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1. Hepatic deletion of serine palmitoyl transferase 2 impairs ceramide/sphingomyelin balance, bile acids homeostasis and leads to liver damage in mice

Author

Lallement, Justine, Raho, Ilyès, Merlen, Grégory, Rainteau, Dominique, Croyal, Mikael, Schiffano, Melody, Kassis, Nadim, Doignon, Isabelle, Soty, Maud, Lachkar, Floriane, Krempf, Michel, Van Hul, Matthias, Cani, Patrice D., Foufelle, Fabienne, Amouyal, Chloé, Le Stunff, Hervé, Magnan, Christophe, Tordjmann, Thierry, Cruciani-Guglielmacci, Céline, and UCL - SSS/LDRI - Louvain Drug Research Institute

Subjects
Liver, Gluconeogenesis, Sphingomyelinase, Cell Biology, Ceramides, Fibrosis, Molecular Biology, Bile acids
Abstract

Ceramides (Cer) have been shown as lipotoxic inducers, which disturb numerous cell-signaling pathways, leading to metabolic disorders such as type 2 diabetes. In this study, we aimed to determine the role of de novo hepatic ceramide synthesis in energy and liver homeostasis in mice. We generated mice lacking serine palmitoyltransferase 2 (Sptlc2), the rate limiting enzyme of ceramide de novo synthesis, in liver under albumin promoter. Liver function, glucose homeostasis, bile acid (BA) metabolism and hepatic sphingolipids content were assessed using metabolic tests and LC-MS. Despite lower expression of hepatic Sptlc2, we observed an increased concentration of hepatic Cer, associated with a 10-fold increase in neutral sphingomyelinase 2 (nSMase2) expression, and a decreased sphingomyelin content in the liver. Sptlc2 mice were protected against obesity induced by high fat diet and displayed a defect in lipid absorption. In addition, an important increase in tauro-muricholic acid was associated with a downregulation of the nuclear BA receptor FXR target genes. Sptlc2 deficiency also enhanced glucose tolerance and attenuated hepatic glucose production, while the latter effect was dampened in presence of nSMase2 inhibitor. Finally, Sptlc2 disruption promoted apoptosis, inflammation and progressive development of hepatic fibrosis, worsening with age. Our data suggest a compensatory mechanism to regulate hepatic ceramides content from sphingomyelin hydrolysis, with deleterious impact on liver homeostasis. In addition, our results show the involvement of hepatic sphingolipid modulation in BA metabolism and hepatic glucose production in an insulin-independent manner, which highlight the still under-researched role of ceramides in many metabolic functions.

Published
2023

2. New rare genetic variants of LMF1 gene identified in severe hypertriglyceridemia

Author

VALERO, RENE, Vergès, Bruno, DANCER, Marine, Di Filippo, Mathilde, Marmontel, Oriane, Piombo Rivarola, Maria Del Carmen, Peretti, Noël, CAUSSY, Cyrielle, Krempf, Michel, Verges, Bruno, Mahl, Murielle, Marcais, Christophe, Moulin, Philippe, CHARRIERE, Sybil, Service d'endocrinologie, diabète, maladies métaboliques [Hôpital de la Conception - APHM], Aix Marseille Université (AMU), Lipides - Nutrition - Cancer (U866) (LNC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, 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), Groupement hospitalier lyon Est (Hospices Civils de Lyon), Hospices Civils de Lyon (HCL), Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), PRES Université Nantes Angers Le Mans (UNAM), Service d'Endocrinologie, Diabétologie et Maladies Métaboliques (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), 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-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), 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), Hôpital de la Conception [CHU - APHM] (LA CONCEPTION ), Centre de Recherche en Nutrition Humaine Rhône-Alpes (CRNH-RH), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Jean Monnet [Saint-Étienne] (UJM)-CHU Saint-Etienne-Hospices Civils de Lyon (HCL)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), Centre de Biologie pour la Gestion des Populations (UMR CBGP), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut National de la Recherche Agronomique (INRA)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Université de Montpellier (UM)-Institut de Recherche pour le Développement (IRD [France-Sud])-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Nutriments Lipidiques et Prévention des Maladies Métaboliques, Université de la Méditerranée - Aix-Marseille 2-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'endocrinologie, nutrition et maladies métaboliques [Hôpital Nord - APHM], Hôpital Nord [CHU - APHM]-Assistance Publique - Hôpitaux de Marseille (APHM), Service de pédiatrie et néonatalogie (CH Roanne), Centre Hospitalier de Roanne, Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Service d'Endocrinologie [Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Institut du thorax, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiologie des Adaptations Nutritionnelles, Institut National de la Recherche Agronomique (INRA), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), 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), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), 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), Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital Nord [CHU - APHM], Physiopathologie des Adaptations Nutritionnelles (PhAN), Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN), 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, 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), and Groupement Hospitalier Lyon-Est (GHE)

