF mutation patients randomly assigned to receive alirocumab, mean percent reduction in LDL-C at 2 weeks was 62.5% (P
Published: 2015
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37. A Long-term Model of the Glucose-Insulin Dynamics of Type 1 Diabetes

Author: Michel Krempf, Nicolas Magdelaine, Lucy Chaillous, Claude H. Moog, Jean-Yves Poirier, Isabelle Guilhem, Eric Le Carpentier, Institut de Recherche en Communications et en Cybernétique de Nantes (IRCCyN), Mines Nantes (Mines Nantes)-École Centrale de Nantes (ECN)-Ecole Polytechnique de l'Université de Nantes (EPUN), Université de Nantes (UN)-Université de Nantes (UN)-PRES Université Nantes Angers Le Mans (UNAM)-Centre National de la Recherche Scientifique (CNRS), Clinique d'Endocrinologie, Maladies Métaboliques et Nutrition, Hôpital Laennec, Centre Hospitalier Universitaire [Rennes], Institut du thorax, and Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Blood Glucose, Male, Basal rate, medicine.medical_specialty, type 1 diabetes, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Biomedical Engineering, Models, Biological, Internal medicine, Diabetes mellitus, [INFO.INFO-AU]Computer Science [cs]/Automatic Control Engineering, medicine, Humans, Insulin, Type 1 diabetes, business.industry, Continuous glucose monitoring, functional insulin therapy, Insulin sensitivity, modeling, Carbohydrate, medicine.disease, Term (time), glycemia, Diabetes Mellitus, Type 1, Endocrinology, clinical data, business, Algorithms
Abstract: International audience; A new glucose-insulin model is introduced which fits with the clinical data from in- and outpatients for two days. Its stability propertiy is consistent with the glycemia behavior for type 1 diabetes. This is in contrast to traditional glucose-insulin models. Prior models fits with clinical data for a few hours only or display some non-natural equilibria. The parameters of this new model are identifiable from standard clinical data as continuous glucose monitoring, insulin injection and carbohydrate estimate. Moreover, it is shown that the parameters from the model allow the computation of the standard tools used in functional insulin therapy as the basal rate of insulin and the insulin sensitivity factor. This is a major outcome as they are required in therapeutic education of type 1 diabetic patient.; Cet article présente un nouveau modèle de l'action de l'insuline sur la glycémie. Les propriétés de ses points d'équilibre sont réalistes et les dynamiques de ce modèle s'ajustent aux données cliniques sur 2 jours. Cela est à comparer aux modèles précédents dont les dynamiques s'ajustent sur quelques heures et qui présentent des points d'équilibre non-naturels. Les paramètres de ce nouveau modèle sont identifiables d'après les données cliniques standard (mesure en continu de glycémie, injection d'insuline, glucides dans l'assiette). Bien plus encore, les paramètres de ce modèle permettent de calculer les outils de l'insulinothérapie tels que le débit basal, les unités-portion, le compensatoire. Cela est une avancée majeure car ces outils sont très utiles dans l'éducation thérapeutique du patient atteint de diabète de type 1.
Published: 2015
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38. Plasma lipidome characterization using UHPLC-HRMS and ion mobility of hypertriglyceridemic patients on nicotinic acid

Author: Véronique Ferchaud-Roucher, Mikaël Croyal, Michel Krempf, Khadija Ouguerram, Physiologie des Adaptations Nutritionnelles (PhAN), Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN), and European Atherosclerosis Society. SWE.
Subjects: 0303 health sciences, 030309 nutrition & dietetics, Chemistry, Uhplc hrms, 030209 endocrinology & metabolism, Lipidome, Ion, 03 medical and health sciences, 0302 clinical medicine, Nicotinic agonist, Biochemistry, Cardiology and Cardiovascular Medicine, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience
Published: 2015
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39. Cardiovascular risk in relation to body mass index and use of evidence-based preventive medications in patients with or at risk of atherothrombosis

