212 results on '"European Genomic Institute for Diabetes (EGID)"'
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2. Posttranscriptional Regulation of the Human LDL Receptor by the U2-Spliceosome
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Joel T. Haas, Jan Albert Kuivenhoven, Justina C. Wolters, Andrzej J. Rzepiela, Mathilde Varret, Ann Verhaegen, Valérie Carreau, Szymon Stoma, Anne Philippi, Alaa Othman, Jerome Robert, N. Dalila, Belle V. van Rosmalen, An Verrijken, Arnold von Eckardstein, Bart van de Sluis, Silvija Radosavljevic, Paolo Zanoni, Simon F. Norrelykke, Roger Meier, M. Yalcinkaya, Bart Staels, Andreas Geier, Lucia Rohrer, Michael Stebler, Michele Visentin, Antoine Rimbert, Catherine Boileau, Antonio Gallo, Melinde Wijers, Nicolette C. A. Huijkman, Steve E. Humphries, Jonas Weyler, Freerk van Dijk, Michaela Keel, Srividya Velagapudi, Jean-Pierre Rabès, Marieke Smit, Anne Tybjærg-Hansen, Adriaan van der Graaf, Luisa Vonghia, Yara Abou-Khalil, Sven Francque, Grigorios Panteloglou, Marta Futema, Luc Van Gaal, University hospital of Zurich [Zurich], Universität Zürich [Zürich] = University of Zurich (UZH), Institute for Molecular Systems Biology [ETH Zurich] (IMSB), Department of Biology [ETH Zürich] (D-BIOL), Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich)- Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires - U1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Lille, Scientific Center for Optical and Electron Microscopy (ScopeM), Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), University of Groningen [Groningen], 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), St George's, University of London, Laboratoire de Recherche Vasculaire Translationnelle (LVTS (UMR_S_1148 / U1148)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Saint-Joseph de Beyrouth (USJ), University of Copenhagen = Københavns Universitet (UCPH), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), AP-HP. Université Paris Saclay, Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Antwerp University Hospital [Edegem] (UZA), University of Antwerp (UA), University of Amsterdam [Amsterdam] (UvA), Columbia University [New York], University Hospital of Würzburg, University College of London [London] (UCL), 603091, ANR-10-LABX-46, 2015T068, CVON2017-2020, AOM06024, 2014/267, Pfizer: 24052829, European Molecular Biology Organization, EMBO: ALTF277-2014, Seventh Framework Programme, FP7, Sixth Framework Programme, FP6: LSHM-CT-2005-018734, Fondation Maladies Rares, FMR, International Atherosclerosis Society, IAS, British Heart Foundation, BHF, European Commission, EC, European Research Council, ERC: 694717, ANR 16-RHUS-0006, Agence Nationale de la Recherche, ANR: ANR-16-RHUS-0007, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, SNF: 310030-185109, 31003A-160126, Fonds De La Recherche Scientifique - FNRS, FNRS, Fonds Wetenschappelijk Onderzoek, FWO: 1802154 N, PG008/08, RG3008, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, NWO: 184.021.007, Universität Zürich, UZH: FK-20-037, We acknowledge the use of data from BIOS-consortium ( http://wiki.bbmri.nl/wiki/BIOS_bios ) which is funded by BBMRI-NL (NWO project 184.021.007). Flow cytometry was performed with equipment of the flow cytometry facility, University of Zurich., This work was conducted as part of the TransCard project of the seventh Framework Program (FP7) granted by the European Commission, to J. Albert Kuivenhoven, A. Tybjaerg-Hansen, and A. von Eckardstein (number 603091) as well as partially the FP7 RESOLVE project (to J.T. Haas, B. Staels, A. Verhaegen, S. Francque, L. Van Gaal, and A. von Eckardstein) and the European Genomic Institute for Diabetes (EGID, ANR-10-LABX-46 to B. Staels). Additional work by A. von Eckardstein’s team was funded by the Swiss National Science Foundation (31003A-160126, 310030-185109) and the Swiss Systems X program (2014/267 [Medical Research and Development (MRD)] HDL-X). P. Zanoni received funding awards from the Swiss Atherosclerosis Society (Arbeitsgruppe Lipide und Atherosklerose [AGLA] and the DACH Society for Prevention of Cardiovascular Diseases). G. Panteloglou received funding from the University of Zurich (Forschungskredit, grant no. FK-20-037). J. Albert Kuivenhoven is an Established Investigator from the Dutch Heart Foundation (2015T068). J. Albert Kuivenhoven was also supported by GeniusII (CVON2017-2020). The Laboratory for Vascular Translational Science (L.V.T.S.) team is supported by Fondation Maladies Rares, Programme Hospitalier de