Subjects
Adult, Male, 0301 basic medicine, Heterozygote, Lipolysis, Endocrinology, Diabetes and Metabolism, 030204 cardiovascular system & hematology, Compound heterozygosity, Polymorphism, Single Nucleotide, Triglyceride, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Genetic, Internal Medicine, Humans, Medicine, Gene, Hypertriglyceridemia, [SDV.GEN]Life Sciences [q-bio]/Genetics, Lipoprotein lipase, Chylomicronemia syndrome, Nutrition and Dietetics, business.industry, Homozygote, GPIHBP1, Membrane Proteins, Heterozygote advantage, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Phenotype, Molecular biology, 3. Good health, HEK293 Cells, 030104 developmental biology, Dyslipidemia, Female, lipids (amino acids, peptides, and proteins), Hepatic lipase, Apolipoprotein C2, Cardiology and Cardiovascular Medicine, business
Abstract

IF 3.58 (2017); International audience; BACKGROUND:The LMF1 (lipase maturation factor 1) gene encodes a protein involved in lipoprotein lipase and hepatic lipase maturation. Homozygous mutations in LMF1 leading to severe hypertriglyceridemia (SHTG) are rare in the literature. A few additional rare LMF1 variants have been described with poor functional studies.OBJECTIVE:The aim of this study was to assess the frequency of LMF1 variants in a cohort of 385 patients with SHTG, without homozygous or compound heterozygous deleterious mutations identified in lipoprotein lipase (LPL), apolipoprotein A5 (APOA5), apolipoprotein C2 (APOC2), glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 (GPIHBP1) genes, and to determine their functionality.METHODS:LMF1 coding variants were screened using denaturing high-performance liquid chromatography followed by direct sequencing. In silico studies of LMF1 variants were performed, followed by in vitro functional studies using human embryonic kidney 293T (HEK-293T) cells cotransfected with vectors encoding human LPL and LMF1 cDNA. LPL activity was measured in cell culture medium after heparin addition using human VLDL-TG as substrate.RESULTS:Nineteen nonsynonymous coding LMF1 variants were identified in 65 patients; 10 variants were newly described in SHTG. In vitro, p.Gly172Arg, p.Arg354Trp, p.Arg364Gln, and p.Arg537Trp LMF1 variants decreased LPL activity, and the p.Trp464Ter variant completely abolished LPL activity. We identified a young girl heterozygote for the p.Trp464Ter variant and a homozygote carrier of the p.Gly172Arg variant with a near 50% decreased LPL activity in vitro and in vivo.CONCLUSION:The study confirms the rarity of LMF1 variants in a large cohort of patients with SHTG. LMF1 variants are likely to be involved in multifactorial hyperchylomicronemia. Partial LMF1 defects could be associated with intermittent phenotype as described for p.Gly172Arg homozygous and p.Trp464Ter heterozygous carriers.