Author: Moses Elisaf, Michel Krempf, Boris Hansel, Ph. Gabriel Steg, Ronan Roussel, Deepak L. Bhatt, Kim A. Eagle, Michel Marre, Y Elbez, Yasuo Ikeda, Hôpitaux Universitaires Paris Nord Val de Seine (HUPNVS), Université Paris Diderot - Paris 7 (UPD7), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), DHU FIRE, Partenaires INRAE, Clinique d'Endocrinologie, Maladies Métaboliques et Nutrition, Hôpital Laennec, Waseda University, University of Michigan, University Hospital of Ioannina, Brigham and Women’s Hospital Heart, ProdInra, Migration, Waseda University [Tokyo, Japan], Brigham and Women’s Hospital [Boston, MA], and Harvard Medical School [Boston] (HMS)
Subjects: Male, medicine.medical_specialty, Epidemiology, 030204 cardiovascular system & hematology, Global Health, Body Mass Index, 03 medical and health sciences, 0302 clinical medicine, Age Distribution, Risk Factors, Internal medicine, medicine, Humans, 030212 general & internal medicine, Prospective Studies, Obesity, Paradox, Prospective cohort study, Aged, 2. Zero hunger, Obesity, Metabolically Benign, Evidence-Based Medicine, business.industry, Cardiovascular Agents, Thrombosis, Middle Aged, medicine.disease, Atherosclerosis, Cardiovascular disease, 3. Good health, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, Treatment Outcome, Optimal therapy, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Cardiovascular Diseases, Cardiovascular agent, Cohort, Physical therapy, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Underweight, medicine.symptom, Cardiology and Cardiovascular Medicine, business, Body mass index, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, Obesity paradox
Abstract: International audience; Aim Explore the relation between body mass index (BMI) and cardiovascular disease, and the influence of optimal medical therapy (OMT) on this relationship. Methods and results Patients from the REACH cohort, an international, prospective cohort of patients with or at high risk of atherosclerosis with documentation of potential confounders, including treatments and risk factors, were followed up to 4 years (n = 54 285). Patients were categorized according to baseline BMI (ranging from underweight to Grade III obesity). Optimal medical therapy was defined as the use of the four cardioprotective medication classes (statins, ACE inhibitors/angiotensin II receptor blockers, β-blockers, and antiplatelet agents). The main outcomes were all-cause mortality, cardiovascular (CV) mortality, and CV events. In primary and secondary prevention, a reverse J-shaped curve best described the relationship between BMI categories and the incidence of the various outcomes. In secondary prevention, the highest adjusted risks were observed for underweight patients (1.97, P < 0.01, and 1.29, P = 0.03, for CV mortality and CV events) and the lowest HRs were observed, respectively, in Grade II and Grade III obese patients (0.73, P < 0.01 and 0.80, P < 0.01). The proportion of patients on OMT increased with BMI from 10.1 to 36% (P < 0.001). The apparent CV protection conferred by obesity persisted in patients receiving OMT. Conclusion An obesity paradox was observed in both primary and secondary CV prevention patients. The intensity of use of evidence-based preventive medications does not account for the paradoxical CV protection associated with obesity. At extremes of BMI, further interventions beyond OMT may be needed to reduce CV risk.
Published: 2015
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40. Laparoscopic gastric banding in obese patients with sleep apnea: a 3-year controlled study and follow-up after 10 years

Author: Maëlle Le Bras, Delphine Drui, Estelle Nobécourt-Dupuy, E. Letessier, Yassine Zair, Barbara Feigel-Guiller, Nuria Fuertes-Zamorano, Bertrand Cariou, Jérôme Dimet, Michel Krempf, Université de Nantes (UN), Hopital La Roche sur Yon, and Partenaires INRAE
Subjects: Adult, Male, medicine.medical_specialty, Gastroplasty, Gastric banding, Endocrinology, Diabetes and Metabolism, law.invention, Randomized controlled trial, Weight loss, law, Laparoscopic adjustable gastric banding, Weight Loss, Medicine, Humans, Nutritional care, Caloric Restriction, Bariatric surgery, Sleep Apnea, Obstructive, Nutrition and Dietetics, Noninvasive Ventilation, business.industry, Sleep apnea, Middle Aged, medicine.disease, Obesity, Surgery, Obesity, Morbid, Treatment Outcome, Anesthesia, Breathing, Patient Compliance, Female, Laparoscopy, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, medicine.symptom, business, Controlled study, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, Follow-Up Studies
Abstract: Background The purpose of this study was to compare the effects of intensive nutritional care (INC) and laparoscopic adjustable gastric banding (LAGB) on nocturnal non-invasive ventilation (NIV) requirement in obese patients using short-, medium-, and long-term follow-up data. Methods This prospective randomized controlled trial included obese patients with obstructive sleep apnea (OSA) treated by NIV. Patients were randomized to the INC and LAGB groups. The primary endpoint was the theoretical rate of weaning from NIV at years 1 and 3. Data were also collected from patients 10 years after randomization. Results Sixty-three patients were randomized. The rate of weaning from NIV did not differ significantly between the LAGB and INC groups at year 1 (35 vs. 13 %) or year 3 (14 vs. 21 %). Percentages of excess weight loss were greater in the LAGB group than in the INC group at years 1 (33 vs. 15 %, p = 0.002) and 3 (27 vs. 8 %, p = 0.014). Decreases in the apnea-hypopnea index were observed in the LAGB group from baseline to year 1 (−44 %, p = 0.001) and from baseline to year 3 (−26 %, p = 0.044). After 10 years, the weaning rate was low and similar between groups. Conclusion LAGB was not superior to INC for weaning from NIV at 1 and 3 years in obese patients with OSA.
Published: 2015
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41. Improvement in LDL-cholesterol levels of patients with familial hypercholesterolemia: can we do better? Analysis of results obtained during the past two decades in 1669 French subjects