Recherche Clinique (PHRC) (AOM06024), and the national project CHOPIN (CHolesterol Personalized Innovation), granted by the Agence Nationale de la Recherche (ANR-16-RHUS-0007). Y. Abou Khalil is supported by a grant from Ministère de l’Education Nationale et de la Technologie (France). J.T. Haas was supported by an EMBO Long Term Fellowship (ALTF277-2014). B. Staels is a recipient of an ERC Advanced Grant (no. 694717). Both are also supported by PreciNASH (ANR 16-RHUS-0006). Research at the Antwerp University Hospital was supported by the European Union: FP6 (HEPADIP Contract LSHM-CT-2005-018734). S. Francque has a senior clinical research fellowship from the Fund for Scientific Research (FWO) Flanders (1802154 N). S.E. Humphries received grants RG3008 and PG008/08 from the British Heart Foundation, and the support of the UCLH NIHR BRC. S.E. Humphries directs the UK Children’s FH Register which has been supported by a grant from Pfizer (24052829) given by the International Atherosclerosis Society., This work was conducted as part of the TransCard project of the seventh Framework Program (FP7) granted by the European Commission, to J. Albert Kuivenhoven, A. Tybjaerg-Hansen, and A. von Eckardstein (number 603091) as well as partially the FP7 RESOLVE project (to J.T. Haas, B. Staels, A. Verhaegen, S. Francque, L. Van Gaal, and A. von Eckardstein) and the European Genomic Institute for Diabetes (EGID, ANR-10-LABX-46 to B. Staels). Additional work by A. von Eckardstein's team was funded by the Swiss National Science Foundation (31003A-160126, 310030-185109) and the Swiss Systems X program (2014/267 [Medical Research and Development (MRD)] HDL-X). P. Zanoni received funding awards from the Swiss Atherosclerosis Society (Arbeitsgruppe Lipide und Atherosklerose [AGLA] and the DACH Society for Prevention of Cardiovascular Diseases). G. Panteloglou received funding from the University of Zurich (Forschungskredit, grant no. FK-20-037). J. Albert Kuivenhoven is an Established Investigator from the Dutch Heart Foundation (2015T068). J. Albert Kuivenhoven was also supported by GeniusII (CVON2017-2020). The Laboratory for Vascular Translational Science (L.V.T.S.) team is supported by Fondation Maladies Rares, Programme Hospitalier de Recherche Clinique (PHRC) (AOM06024), and the national project CHOPIN (CHolesterol Personalized Innovation), granted by the Agence Nationale de la Recherche (ANR-16-RHUS-0007). Y. Abou Khalil is supported by a grant from Minist?re de l'Education Nationale et de la Technologie (France). J.T. Haas was supported by an EMBO Long Term Fellowship (ALTF277-2014). B. Staels is a recipient of an ERC Advanced Grant (no. 694717). Both are also supported by PreciNASH (ANR 16-RHUS-0006). Research at the Antwerp University Hospital was supported by the European Union: FP6 (HEPADIP Contract LSHMCT- 2005-018734). S. Francque has a senior clinical research fellowship from the Fund for Scientific Research (FWO) Flanders (1802154 N). S.E. Humphries received grants RG3008 and PG008/08 from the British Heart Foundation, and the support of the UCLH NIHR BRC. S.E. Humphries directs the UK Children's FH Register which has been supported by a grant from Pfizer (24052829) given by the International Atherosclerosis Society., ANR-16-RHUS-0006,PreciNASH,PreciNASH(2016), ANR-16-RHUS-0007,CHOPIN,CHOPIN(2016), Center for Liver, Digestive and Metabolic Diseases (CLDM), Restoring Organ Function by Means of Regenerative Medicine (REGENERATE), HAL UVSQ, Équipe, Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires (RNMCD - U1011), Service d'Endocrinologie, Métabolisme et Prévention des Maladies Cardio-vasculaires [CHU Pitié-Salpêtrière], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
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Spliceosome ,Physiology ,RNA Splicing ,Population ,Hypercholesterolemia ,Familial hypercholesterolemia ,030204 cardiovascular system & hematology ,Biology ,03 medical and health sciences ,0302 clinical medicine ,[SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system ,Gene expression ,medicine ,Humans ,education ,Gene ,030304 developmental biology ,0303 health sciences ,Gene knockdown ,education.field_of_study ,Intron ,Nuclear Proteins ,Hep G2 Cells ,medicine.disease ,Molecular biology ,Endocytosis ,[SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system ,Lipoproteins, LDL ,Cholesterol ,HEK293 Cells ,Cardiovascular diseases ,Liver ,Receptors, LDL ,Mutation ,LDL receptor ,Hepatocytes ,Spliceosomes ,lipids (amino acids, peptides, and proteins) ,Human medicine ,Cardiology and Cardiovascular Medicine - Abstract