Published
2018

3. The selective peroxisome proliferator-activated receptor alpha modulator (SPPARMα) paradigm: conceptual framework and therapeutic potential : A consensus statement from the International Atherosclerosis Society (IAS) and the Residual Risk Reduction Initiative (R3i) Foundation

Author

Fruchart, Jean-Charles, Santos, Raul D, Aguilar-Salinas, Carlos, Aikawa, Masanori, Al Rasadi, Khalid, Amarenco, Pierre, Barter, Philip J, Ceska, Richard, Corsini, Alberto, Després, Jean-Pierre, Duriez, Patrick, Eckel, Robert H, Ezhov, Marat V, Farnier, Michel, Ginsberg, Henry N, Hermans, Michel, Ishibashi, Shun, Karpe, Fredrik, Kodama, Tatsuhiko, Koenig, Wolfgang, Krempf, Michel, Lim, Soo, Lorenzatti, Alberto J, McPherson, Ruth, Nuñez-Cortes, Jesus Millan, Nordestgaard, Børge G, Ogawa, Hisao, Packard, Chris J, Plutzky, Jorge, Ponte-Negretti, Carlos I, Pradhan, Aruna, Ray, Kausik K, Reiner, Željko, Ridker, Paul M, Ruscica, Massimiliano, Sadikot, Shaukat, Shimano, Hitoshi, Sritara, Piyamitr, Stock, Jane K, Su, Ta-Chen, Susekov, Andrey V, Tartar, André, Taskinen, Marja-Riitta, Tenenbaum, Alexander, Tokgözoğlu, Lale S, Tomlinson, Brian, Tybjærg-Hansen, Anne, Valensi, Paul, Vrablík, Michal, Wahli, Walter, Watts, Gerald F, Yamashita, Shizuya, Yokote, Koutaro, Zambon, Alberto, Libby, Peter, UCL - SSS/IREC/EDIN - Pôle d'endocrinologie, diabète et nutrition, and UCL - (SLuc) Service d'endocrinologie et de nutrition

Subjects
SPPARMalpha, Consensus, Pemafibrate (K-877), Review, Risk Assessment, Visceral obesity, Selective peroxisome proliferator-activated receptor alpha modulator, Risk Factors, Animals, Humans, PPAR alpha, Molecular Targeted Therapy, Triglycerides, Dyslipidemias, Hypolipidemic Agents, Inflammation, Benzoxazoles, Remnant cholesterol, Diabetes, Atherogenic dyslipidemia, PROMINENT, Lipids, Butyrates, Treatment Outcome, Cardiovascular Diseases, Residual cardiovascular risk, Patient Safety, Biomarkers, Signal Transduction
Abstract

In the era of precision medicine, treatments that target specific modifiable characteristics of high-risk patients have the potential to lower further the residual risk of atherosclerotic cardiovascular events. Correction of atherogenic dyslipidemia, however, remains a major unmet clinical need. Elevated plasma triglycerides, with or without low levels of high-density lipoprotein cholesterol (HDL-C), offer a key modifiable component of this common dyslipidemia, especially in insulin resistant conditions such as type 2 diabetes mellitus. The development of selective peroxisome proliferator-activated receptor alpha modulators (SPPARMα) offers an approach to address this treatment gap. This Joint Consensus Panel appraised evidence for the first SPPARMα agonist and concluded that this agent represents a novel therapeutic class, distinct from fibrates, based on pharmacological activity, and, importantly, a safe hepatic and renal profile. The ongoing PROMINENT cardiovascular outcomes trial is testing in 10,000 patients with type 2 diabetes mellitus, elevated triglycerides, and low levels of HDL-C whether treatment with this SPPARMα agonist safely reduces residual cardiovascular risk. Electronic supplementary material The online version of this article (10.1186/s12933-019-0864-7) contains supplementary material, which is available to authorized users.