Author: G. Luc, Alain Carrié, Valérie Carreau, Jean Ferrières, Eric Bruckert, P. Moulin, Michel Krempf, Philippe Giral, Alexandre Fredenrich, Michel Farnier, E. Duchêne, S. Béliard, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), and Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, medicine.medical_specialty, Time Factors, Cross-sectional study, [SDV]Life Sciences [q-bio], Population, Disease, Familial hypercholesterolemia, 030204 cardiovascular system & hematology, Hyperlipoproteinemia Type II/*blood/*drug therapy, Hyperlipoproteinemia Type II, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Potency, Humans, 030212 general & internal medicine, education, Ldl cholesterol, education.field_of_study, business.industry, Cholesterol, LDL, Middle Aged, medicine.disease, LDL/*blood, 3. Good health, Endocrinology, Increased risk, Cholesterol, Cross-Sectional Studies, Hydroxymethylglutaryl-CoA Reductase Inhibitors/*therapeutic use, lipids (amino acids, peptides, and proteins), Female, France, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Cardiology and Cardiovascular Medicine, business
Abstract: International audience; BACKGROUND: Heterozygous Familial Hypercholesterolemia (heFH) is an autosomal disease that affects about 1/500 people. It is characterized by markedly elevated plasma LDL-cholesterol (C) levels and an increased risk of cardiovascular disease (CVD). The aim of this study was to measure changes in LDL-C levels in heFH patients over two decades, and to evaluate if patients achieved LDL-C targets. METHODS: Data from 1669 heFH patients in five academic French centers were recorded between 1988 and 2011. RESULTS: The mean LDL-C concentrations under medical care improved between 1988 and 2011 (245 mg/dL before 1995, 164 mg/dL after 2009; p \textless 0.0001). However, mean LDL-C level and the number of patients treated with statins (79.3%) have not improved since 2005. In patients registered and treated after 2005 (n = 616), only 10.4% reached target LDL-C levels of \textless100 mg/dL. Indeed, 29.4% (n = 181) were treated with a maximal therapy (statins with a potency of \textgreater45% LDL-C reduction plus at least another lipid-lowering agent). Despite maximal treatment, only 18.8% of these heFH patients (n = 34/181) reached target LDL-C levels of \textless100 mg/dL. In addition, 75.3% of patients with CVD did not reach the LDL-C of \textless100 mg/dL. CONCLUSION: This study demonstrates that after significant improvement over the past two decades, the mean LDL-C levels in heFH French patients has remained stable since 2005. We also show that most heFH patients are not achieving their recommended LDL-C goals: this highlights the need for improved treatment and for new therapeutics in this population.
Published: 2014
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42. n-3 PUFA prevent metabolic disturbances associated with obesity and improve endothelial function in golden Syrian hamsters fed with a high-fat diet