Background: The LDLR (low-density lipoprotein receptor) in the liver is the major determinant of LDL-cholesterol levels in human plasma. The discovery of genes that regulate the activity of LDLR helps to identify pathomechanisms of hypercholesterolemia and novel therapeutic targets against atherosclerotic cardiovascular disease. Methods: We performed a genome-wide RNA interference screen for genes limiting the uptake of fluorescent LDL into Huh-7 hepatocarcinoma cells. Top hit genes were validated by in vitro experiments as well as analyses of data sets on gene expression and variants in human populations. Results: The knockdown of 54 genes significantly inhibited LDL uptake. Fifteen of them encode for components or interactors of the U2-spliceosome. Knocking down any one of 11 out of 15 genes resulted in the selective retention of intron 3 of LDLR . The translated LDLR fragment lacks 88% of the full length LDLR and is detectable neither in nontransfected cells nor in human plasma. The hepatic expression of the intron 3 retention transcript is increased in nonalcoholic fatty liver disease as well as after bariatric surgery. Its expression in blood cells correlates with LDL-cholesterol and age. Single nucleotide polymorphisms and 3 rare variants of one spliceosome gene, RBM25 , are associated with LDL-cholesterol in the population and familial hypercholesterolemia, respectively. Compared with overexpression of wild-type RBM25 , overexpression of the 3 rare RBM25 mutants in Huh-7 cells led to lower LDL uptake. Conclusions: We identified a novel mechanism of posttranscriptional regulation of LDLR activity in humans and associations of genetic variants of RBM25 with LDL-cholesterol levels.
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- 2022
3. Beyond the Rule of 5: Impact of PEGylation with Various Polymer Sizes on Pharmacokinetic Properties, Structure–Properties Relationships of mPEGylated Small Agonists of TGR5 Receptor
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Florence Leroux, Maxime Culot, Laura Butruille, Fabien Gosselet, Benoit Deprez, Rajaa Boulahjar, Julie Dumont, Mathieu Maingot, Geoffroy Dequirez, Vanessa Hoguet, Anne Tailleux, Manuel Lasalle, Nathalie Hennuyer, Oscar Chávez-Talavera, Isabelle Duplan, Julie Charton, Emmanuel Sevin, Catherine Piveteau, Bart Staels, Loic Belloy, Sophie Lestavel, Adrien Herledan, Alexandre Biela, Médicaments et molécules pour agir sur les Systèmes Vivants - U 1177 (M2SV), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires - U1011 (RNMCD), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Laboratoire de la Barrière Hémato-Encéphalique (LBHE), Université d'Artois (UA), We are grateful to the institutions that supported our laboratory: INSERM, Université de Lille, Institut Pasteur de Lille. This project was supported by Conseil Régional Nord-Pas de Calais, ERDF (convention no. 11003609), Etat DRRT, European Genomic Institute for Diabetes (EGID, ANR-10-LABX-46), the European Research Council (ERC Grant Immunobile, contract 694717), European Commission, INSERM, Université Lille 2 (Appel à projets 'orientations stratégiques': convention no. A007), and SATT Nord (M0075/SATTNORD), ANR (BABrain, convention n°ANR-17-CE14-0007-03), CPER CTRL17 FEDER TIIMaging. M.L. and V.H. are recipients of a doctoral fellowship of the French Ministère de la Recherche. NMR acquisitions were done at the Laboratoire d’Application de Résonance Magnétique Nucléaire (LARMN), Lille, France. B.S. is honorary member of the Institut Universitaire de France., ANR-10-LABX-0046,EGID,EGID Diabetes Pole(2010), ANR-17-CE14-0007,BABrain,La signalisation des acides biliaires dans le cerveau et son rôle dans le contrôle métabolique(2017), European Project: 694717,H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) ,ImmunoBile(2016), and Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires (RNMCD - U1011)
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Agonist ,Male ,medicine.drug_class ,Antibiotic resistance ,[SDV]Life Sciences [q-bio] ,01 natural sciences ,Permeability ,Polyethylene Glycols ,Receptors, G-Protein-Coupled ,03 medical and health sciences ,Mice ,Structure-Activity Relationship ,In vivo ,Drug Discovery ,PEG ratio ,medicine ,Animals ,Humans ,Hypoglycemic Agents ,030304 developmental biology ,0303 health sciences ,Conjugate acid-base pairs ,Chemistry ,G protein-coupled bile acid receptor ,0104 chemical sciences ,Mice, Inbred C57BL ,010404 medicinal & biomolecular chemistry ,HEK293 Cells ,Blood-Brain Barrier ,Alcohols ,PEGylation ,Biophysics ,Lipinski's rule of five ,Microsomes, Liver ,Molecular Medicine ,Pharmacophore ,Caco-2 Cells ,Conjugate ,Agonists - Abstract