Published
2019

4. The selective peroxisome proliferator-activated receptor alpha modulator (SPPARMα) paradigm: conceptual framework and therapeutic potential

Author

Fruchart, Jean-Charles, Santos, Raul D., Aguilar-Salinas, Carlos, Aikawa, Masanori, Al Rasadi, Khalid, Amarenco, Pierre, Barter, Philip J., Ceska, Richard, Corsini, Alberto, Després, Jean-Pierre, Duriez, Patrick, Eckel, Robert H., Ezhov, Marat V., Farnier, Michel, Ginsberg, Henry N., Hermans, Michel P., Ishibashi, Shun, Karpe, Fredrik, Kodama, Tatsuhiko, Koenig, Wolfgang, Krempf, Michel, Lim, Soo, Lorenzatti, Alberto J., McPherson, Ruth, Nuñez-Cortes, Jesus Millan, Nordestgaard, Børge G., Ogawa, Hisao, Packard, Chris J., Plutzky, Jorge, Ponte-Negretti, Carlos I., Pradhan, Aruna, Ray, Kausik K., Reiner, Željko, Ridker, Paul M., Ruscica, Massimiliano, Sadikot, Shaukat, Shimano, Hitoshi, Sritara, Piyamitr, Stock, Jane K., Su, Ta-Chen, Susekov, Andrey V., Tartar, André, Taskinen, Marja-Riitta, Tenenbaum, Alexander, Tokgözoğlu, Lale S., Tomlinson, Brian, Tybjærg-Hansen, Anne, Valensi, Paul, Vrablík, Michal, Wahli, Walter, Watts, Gerald F., Yamashita, Shizuya, Yokote, Koutaro, Zambon, Alberto, and Libby, Peter

Subjects
ddc
Published
2018

5. Niacin action in the atherogenic mixed dyslipidemia of metabolic syndrome: Insights from metabolic biomarker profiling and network analysis

Author

Adiels, Martin, Chapman, M John, Robillard, Paul, Krempf, Michel, Laville, Martine, Borén, Jan, Niacin Study Group, ., Hôpital Guillaume et René Laennec - Centre Hospitalier Universitaire de Nantes, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), 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), University of Gothenburg (GU), Dyslipidémies, inflammation et athérosclérose dans les maladies métaboliques, Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes (UN)-Institut National de la Recherche Agronomique (INRA), Mécanisme Moléculaire du Diabète (MMD), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), GlaxoSmithKline (Les Ulis, France), Randox Laboratories (Crumlin, N. Ireland), Sahlgrenska University Hospital ALF Research Grants, National Institute for Health and Medical Research, ARLA (Association for Research on Lipoproteins and Atherogenesis), Randox Laboratories, 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 la Recherche Agronomique (INRA)-Université de Nantes (UN), and ProdInra, Migration

Subjects
Male, HDL, [SDV]Life Sciences [q-bio], cardiovascular-disease, adipose-tissue, Triglyceride, Niacin, insulin-resistance, LDL, hepg2 cells, high-risk, Apolipoprotein CIII, Mixed dyslipidemia, Humans, Pharmacology & Pharmacy, ER niacin, Blood Coagulation, nicotinic-acid, Dyslipidemias, Inflammation, Metabolic Syndrome, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, adiponectin, Interleukin-6, Macrophages, extended-release niacin, Middle Aged, Apolipoprotein, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, apolipoprotein-a-i, Phenotype, Liver, lipids (amino acids, peptides, and proteins), type-2 diabetes-mellitus, Insulin Resistance, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, CIII, Biomarkers
Abstract