Author: Gervaise Loirand, Agnès André, Fatima Kasbi Chadli, Michel Krempf, Khadija Ouguerram, Xavier Prieur, Patrick Nguyen, Anne Meynier, Institut National de la Santé et de la Recherche Médicale (INSERM), LUNAM Université [Nantes Angers Le Mans], Centre hospitalier universitaire de Nantes (CHU Nantes), Unité de recherche sur les Biopolymères, Interactions Assemblages (BIA), Institut National de la Recherche Agronomique (INRA), CRNH (Centre de Recherche en Nutrition Humaine, Nantes, France), Region Pays de la Loire, and ProdInra, Migration
Subjects: CD36 Antigens, Male, Dyslipidaemia, RECEPTOR-DEFICIENT MICE, Medicine (miscellaneous), Adipose tissue, Lipoproteins, VLDL, n-3 PUFA, ADIPOSE-TISSUE INFLAMMATION, chemistry.chemical_compound, 0302 clinical medicine, Cricetinae, [SDV.IDA]Life Sciences [q-bio]/Food engineering, Adipocytes, Endothelial dysfunction, Aorta, FISH-OIL, 2. Zero hunger, chemistry.chemical_classification, 0303 health sciences, Nutrition and Dietetics, Muscles, [SDV.IDA] Life Sciences [q-bio]/Food engineering, Lipids, medicine.anatomical_structure, Adipose Tissue, Liver, Body Composition, Hamsters, Carbohydrate Metabolism, SERUM-LIPIDS, lipids (amino acids, peptides, and proteins), medicine.drug, Polyunsaturated fatty acid, medicine.medical_specialty, Endothelium, APOLIPOPROTEIN-B, [SPI.GPROC] Engineering Sciences [physics]/Chemical and Process Engineering, 030209 endocrinology & metabolism, Diet, High-Fat, 03 medical and health sciences, Internal medicine, Fatty Acids, Omega-3, medicine, Animals, EICOSAPENTAENOIC ACPREVENTS, [SPI.GPROC]Engineering Sciences [physics]/Chemical and Process Engineering, Carnitine, Obesity, Scavenger receptor, HEPATIC STEATOSIS, Glucose intolerance, 030304 developmental biology, Dyslipidemias, Mesocricetus, Cholesterol, business.industry, Macrophages, Body Weight, Endothelial function, Carbohydrate, DOCOSAHEXAENOIC ACID, medicine.disease, Lipid Metabolism, Animal Feed, Endocrinology, Glucose, chemistry, Endothelium, Vascular, INDUCED INSULIN-RESISTANCE, business, HIGH-DENSITY-LIPOPROTEIN
Abstract: Glucose intolerance and dyslipidaemia are independent risk factors for endothelium dysfunction and CVD. The aim of the present study was to analyse the preventive effect ofn-3 PUFA (EPA and DHA) on lipid and carbohydrate disturbances and endothelial dysfunction. Three groups of adult hamsters were studied for 20 weeks: (1) control diet (Control); (2) high-fat diet (HF); (3) high-fat diet enriched withn-3 PUFA (HFn-3) groups. The increase in body weight and fat mass in the HF compared to the Control group (P n-3 group. Muscle TAG content was similar in the Control and HF groups, but significantly lower in the HFn-3 group (P = 0·008). Glucose tolerance was impaired in the HF compared to the Control group, but this impairment was prevented byn-3 PUFA in the HFn-3 group (P P n-3 group compared to the HF group (P n-3 group compared to the Control and HF groups (P n-3 group compared to the HF group (P O-acyltransferase 2 and stearyl CoA desaturase 1 was lower in the HFn-3 group, whereas carnitine palmitoyl transferase 1 and scavenger receptor class B type 1 expression was higher (P n-3 groups compared to the Control group. Endothelium relaxation was higher in the HFn-3 (P P = 0·03) and cholesterol (P = 0·0003). In conclusion,n-3 PUFA prevent some metabolic disturbances induced by high-fat diet and improve endothelial function in hamsters.
Published: 2012
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43. Fasting plasma chenodeoxycholic acid and cholic acid concentrations are inversely correlated with insulin sensitivity in adults