International audience; PEGylation of therapeutic agents is known to improve the pharmacokinetic behavior of macromolecular drugs and nanoparticles. In this work, we performed the conjugation of polyethylene glycols (220-5000 Da) to a series of non-steroidal small agonists of the bile acids receptor TGR5. A suitable anchoring position on the agonist was identified to retain full agonistic potency with the conjugates. We describe herein an extensive structure-properties relationships study allowing us to finely describe the non-linear effects of the PEG length on the physicochemical as well as the in vitro and in vivo pharmacokinetic properties of these compounds. When appending a PEG of suitable length to the TGR5 pharmacophore, we were able to identify either systemic or gut lumen-restricted TGR5 agonists.
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- 2021
4. Hepatic molecular signatures highlight the sexual dimorphism of Non-Alcoholic SteatoHepatitis (NASH)
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Vandel, Jimmy, Dubois-Chevalier, Julie, Gheeraert, Celine, Derudas, Bruno, Raverdy, Violetta, Thuillier, Dorothée, Van Gaal, Luc, Francque, Sven, Pattou, Francois, Staels, Bart, Eeckhoute, Jérôme, Lefebvre, Philippe, Derudas, Marie-Hélène, Bile acid, immune-metabolism, lipid and glucose homeostasis - ImmunoBile - - H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) 2016-09-01 - 2021-08-31 - 694717 - VALID, Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), European Genomic Institute for Diabetes (EGID), Faculté de Médecine-Université de Lille, Droit et Santé, Thérapie cellulaire du diabète, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Department of Endocrinology, Diabetology and Metabolism [Antwerp, Belgium], Antwerp University Hospital [Edegem] (UZA), Department of Gastroenterology and Hepatology [Antwerp, Belgium], European Project: 694717,H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) ,ImmunoBile(2016), Institut Européen de Génomique du Diabète - European Genomic Institute for Diabetes - FR 3508 (EGID), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), and ANR-16-RHUS-0006,PreciNASH,PreciNASH(2016)
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Male ,Transcriptomic signatures ,[SDV]Life Sciences [q-bio] ,Steatohepatitis and Metabolic Liver Disease ,NASH ,nutritional and metabolic diseases ,Random forest Accepted Article ,Original Articles ,Middle Aged ,digestive system ,digestive system diseases ,[SDV] Life Sciences [q-bio] ,Sexual dimorphism ,Sex Factors ,Liver ,Non-alcoholic Fatty Liver Disease ,Risk Factors ,Humans ,Original Article ,Female ,Obesity ,Human medicine ,Transcriptome ,Random forest - Abstract
Background and Aims Nonalcoholic steatohepatitis (NASH) is considered as a pivotal stage in nonalcoholic fatty liver disease (NAFLD) progression, given that it paves the way for severe liver injuries such as fibrosis and cirrhosis. The etiology of human NASH is multifactorial, and identifying reliable molecular players and/or biomarkers has proven difficult. Together with the inappropriate consideration of risk factors revealed by epidemiological studies (altered glucose homeostasis, obesity, ethnicity, sex, etc.), the limited availability of representative NASH cohorts with associated liver biopsies, the gold standard for NASH diagnosis, probably explains the poor overlap between published “omics”‐defined NASH signatures. Approach and Results Here, we have explored transcriptomic profiles of livers starting from a 910‐obese‐patient cohort, which was further stratified based on stringent histological characterization, to define “NoNASH” and “NASH” patients. Sex was identified as the main factor for data heterogeneity in this cohort. Using powerful bootstrapping and random forest (RF) approaches, we identified reliably differentially expressed genes participating in distinct biological processes in NASH as a function of sex. RF‐calculated gene signatures identified NASH patients in independent cohorts with high accuracy. Conclusions This large‐scale analysis of transcriptomic profiles from human livers emphasized the sexually dimorphic nature of NASH and its link with fibrosis, calling for the integration of sex as a major determinant of liver responses to NASH progression and responses to drugs.