International audience; BACKGROUND: Niacin as an adjunct to statin treatment to reduce cardiovascular risk is questioned. OBJECTIVE: To evaluate interrelationships between the effects of niacin on mixed dyslipidemia and a spectrum of metabolic and inflammatory biomarkers. METHODS: Obese, nondiabetic, hypertriglyceridemic males (n = 19) with low high-density lipoprotein cholesterol levels received extended-release nicotinic acid for 8 weeks. Multiple biomarkers were measured using enzyme-linked immunosorbent assay, enzymatic/absorptiometric, or multiplex biochip assays. Treatment effects were determined for each variable and a differential correlation network created on the basis of univariate correlations between baseline and response to niacin treatment for all pairs of variables. RESULTS: Extended-release niacin treatment favoured normalization of plasma lipid and apolipoprotein profile. Plasma markers of inflammation, hepatic function, cellular adhesion and proliferation, and macrophage phenotype were attenuated; however, insulin resistance increased. Differential network analysis revealed that changes in triglycerides and high-density lipoprotein cholesterol were closely linked; equally, niacin mediated reductions in total cholesterol, apolipoprotein B, low-density lipoprotein cholesterol and lipoprotein(a) clustered together, as did homeostatic model assessment of insulin resistance, insulin, and interleukin-6 levels. Two clusters of inflammatory markers were identified, involving (1) intercellular adhesion molecule 1 and high-sensitive C-reactive protein and (2) soluble tumor necrosis factor receptors; and novel clusters involving matrix metallopeptidase 9 and apolipoprotein E, and adiponectin and cystatin C, respectively, were equally revealed. At lower stringency, lipid and insulin resistance clusters were linked; a C-reactive protein-centered cluster linked reduction in apolipoprotein Cu to intercellular adhesion molecule 1, gamma-glutamyltransferase, soluble tumor necrosis factor receptors, and E-selectin. CONCLUSION: A niacin-mediated trend to normalize atherogenic mixed dyslipidemia was intimately linked to attenuation of biomarkers of inflammation, cell adhesion, hepatic dysfunction and cell proliferation, but to enhanced insulin resistance and plasma homocysteine elevation. (C) 2018 National Lipid Association. Published by Elsevier Inc.