Author: Martine Laville, Béatrice Guyomarc’h-Delasalle, Yassine Zair, Bertrand Cariou, Michel Krempf, Emmanuel Disse, Etienne Pouteau, Maud Chétiveaux, Institut du thorax, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), Nestlé Research Center, R&D Santiago, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), This work was supported by grant from the Agence Nationale de la Recherche (N° A05056G), and from the ALFEDIAM/SFD (grant Novo-Nordisk, 2007)., Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), BMC, Ed., and Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL)
Subjects: medicine.medical_specialty, [SDV.MHEP.PHY] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Medicine (miscellaneous), 030209 endocrinology & metabolism, lcsh:TX341-641, Type 2 diabetes, Brief Communication, hyperinsulinemic-euglycemic clamp, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Insulin resistance, Internal medicine, Chenodeoxycholic acid, insulin resistance, energy expenditure, medicine, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], lcsh:RC620-627, 030304 developmental biology, bile acids, 0303 health sciences, Nutrition and Dietetics, medicine.diagnostic_test, business.industry, Insulin, Deoxycholic acid, TGR5, Cholic acid, medicine.disease, G protein-coupled bile acid receptor, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, lcsh:Nutritional diseases. Deficiency diseases, Endocrinology, chemistry, FXR, type 2 diabetes, Lipid profile, business, lcsh:Nutrition. Foods and food supply, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition
Abstract: Background Accumulating data suggest a novel role for bile acids (BAs) in modulating metabolic homeostasis. BA treatment has been shown to improve glucose tolerance and to increase energy expenditure in mice. Here, we investigated the relationship between fasting plasma BAs concentrations and metabolic parameters in humans. Findings Fasting plasma glucose, insulin and lipid profile were measured in 14 healthy volunteers, 20 patients with type 2 diabetes (T2D), and 22 non-diabetic abdominally obese subjects. Insulin sensitivity was also assessed by the determination of the glucose infusion rate (GIR) during a hyperinsulinemic-euglycemic clamp in a subgroup of patients (9 healthy and 16 T2D subjects). Energy expenditure was measured by indirect calorimetry. Plasma cholic acid (CA), chenodeoxycholic acid (CDCA) and deoxycholic acid (DCA) concentrations were analyzed by gas chromatograph-mass spectrometry. In univariable analysis, a positive association was found between HOMA-IR and plasma CDCA (β = 0.09, p = 0.001), CA (β = 0.03, p = 0.09) and DCA concentrations (β = 0.07, p < 0.0001). Spearman analysis retrieved an inverse relationship between plasma CDCA (r = -0.44, p = 0.03), CA (r = -0.65, p = 0.001) and the GIR. HOMA-IR remained positively associated with CDCA (β = 0.11, p = 0.01), CA (β = 0.04, p = 0.01) and DCA (β = 0.06, p = 0.007) in multivariable analysis, after adjustment for age, gender, BMI, HbA1C and plasma lipid parameters. In contrast, HbA1c, energy expenditure and plasma lipid concentrations were not correlated with plasma BAs levels in multivariable analysis. Conclusions Both plasma CDCA, CA and DCA concentrations were negatively associated with insulin sensitivity in a wide range of subjects.
Published: 2011
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44. Association between plasma PCSK9 and gamma-glutamyl transferase levels in diabetic patients

Author: Cédric Langhi, Bertrand Cariou, Béatrice Guyomarc’h-Delasalle, Cédric Le May, Philippe Costet, Michel Krempf, Maëlle Le Bras, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, medicine.medical_specialty, Blood Pressure, Enzyme-Linked Immunosorbent Assay, 030204 cardiovascular system & hematology, Gene Expression Regulation, Enzymologic, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Diabetes mellitus, Internal medicine, medicine, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Humans, Prospective Studies, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Glycated Hemoglobin, 2. Zero hunger, 0303 health sciences, Type 1 diabetes, business.industry, PCSK9, Serine Endopeptidases, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, gamma-Glutamyltransferase, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Proprotein convertase, medicine.disease, Cholesterol, Diabetes Mellitus, Type 1, Endocrinology, Diabetes Mellitus, Type 2, Receptors, LDL, Regression Analysis, Kexin, Female, Proprotein Convertases, Liver function, Proprotein Convertase 9, Cardiology and Cardiovascular Medicine, business, Body mass index, Lipoprotein
Abstract: Background Proprotein convertase subtilisin kexin type 9 (PCSK9) is a secreted proprotein convertase acting as a natural inhibitor of the low-density lipoprotein (LDL) receptor. Here, we prospectively investigated the relationship between the circulating levels of PCSK9 and metabolic parameters in 117 diabetic patients. Results Plasma PCSK9 level was significantly higher in type 2 than in type 1 diabetes ( P =0.04), in diabetic patients under statins ( P −4 ) and in those with macrovascular complications ( P =0.002). Univariable regression analysis revealed that plasma PCSK9 level correlated positively with age ( P =0.003), body mass index ( P =0.04), systolic blood pressure (SBP) ( P =0.01), gamma-glutamyl transferase (GGT) levels ( P =0.0002) and statin treatment ( P =0.001). In a multivariable linear regression analysis, PCSK9 correlated positively with GGT level ( β =21.91, P =0.0019) after adjustment for gender, age, type of diabetes, statin treatment, BMI, SBP and HbA1c. Conclusion PCSK9 level was independently associated with GGT level in diabetic patients, suggesting potential interaction between PCSK9 and liver function.
Published: 2010
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45. PCSK9 is expressed in pancreatic δ-cells and does not alter insulin secretion