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- 2020
5. SMMB: a stochastic Markov blanket framework strategy for epistasis detection in GWAS
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Ghislain Rocheleau, Clément Niel, Christine Sinoquet, Christian Dina, Laboratoire des Sciences du Numérique de Nantes (LS2N), 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 (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT), Data User Knowledge (LS2N - équipe DUKe), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Nantes - UFR des Sciences et des Techniques (UN UFR ST), Unité de recherche de l'institut du thorax (ITX-lab), 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), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Clément Niel is supported by the Regional Bioinformatics Research project GRIOTE granted by the Pays de la Loire region on the one hand, and the European Genomic Institute for Diabetes (EGID) Labex (Lille) on the other hand. Ghislain Rocheleau's work is supported by a Chair in Biostatistics jointly sponsored by the Centre National de la Recherche Scientifique and Lille 2 University., The two co-first authors, CN and CS, would like to thank the anonymous reviewers for their constructive comments, which helped them to substantially improve the manuscript. This study makes use of data generated by the Wellcome Trust Case Control Consortium. A full list of investigators who contributed to the generation of the data is available at https://www.wtccc.org.uk/. Part of the experiments were performed at the CCIPL (Centre de Calcul Intensif des Pays de la Loire). The development of the SMMB software is performed at the CCIPL, 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), Data User Knowledge (DUKe), 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), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur de Lille, and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)
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0106 biological sciences ,0301 basic medicine ,Statistics and Probability ,Computer science ,Bayesian probability ,Epistasis and functional genomics ,Machine learning ,computer.software_genre ,01 natural sciences ,Biochemistry ,Polymorphism, Single Nucleotide ,03 medical and health sciences ,[INFO.INFO-LG]Computer Science [cs]/Machine Learning [cs.LG] ,Humans ,[INFO]Computer Science [cs] ,Molecular Biology ,Statistical hypothesis testing ,Genetic association ,Markov blanket ,business.industry ,Univariate ,Bayes Theorem ,Epistasis, Genetic ,[INFO.INFO-RO]Computer Science [cs]/Operations Research [cs.RO] ,Computer Science Applications ,Random forest ,Minor allele frequency ,Computational Mathematics ,030104 developmental biology ,Computational Theory and Mathematics ,Epistasis ,Artificial intelligence ,[INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM] ,business ,computer ,Algorithms ,010606 plant biology & botany ,Genome-Wide Association Study - Abstract
Motivation Large scale genome-wide association studies (GWAS) are tools of choice for discovering associations between genotypes and phenotypes. To date, many studies rely on univariate statistical tests for association between the phenotype and each assayed single nucleotide polymorphism (SNP). However, interaction between SNPs, namely epistasis, must be considered when tackling the complexity of underlying biological mechanisms. Epistasis analysis at large scale entails a prohibitive computational burden when addressing the detection of more than two interacting SNPs. In this paper, we introduce a stochastic causal graph-based method, SMMB, to analyze epistatic patterns in GWAS data. Results We present Stochastic Multiple Markov Blanket algorithm (SMMB), which combines both ensemble stochastic strategy inspired from random forests and Bayesian Markov blanket-based methods. We compared SMMB with three other recent algorithms using both simulated and real datasets. Our method outperforms the other compared methods for a majority of simulated cases of 2-way and 3-way epistasis patterns (especially in scenarii where minor allele frequencies of causal SNPs are low). Our approach performs similarly as two other compared methods for large real datasets, in terms of power, and runs faster. Availability and implementation Parallel version available on https://ls2n.fr/listelogicielsequipe/DUKe/128/. Supplementary information Supplementary data are available at Bioinformatics online.