Published
2017

6. A Randomized, Controlled Trial of 3.0 mg of Liraglutide in Weight Management

Author

Pi-Sunyer, Xavier, Astrup, Arne, Fujioka, Ken, Greenway, Frank, Halpern, Alfredo, Krempf, Michel, Lau, David C. W., le Roux, Carel W., Ortiz, Violante, Jensen, Christine Bjorn, Wilding, John P. H., Hamann, A, Barakat, A, Blüher, M, Linn, T, DALLE MOLLE, Alberto, Segner, A, Stübler, P, Tosch-Sisting, R, Pacini, F, Santini, F, Marchesini, G, Rotella, Cm, Invitti, C, Vettor, R, Buscemi, S, Raya, Pm, Freijoo, Fc, de Barbará RG, Carraro, R, Bobillo, Er, de la Cuesta, C, Farsang, C, Csaszar, A, Zahorska-Markiewicz, B, Pupek-Musialik, D, Franek, E, Ostrowska, L, Olszanecka-Glinianowicz, M, Lalic, N, Micic, D, Ludvik, B, Paulweber, B, Prager, R, Scheen, A, Van Gaal, L, Astrup, Av, Hermansen, K, Madsbad, S, Rissanen, A, Nieminen, S, Savolainen, M, Krempf, M, Romon, M, Laville, M, Marre, M, Mira, R, Finucane, F, Veenendaal, A, van Berkum, F, Johannsson-Vidarsdóttir, S, Van de Walle, V, Meesters, E, Hjelmesæth, J, Klemsdal, To, Kulseng, B, Bach-Kliegel, B, Laederach, K, Villiger, L, Golay, A, Bilz, S, Sathyapalan, T, Bain, S, Kumar, S, Le Roux CW, Lean, Me, Mcgowan, B, Rehman, T, Wilding, J, Wittert, G, Caterson, I, Proietto, J, Prins, J, Geloneze Neto, B, Gross, Jl, Chacra, Ar, Halpern, A, Suplicy Hde, A, Chow, Fc, Thacker, Hp, Chadha, M, Chandalia, H, Unnikrishnan, A, Kalra, S, Deshpande, N, Shunmugavelu, M, Deshmukh, Vc, Maislos, M, Lieberman, Gs, Shimon, I, Stern, N, Nabriski, D, Karnieli, E, Shehadeh, N, Gonzalez-Galvez, G, Arechavaleta-Granell Mdel, R, Violante Ortiz RM, Franco, Gm, Gurieva, I, Suplotova, La, Troshina, E, Ruyatkina, La, Voychik, Ea, Martsevich, S, Startseva, Ma, Seeber, Me, Badat, A, Ellis, G, Altuntas, Y, Guler, S, Ulgen, E, Delibasi, T, Chetty, T, Hart, R, Janzen, J, Labonte, I, Lau, D, Liutkus, J, O'Keefe, D, Padwal, R, Ransom, Tp, Tytus, R, Weisnagel, Sj, Adler, J, Aqua, K, Aronoff, Sl, Bedel, Gw, Blevins, Tc, Blumenau, J, Brockmyre, Ap, Call, Rs, Canadas, R, Chaykin, Lb, Cohen, K, Conrow, Jk, Davis, Mg, Downey, Hj, Drosman, Sr, Duckor, S, Farmer, H, Farrell, J, Fehnel, S, Finneran, Mp, Forbes, R, Forker, A, Fredrick, M, Fujioka, K, Geller, Sa, Gill, S, Glaser, L, Greco, Sn, Greenway, Fl, Harper, W, Herman, L, Hoekstra, J, Ingebretsen, R, Ison, R, Jain, Rk, Kaplan, R, Kaster, Sr, Haase, Ga, Kerzner, B, Kirstein, Jl, Koltun, W, Krieger, Dr, Lewis, Ce, Madder, R, Marple, Rn, Mcdermott, Ej, Mello, Cj, Miller, Ab, Mullen, J, Nardandrea, J, O'Neil, P, Pi-Sunyer, F, Pucillo, Rm, Rhee, C, Redrick, S, Pardini, A, Rothman, J, Rubino, Dm, Sellers, G, Smith, T, Byars, Wd, Soufer, J, Sussman, Am, Patrick, K, Schramm, El, Van Cleeff, M, Berg, Sr, Wyatt, Hr, Simon, Ja., Columbia University [New York], Obesity Research Center, The University of Tennessee [Knoxville], Department of Nutrition, Exercise and Sports [Copenhagen], Faculty of Science [Copenhagen], University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), Scripps Research