Author: Bertrand Cariou, Brigitte Vandewalle, Julie Kerr-Conte, François Pattou, Cédric Langhi, Philippe Costet, Cédric Le May, Valery Gmyr, Michel Krempf, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Somatostatin-Secreting Cells, endocrine system, medicine.medical_specialty, Biophysics, 030204 cardiovascular system & hematology, Biochemistry, Cell Line, Mice, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Insulin-Secreting Cells, Internal medicine, Insulin Secretion, medicine, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Animals, Humans, Insulin, Receptor, Molecular Biology, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Chemistry, Pancreatic islets, PCSK9, Serine Endopeptidases, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Cell Biology, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Streptozotocin, Proprotein convertase, Cholesterol, Glucose, Endocrinology, medicine.anatomical_structure, Somatostatin, Receptors, LDL, LDL receptor, Kexin, Proprotein Convertases, Proprotein Convertase 9, medicine.drug
Abstract: PCSK9 (Proprotein Convertase Subtilisin Kexin type 9) is a proprotein convertase that plays a key role in cholesterol homeostasis by decreasing hepatic low-density lipoprotein receptor (LDLR) protein expression. Here, we investigated the expression and the function of PCSK9 in pancreatic islets. Immunohistochemistry analysis showed that PCSK9 co-localized specifically with somatostatin in human pancreatic delta-cells, with no expression in alpha- and beta-cells. PCSK9 seems not to be secreted by mouse isolated islets maintained in culture. Pcsk9-deficiency led to a 200% increase in LDLR protein content in mouse isolated islets, mainly in beta-cells. Conversely, incubation of islets with recombinant PCSK9 almost abolished LDLR expression. However, Pcsk9-deficiency did not alter cholesterol content nor glucose-stimulated insulin secretion in mouse islets. Finally, invivo glucose tolerance was similar in Pcsk9(+/+) and Pcsk9(-/-) mice under basal conditions and following streptozotocin treatment. These results suggest, at least in mice, that PCSK9 does not alter insulin secretion.
Published: 2009
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46. Proprotein Convertase Subtilisin Kexin Type 9 Null Mice Are Protected From Postprandial Triglyceridemia

Author: Xavier Collet, Bertrand Cariou, Christine Coméra, Maud Chétiveaux, Anne Jarry, Folkert Kuipers, Philippe Costet, Cédric Le May, Michel Krempf, Cédric Langhi, Sanae Kourimate, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), ProdInra, Migration, Cardiopathies et mort subite [ERL 3147], Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), EA Biométadys, Université de Nantes (UN), Neuro-Gastroentérologie & Nutrition (ToxAlim-NGN), ToxAlim (ToxAlim), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Center for Liver, Digestive and Metabolic Diseases, Physiopathologie des Adaptations Nutritionnelles (PhAN), Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN), ANR PNRA Absinthe, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA), Physiologie des Adaptations Nutritionnelles (PhAN), and Center for Liver, Digestive and Metabolic Diseases (CLDM)
Subjects: Apolipoprotein B, [SDV]Life Sciences [q-bio], postprandial, 030204 cardiovascular system & hematology, Intestin, PCSK9, Mice, 0302 clinical medicine, INTESTINE, Chylomicrons, Intestine, Small, CaCo-2, FAMILIAL HYPERCHOLESTEROLEMIA, ComputingMilieux_MISCELLANEOUS, Métabolisme des lipides, Mice, Knockout, 0303 health sciences, Microscopy, Confocal, biology, Serine Endopeptidases, chylomicron, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 3. Good health, Absoprtion intestinale, [SDV] Life Sciences [q-bio], Postprandial, SECRETION, Kexin, Goblet Cells, Proprotein Convertases, Proprotein Convertase 9, Cardiology and Cardiovascular Medicine, EXPRESSION, medicine.medical_specialty, Duodenum, HEART-DISEASE, METABOLISM, LDL RECEPTOR, 03 medical and health sciences, Chylomicron remnant, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Ileum, Internal medicine, medicine, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Animals, Humans, Triglycerides, 030304 developmental biology, Apolipoproteins B, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Proprotein convertase, CHYLOMICRON REMNANTS, NONFASTING TRIGLYCERIDES, Endocrinology, Enterocytes, biology.protein, Caco-2 Cells, Lipoprotein, Chylomicron
Abstract: Objectives— Proprotein convertase subtilisin kexin type 9 (PCSK9) is a natural inhibitor of the low-density lipoprotein receptor, and its deficiency in humans results in low plasma LDL-cholesterol and protection against cardiovascular disease. We explored whether PCSK9 expression impacts postprandial triglyceridemia, another important cardiovascular risk factor. Methods and Results— Real-time PCR and confocal microscopy were used to show that PCSK9 is expressed throughout the entire small intestine and in human enterocytes. On olive oil gavage, PCSK9-deficient mice showed a dramatically decreased postprandial triglyceridemia compared with their wild-type littermates. Lymph analysis revealed that intestinal TG output is not quantitatively modified by PCSK9 deletion. However, PCSK9 −/− mice present with a significant reduction of lymphatic apoB secretion compared to PCSK9 +/+ mice. Modulating PCSK9 expression in polarized CaCo-2 cells confirmed the relationship between PCSK9 and apoB secretion; PCSK9 −/− mice consistently secrete larger TG-rich lipoprotein than wild-type littermates. Finally, kinetic studies showed that PCSK9-deficient mice have an increased ability to clear chylomicrons compared to wild-type littermates. Conclusion— These findings indicate that in addition to its effect on LDL-cholesterol, PCSK9 deficiency might protect against cardiovascular disease by reducing postprandial triglyceridemia.
Published: 2009
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47. Dual Mechanisms for the Fibrate-mediated Repression of Proprotein Convertase Subtilisin/Kexin Type 9