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- 2018
6. MuscleJ: a high-content analysis method to study skeletal muscle with a new Fiji tool
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Hélène Duez, Adrien Bouglé, David Briand, Pascal Roux, Bart Staels, Lorna Guéniot, Anne Danckaert, Spencer L. Shorte, Alicia Mayeuf-Louchart, Quentin Thorel, Fabrice Chrétien, David Hardy, Aurélien Mazeraud, Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Neuropathologie expérimentale - Experimental neuropathology, Institut Pasteur [Paris]-Université Paris Descartes - Paris 5 (UPD5), Institut Pasteur [Paris], BioImagerie Photonique – Photonic BioImaging (UTechS PBI), This work was supported by research grants from the Association Française contre les Myopathies AFM (to AML, FC and DH), Fédération Francophone de Recherche sur le Diabète FFRD, sponsored by Fédération Française des Diabétiques (AFD), AstraZeneca, Eli Lilly, Merck Sharp & Dohme (MSD), Novo Nordisk & Sanofi, (to HD), Fondation de France (to HD), the 'European Genomic Institute for Diabetes' (EGID, ANR-10-LABX-46) (to HD and BS), the Fondation des Gueules Cassées (DH and FC), and an ERC-Région Hauts de France funding (to HD). BS is a holder of an ERC advanced grant no. 694717 'Bile acid, immune-metabolism, lipid and glucose homeostasis'. The PBI (AD, PR, and SLS) is part of the France BioImaging infrastructure supported by the French National Research Agency (ANR-10-INSB-04-01, 'Investments for the future'), ANR-10-LABX-0046,EGID,EGID Diabetes Pole(2010), ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), European Project: 694717,H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) ,ImmunoBile(2016), Récepteurs nucléaires, maladies cardiovasculaires et diabète (EGID), Université de Lille, Droit et Santé-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Technologie et Service BioImagerie Photonique – Photonic BioImaging (UTechS PBI), Centre de Ressources et de Recherche Technologique - Center for Technological Resources and Research (C2RT), Institut Pasteur [Paris]-Institut Pasteur [Paris], ANR-10-LABX-0046/10-LABX-0046,EGID,EGID Diabetes Pole(2010), ANR-10-INBS-04-01/10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), Institut Pasteur [Paris] (IP)-Université Paris Descartes - Paris 5 (UPD5), and Institut Pasteur [Paris] (IP)
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0301 basic medicine ,lcsh:Diseases of the musculoskeletal system ,Histology ,Computer science ,Muscle Fibers, Skeletal ,Stem cells ,In situ cartography ,03 medical and health sciences ,Mice ,Software ,Satellite cells ,medicine ,Image Processing, Computer-Assisted ,[SDV.MHEP.AHA]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO] ,Animals ,Orthopedics and Sports Medicine ,Segmentation ,Statistical analysis ,Muscle fibre ,Molecular Biology ,business.industry ,Optical Imaging ,Methodology ,Skeletal muscle ,Cell Biology ,Skeletal muscle fiber ,030104 developmental biology ,medicine.anatomical_structure ,Open source ,Fiber typing ,Image automated quantification ,Vessels ,Experimental methods ,lcsh:RC925-935 ,business ,Biomedical engineering ,Muscle physiology - Abstract
Background Skeletal muscle has the capacity to adapt to environmental changes and regenerate upon injury. To study these processes, most experimental methods use quantification of parameters obtained from images of immunostained skeletal muscle. Muscle cross-sectional area, fiber typing, localization of nuclei within the muscle fiber, the number of vessels, and fiber-associated stem cells are used to assess muscle physiology. Manual quantification of these parameters is time consuming and only poorly reproducible. While current state-of-the-art software tools are unable to analyze all these parameters simultaneously, we have developed MuscleJ, a new bioinformatics tool to do so. Methods Running on the popular open source Fiji software platform, MuscleJ simultaneously analyzes parameters from immunofluorescent staining, imaged by different acquisition systems in a completely automated manner. Results After segmentation of muscle fibers, up to three other channels can be analyzed simultaneously. Dialog boxes make MuscleJ easy-to-use for biologists. In addition, we have implemented color in situ cartographies of results, allowing the user to directly visualize results on reconstituted muscle sections. Conclusion We report here that MuscleJ results were comparable to manual observations made by five experts. MuscleJ markedly enhances statistical analysis by allowing reliable comparison of skeletal muscle physiology-pathology results obtained from different laboratories using different acquisition systems. Providing fast robust multi-parameter analyses of skeletal muscle physiology-pathology, MuscleJ is available as a free tool for the skeletal muscle community. Electronic supplementary material The online version of this article (10.1186/s13395-018-0171-0) contains supplementary material, which is available to authorized users.