Institute, Louisiana State University (LSU), Universidade de São Paulo (USP), Centre hospitalier universitaire de Nantes (CHU Nantes), University of Calgary, University College Dublin (UCD), Instituto Mexicano del Seguro Social [Mexico City, Mexico] (IMSS), Novo Nordisk, Department of Obesity and Endocrinology, University of Liverpool, Pi-Sunyer, Xavier, Astrup, Arne, Fujioka, Ken, Greenway, Frank, Halpern, Alfredo, Krempf, Michel, Lau, David C.W., Le Roux, Carel W., Ortiz, Rafael Violante, Jensen, Christine Bjørn, Wilding, John P.H., the SCALE Obesity and Prediabetes NN8022-1839 Study Group [.., Marchesini, Giulio, ], Pi-Sunyer, X., Astrup, A., Fujioka, K., Greenway, F., Halpern, A., Krempf, M., Lau, D., le Roux, C., Violante Ortiz, R., Jensen, C., Wilding, J. COLLABORATORS: amann A, Barakat A, Blüher M, Linn T, Mölle A, Segner A, Stübler P, Tosch-Sisting R, Pacini F, Santini F, Marchesini G, Rotella CM, Invitti C, Vettor R, Buscemi S, and Raya PM, Freijoo FC, de Barbará RG, Carraro R, Bobillo ER, de la Cuesta C, Farsang C, Csaszar A, Zahorska-Markiewicz B, Pupek-Musialik D, Franek E, Ostrowska L, Olszanecka-Glinianowicz M, Lalic N, Micic D, Ludvik B, Paulweber B, Prager R, Scheen A, Van Gaal L, Astrup AV, Hermansen K, Madsbad S, Rissanen A, Nieminen S, Savolainen M, Krempf M, Romon M, Laville M, Marre M, Mira R, Finucane F, Veenendaal A, van Berkum F, Johannsson-Vidarsdóttir S, Van de Walle V, Meesters E, Hjelmesæth J, Klemsdal TO, Kulseng B, Bach-Kliegel B, Laederach K, Villiger L, Golay A, Bilz S, Sathyapalan T, Bain S, Kumar S, Le Roux CW, Lean ME, McGowan B, Rehman T, Wilding J, Wittert G, Caterson I, Proietto J, Prins J, Geloneze Neto B, Gross JL, Chacra AR, Halpern A, Suplicy Hde A, Chow FC, Thacker HP, Chadha M, Chandalia H, Unnikrishnan A, Kalra S, Deshpande N, Shunmugavelu M, Deshmukh VC, Maislos M, Lieberman GS, Shimon I, Stern N, Nabriski D, Karnieli E, Shehadeh N, Gonzalez-Galvez G, Arechavaleta-Granell Mdel R, Violante Ortiz RM, Franco GM, Gurieva I, Suplotova LA, Troshina E, Ruyatkina LA, Voychik EA, Martsevich S, Startseva MA, Seeber ME, Badat A, Ellis G, Altuntas Y, Guler S, Ulgen E, Delibasi T, Chetty T, Hart R, Janzen J, Labonte I, Lau D, Liutkus J, O'Keefe D, Padwal R, Ransom TP, Tytus R, Weisnagel SJ, Adler J, Aqua K, Aronoff SL, Bedel GW, Blevins TC, Blumenau J, Brockmyre AP, Call RS, Canadas R, Chaykin LB, Cohen K, Conrow JK, Davis MG, Downey HJ, Drosman SR, Duckor S, Farmer H, Farrell J, Fehnel S, Finneran MP, Forbes R, Forker A, Fredrick M, Fujioka K, Geller SA, Gill S, Glaser L, Greco SN, Greenway FL, Harper W, Herman L, Hoekstra J, Ingebretsen R, Ison R, Jain RK, Kaplan R, Kaster SR, Haase GA, Kerzner B, Kirstein JL, Koltun W, Krieger DR, Lewis CE, Madder R, Marple RN, McDermott EJ, Mello CJ, Miller AB, Mullen J, Nardandrea J, O'Neil P, Pi-Sunyer F, Pucillo RM, Rhee C, Redrick S, Pardini A, Rothman J, Rubino DM, Sellers G, Smith T, Byars WD, Soufer J, Sussman AM, Patrick K, Schramm EL, Van Cleeff M, Berg SR, Wyatt HR, Simon JA.