Author: Cédric Langhi, Sanae Kourimate, Michel Krempf, Khadija Ouguerram, Anne Laure Jarnoux, Philippe Costet, Cédric Le May, Yassine Zair, Bertrand Cariou, Patrick Nguyen, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Hydrocarbons, Fluorinated, Receptors, Cytoplasmic and Nuclear, Fibrate, 030204 cardiovascular system & hematology, Biochemistry, Clofibric Acid, 0302 clinical medicine, Fenofibrate, Promoter Regions, Genetic, Furin, ComputingMilieux_MISCELLANEOUS, Liver X Receptors, Pravastatin, 0303 health sciences, Sulfonamides, biology, Chemistry, Anticholesteremic Agents, Serine Endopeptidases, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Orphan Nuclear Receptors, Up-Regulation, DNA-Binding Proteins, Proprotein Convertase 5, Kexin, lipids (amino acids, peptides, and proteins), Proprotein Convertases, Proprotein Convertase 9, medicine.medical_specialty, animal structures, medicine.drug_class, Gene Expression Regulation, Enzymologic, Hyperlipoproteinemia Type II, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, Cell Line, Tumor, medicine, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Humans, PPAR alpha, Proprotein, Molecular Biology, 030304 developmental biology, PCSK9, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Cell Biology, Proprotein convertase, Lipid Metabolism, Endocrinology, Receptors, LDL, LDL receptor, biology.protein, Hepatocytes
Abstract: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is associated with familial autosomal dominant hypercholesterolemia and is a natural inhibitor of the LDL receptor (LDLr). PCSK9 is degraded by other proprotein convertases: PC5/6A and furin. Both PCSK9 and the LDLr are up-regulated by the hypocholesterolemic statins. Thus, inhibitors or repressors of PCSK9 should amplify their beneficial effects. In the present study, we showed that PPARalpha activation counteracts PCSK9 induction by statins by repressing PCSK9 promoter activity and by increasing PC5/6A and furin expression. Quantification of mRNA and protein levels showed that various fibrates decreased PCSK9 and increased PC5/6A and furin expression. Fenofibric acid (FA) reduced PCSK9 protein content in immortalized human hepatocytes (IHH) as well as its cellular secretion. FA suppressed PCSK9 induction by statins or by the liver X receptor agonist TO901317. PCSK9 repression is occurring at the promoter level. We showed that PC5/6A and furin fibrate-mediated up-regulation is PPARalpha-dependent. As a functional test, we observed that FA increased by 30% the effect of pravastatin on the LDLr activity in vitro. In conclusion, fibrates simultaneously decreased PCSK9 expression while increasing PC5/6A and furin expression, indicating a broad action of PPARalpha activation in proprotein convertase-mediated lipid homeostasis. Moreover, this study validates the functional relevance of a combined therapy associating PCSK9 repressors and statins.
Published: 2008
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48. Metabolic fate of starch ingested in a complex meal