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- 2018
7. Endospanin-2 enhances skeletal muscle energy metabolism and running endurance capacity
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Lancel, S. (Steve), Hesselink, M.K. (Matthijs Kc), Woldt, E. (Estelle), Rouille, Y. (Yves), Dorchies, E. (Emilie), Delhaye, S. (Stephane), Duhem, C. (Christian), Thorel, Q. (Quentin), Mayeuf-Louchart, A. (Alicia), Pourcet, B. (Benoit), Montel, V. (Valerie), Schaart, G. (Gert), Beton, N. (Nicolas), Picquet, F. (Florence), Briand, O. (Olivier), Salles, J.P. (Jean Pierre), Duez, H. (Helene), Schrauwen, P. (Patrick), Bastide, B. (Bruno), Bailleul, B. (Bernard), Staels, B. (Bart), Sebti, Y. (Yasmine), Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM), Maastricht University [Maastricht], Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Unité de Recherche Pluridisciplinaire Sport, Santé, Société (URePSSS) - ULR 7369 - ULR 4488 (URePSSS), Université d'Artois (UA)-Université de Lille-Université du Littoral Côte d'Opale (ULCO), Centre de Physiopathologie Toulouse Purpan (CPTP), 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)-Centre National de la Recherche Scientifique (CNRS), European Project: 694717,H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) ,ImmunoBile(2016), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Université d'Artois (UA)-Université du Littoral Côte d'Opale (ULCO)-Université de Lille, Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Récepteurs nucléaires, maladies cardiovasculaires et diabète (EGID), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Maastricht University Medical Center (MUMC), Centre d’Infection et d’Immunité de Lille (CIIL) - INSERM U1019 - UMR 9017 (CIIL), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Unité de Recherche Pluridisciplinaire Sport, Santé, Société (URePSSS) - EA 7369 (URePSSS), Université du Littoral Côte d'Opale (ULCO)-Université de Lille-Université d'Artois (UA), Centre de Physiopathologie Toulouse Purpan ex IFR 30 et IFR 150 (CPTP), This research was supported by the European Genomic Institute for Diabetes (EGID, ANR-10-LABX-46) and European Commission, Lille Métropole Communauté Urbaine (to YS), Région Nord Pas-de-Calais/FEDER (to BS), CPER 2011-R3-P12A (to B. Bailleul), a joint Société Francophone du Diabète (SFD)/Menarini research fellowship (to B. Bailleul), EFSD/Lilly research grant and CPER emerging team (to HD), Eurhythdia (to BS and HD), ERC Région Haut de France (to HD), and Pfizer France and Ipsen Beaufour (to JPS). BS hold an ERC advanced grant (no. 694717)., ANR-10-LABX-0046/10-LABX-0046,EGID,EGID Diabetes Pole(2010), Nutrition and Movement Sciences, RS: NUTRIM - R1 - Obesity, diabetes and cardiovascular health, Ondersteunend personeel NTM, Université de Lille, Univ. Artois, Univ. Littoral Côte d’Opale, Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 [RNMCD], Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL], Unité de Recherche Pluridisciplinaire Sport, Santé, Société (URePSSS) - ULR 7369 - ULR 4488 [URePSSS], and Centre de Physiopathologie Toulouse Purpan [CPTP]
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Male ,[SDV]Life Sciences [q-bio] ,Cell Plasticity ,Messenger ,Skeletal muscle ,[SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC] ,MOUSE ,STAT3 ,Mice ,Phosphorylation ,Extracellular Signal-Regulated MAP Kinases ,Cells, Cultured ,Glucose metabolism ,Cultured ,ACTIVATED PROTEIN-KINASE ,Intracellular Signaling Peptides and Proteins ,Adaptor Proteins ,MITOCHONDRIAL BIOGENESIS ,Skeletal ,Mitochondria ,ERK ,Muscle Fibers, Slow-Twitch ,Phenotype ,[SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology ,Muscle Fibers, Fast-Twitch ,Muscle ,Female ,PHENOTYPIC ANALYSIS ,Research Article ,PERMEABILITY TRANSITION ,MAP Kinase Signaling System ,Cells ,Physical Exertion ,EXERCISE ,Slow-Twitch ,Muscle Fibers ,Signal Transducing ,Animals ,Autophagy ,Caloric Restriction ,Energy Metabolism ,Humans ,Membrane Proteins ,Fast-Twitch ,Oxidative Stress ,Physical Endurance ,RNA ,Metabolism ,Muscle Biology ,RNA, Messenger ,Muscle, Skeletal ,Adaptor Proteins, Signal Transducing ,ELECTRON-TRANSPORT CHAIN - Abstract
International audience; Metabolic stresses such as dietary energy restriction or physical activity exert beneficial metabolic effects. In the liver, endospanin-1 and endospanin-2 cooperatively modulate calorie restriction-mediated (CR-mediated) liver adaptations by controlling growth hormone sensitivity. Since we found CR to induce endospanin protein expression in skeletal muscle, we investigated their role in this tissue. In vivo and in vitro endospanin-2 triggers ERK phosphorylation in skeletal muscle through an autophagy-dependent pathway. Furthermore, endospanin-2, but not endospanin-1, overexpression decreases muscle mitochondrial ROS production, induces fast-to-slow fiber-type switch, increases skeletal muscle glycogen content, and improves glucose homeostasis, ultimately promoting running endurance capacity. In line, endospanin-2-/- mice display higher lipid peroxidation levels, increased mitochondrial ROS production under mitochondrial stress, decreased ERK phosphorylation, and reduced endurance capacity. In conclusion, our results identify endospanin-2 as a potentially novel player in skeletal muscle metabolism, plasticity, and function.