Subjects
Blood Glucose, Counseling, Male, Type 2 diabetes, law.invention, Body Mass Index, Randomized controlled trial, Weight loss, law, Glucagon-Like Peptide 1, Weight management, Subcutaneous, Medicine (all), Reducing, Nausea, General Medicine, Middle Aged, Combined Modality Therapy, 3. Good health, Female, type 2 diabetes, medicine.symptom, Human, medicine.drug, Adult, Diarrhea, medicine.medical_specialty, Diet, Reducing, Injections, Subcutaneous, Injections, Subcutaneou, Placebo, Injections, Double-Blind Method, Internal medicine, Weight Loss, medicine, Humans, Hypoglycemic Agents, Obesity, Exercise, Hypoglycemic Agent, Liraglutide, business.industry, medicine.disease, Weight Lo, Diet, Endocrinology, business, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, Body mass index, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Dyslipidemia
Abstract

BACKGROUND: Obesity is a chronic disease with serious health consequences, but weight loss is difficult to maintain through lifestyle intervention alone. Liraglutide, a glucagon-like peptide-1 analogue, has been shown to have potential benefit for weight management at a once-daily dose of 3.0 mg, injected subcutaneously. METHODS: We conducted a 56-week, double-blind trial involving 3731 patients who did not have type 2 diabetes and who had a body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) of at least 30 or a BMI of at least 27 if they had treated or untreated dyslipidemia or hypertension. We randomly assigned patients in a 2:1 ratio to receive once-daily subcutaneous injections of liraglutide at a dose of 3.0 mg (2487 patients) or placebo (1244 patients); both groups received counseling on lifestyle modification. The coprimary end points were the change in body weight and the proportions of patients losing at least 5% and more than 10% of their initial body weight. RESULTS: At baseline, the mean (±SD) age of the patients was 45.1±12.0 years, the mean weight was 106.2±21.4 kg, and the mean BMI was 38.3±6.4; a total of 78.5% of the patients were women and 61.2% had prediabetes. At week 56, patients in the liraglutide group had lost a mean of 8.4±7.3 kg of body weight, and those in the placebo group had lost a mean of 2.8±6.5 kg (a difference of -5.6 kg; 95% confidence interval, -6.0 to -5.1; P

Published
2015

7. High protein intake reduces intrahepatocellular lipid deposition in humans

Author

Bortolotti, Murielle, Kreis, Roland, Debard, Cyrille, Cariou, Bertrand, Faeh, David, Chetiveaux, Maud, Ith, Michael, Vermathen, Peter, Stefanoni, Nathalie, Lê, Kim-Anne, Schneiter, Philippe, Krempf, Michel, Vidal, Hubert, Boesch, Chris, Tappy, Luc, University of Zurich, and Tappy, L

Subjects
2916 Nutrition and Dietetics, 610 Medicine & health, 2701 Medicine (miscellaneous), 10060 Epidemiology, Biostatistics and Prevention Institute (EBPI)
Abstract

BACKGROUND: High sugar and fat intakes are known to increase intrahepatocellular lipids (IHCLs) and to cause insulin resistance. High protein intake may facilitate weight loss and improve glucose homeostasis in insulin-resistant patients, but its effects on IHCLs remain unknown. OBJECTIVE: The aim was to assess the effect of high protein intake on high-fat diet-induced IHCL accumulation and insulin sensitivity in healthy young men. DESIGN: Ten volunteers were studied in a crossover design after 4 d of either a hypercaloric high-fat (HF) diet; a hypercaloric high-fat, high-protein (HFHP) diet; or a control, isocaloric (control) diet. IHCLs were measured by (1)H-magnetic resonance spectroscopy, fasting metabolism was measured by indirect calorimetry, insulin sensitivity was measured by hyperinsulinemic-euglycemic clamp, and plasma concentrations were measured by enzyme-linked immunosorbent assay and gas chromatography-mass spectrometry; expression of key lipogenic genes was assessed in subcutaneous adipose tissue biopsy specimens. RESULTS: The HF diet increased IHCLs by 90 +/- 26% and plasma tissue-type plasminogen activator inhibitor-1 (tPAI-1) by 54 +/- 11% (P < 0.02 for both) and inhibited plasma free fatty acids by 26 +/- 11% and beta-hydroxybutyrate by 61 +/- 27% (P < 0.05 for both). The HFHP diet blunted the increase in IHCLs and normalized plasma beta-hydroxybutyrate and tPAI-1 concentrations. Insulin sensitivity was not altered, whereas the expression of sterol regulatory element-binding protein-1c and key lipogenic genes increased with the HF and HFHP diets (P < 0.02). Bile acid concentrations remained unchanged after the HF diet but increased by 50 +/- 24% after the HFHP diet (P = 0.14). CONCLUSIONS: Protein intake significantly blunts the effects of an HF diet on IHCLs and tPAI-1 through effects presumably exerted at the level of the liver. Protein-induced increases in bile acid concentrations may be involved. This trial was registered at www.clinicaltrials.gov as NCT00523562.

Published
2009
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