Author: Michel Krempf, Y. Zaïr, N. Noah, P. Maugère, Martine Champ, and Revues Inra, Import
Subjects: Meal, Starch, 0402 animal and dairy science, [SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology, 04 agricultural and veterinary sciences, Biology, 040201 dairy & animal science, chemistry.chemical_compound, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, chemistry, Biochemistry, [SDV.BDD] Life Sciences [q-bio]/Development Biology, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, [SDV.BDD]Life Sciences [q-bio]/Development Biology, ComputingMilieux_MISCELLANEOUS, [SDV.BDLR] Life Sciences [q-bio]/Reproductive Biology
Abstract: International audience
Published: 1998

49. Whole-body, peripheral and intestinal endogenous acetate turnover in dogs using stable isotopes

Author: Patrick Nguyen, Henri Dumon, Etienne Pouteau, Dominique Darmaun, Martine Champ, Michel Krempf, Laboratoire de technologie appliquée à la nutrition, Institut National de la Recherche Agronomique (INRA), and ProdInra, Migration
Subjects: Male, medicine.medical_specialty, 030309 nutrition & dietetics, Medicine (miscellaneous), Endogeny, Acetates, Veins, 03 medical and health sciences, Dogs, Internal medicine, Forelimb, medicine, Carnivora, Animals, Intestinal Mucosa, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Distribution Volume, 0303 health sciences, Carbon Isotopes, Nutrition and Dietetics, biology, Chemistry, Portal Vein, Fissipedia, Venous Plasma, Metabolism, biology.organism_classification, RENOUVELLEMENT, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, Endocrinology, Carotid Arteries, Breath Tests, Arterial blood, Female, Energy source, Food Deprivation, Methane, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, Hydrogen
Abstract: Acetate metabolism supplies about 10% of energy requirements in food-deprived nonruminant animals. This study used a stable isotope dilution method to investigate the fate of acetate in 24-h food-deprived dogs free of colonic fermentation. Three dogs received intravenous bolus injections of 40 or 70 micromol/kg of [1-13C] acetate, and carotid blood was then sampled during a 15-min period to estimate the acetate distribution volume. Ten dogs received intravenous [1-13C] acetate infusions of 1.05 +/- 0.02 or 2.10 +/- 0. 10 micromol/(kg.min) for 120 or 200 min after a prime of 200 or 70 micromol/kg, respectively. Cephalic venous and carotid arterial blood were sampled for all dogs, and portal blood for five. Acetate distribution volume was 0.27 +/- 0.16 L/kg (mean +/- SEM). The concentrations of acetate in arterial (144 +/- 17 micromol/L), venous (155 +/- 20 micromol/L) and portal plasma (131 +/- 16 micromol/L) were not significantly different during infusion, whereas isotopic enrichments [mole percent excess (MPE): labeled acetate/all acetate molecules] in portal (1.2 +/- 0.2 MPE) and venous plasma (1.7 +/- 0.3 and 2.6 +/- 0.7 MPE) were lower than in arterial plasma for both infusion rates (4.9 +/- 0.6 and 7.6 +/- 0.8 MPE, respectively, P0.005). Whole-body acetate turnover was 24.4 +/- 2.4 micromol/(kg.min). Fractional acetate extractions for forelimb and intestine were 62 +/- 7 and 72 +/- 6%, respectively, and the production for each organ was 0.3 and 1.1 micromol/(kg.min) respectively, similar to that of utilization (P0.05). It is concluded that the forelimb and intestine produce and utilize acetate as an energy source in 24-h food-deprived dogs free of colonic fermentation.
Published: 1998

50. Altered apolipoprotein AI metabolism in subjects with type IIA heterozygous familial hypercholesterolemia: a kinetic study

Author: R. Frénais, V. De Mallmann, Jean-Marie Bard, Michel Krempf, Khadija Ouguerram, Cyrille Maugeais, Thierry Magot, and Revues Inra, Import
Subjects: Genetics, medicine.medical_specialty, Apolipoprotein AI, 0402 animal and dairy science, [SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology, 04 agricultural and veterinary sciences, Metabolism, Familial hypercholesterolemia, Biology, medicine.disease, 040201 dairy & animal science, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, Endocrinology, Internal medicine, [SDV.BDD] Life Sciences [q-bio]/Development Biology, medicine, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, [SDV.BDD]Life Sciences [q-bio]/Development Biology, ComputingMilieux_MISCELLANEOUS, [SDV.BDLR] Life Sciences [q-bio]/Reproductive Biology
Abstract: International audience
Published: 1998

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