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- 2018
8. Shared genetic predisposition in rheumatoid arthritis-interstitial lung disease and familial pulmonary fibrosis
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Steven Gazal, Hilario Nunes, Jean Sibilia, Christelle Ménard, Aurélien Justet, Philippe Dieudé, Isabelle Callebaut, Amélie Bonnefond, Martin Soubrier, Patrick Revy, Catherine Boileau, Pierre-Antoine Juge, Thierry Schaeverbeke, Aline Frazier, Nathalie Saidenberg, Sébastien Ottaviani, Nadia Nathan, Bruno Crestani, Christophe Béroud, Baptiste Coustet, Vincent Cottin, Lidwine Wemeau-Stervinou, Jean-Pierre Desvignes, Marie-Christophe Boissier, Florence Dastot-Le Moal, Serge Amselem, Philippe Froguel, Yannick Allanore, Annick Clement, Olivier Sand, Gabriel Thabut, Marie-Pierre Debray, Pascal Richette, Caroline Kannengiesser, Benoit Wallaert, Christophe Richez, Dominique Valeyre, Sylvain Marchand-Adam, Huguette Lioté, Nicolas Leulliot, René-Marc Flipo, Raphael Borie, Claire Dromer, David Salgado, Service de Rhumathologie, Hôpital Bichat - Claude Bernard, Assistance Publique - Hôpitaux de Paris (AP-HP), Université Paris Diderot - Paris 7 (UPD7), Université Sorbonne Paris Cité (USPC), Service de Pneumologie, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), UMR 1152, Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Génétique, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), UMR 1149, Centre de Recherches sur l'Inflammation, Ecologie et Ecophysiologie Forestières [devient SILVA en 2018] (EEF), Institut National de la Recherche Agronomique (INRA)-Université de Lorraine (UL), Plateforme de génomique constitutionnelle, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Pneumologie et Immuno-Allergologie [CHU LIlle], Pole Cardio-vasculaire et pulmonaire [CHU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université de Lille, Service de Radiologie, Hospices Civils de Lyon (HCL), UMR 1100, Université Francois Rabelais [Tours], Physiopathologie des maladies génétiques d'expression pédiatrique, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Rhumatologie, CH Belfort-Montbéliard, UMR 5164, Immuno ConcEpT Lab, Centre National de la Recherche Scientifique (CNRS), Université de Bordeaux (UB), Sorbonne Université (SU), Institut de minéralogie, de physique des matériaux et de cosmochimie (IMPMC), Muséum national d'Histoire naturelle (MNHN)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de recherche pour le développement [IRD] : UR206-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche pour le Développement (IRD [France-Ouest]), Muséum national d'Histoire naturelle (MNHN), Laboratoire de cristallographie et RMN biologiques (LCRB - UMR 8015), Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5), Université de Lille, Droit et Santé, Institut Européen de Génomique du Diabète - European Genomic Institute for Diabetes - FR 3508 (EGID), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Génétique Médicale et Génomique Fonctionnelle (GMGF), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), UMR 1132, Service de Rhumatologie, Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), Department of Genomics of Common Diseases, Imperial College London, Service Rhumatologie A, Hôpital Cochin [AP-HP], Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service Imagerie, service de Rhumatologie, Centre Hospitalier Universitaire de Lille (CHU de Lille), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Service Rhumatologie, Hôpital La Rabta [Tunis], FMTS, CRHI, Laboratoire Immunologie Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA), Fédération Hospitalo-Universitaire OMICARE, Rétrovirus et Pathologie Comparée (RPC), Institut National de la Recherche Agronomique (INRA)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Ecole Nationale Vétérinaire de Lyon (ENVL), Maladie Pulmonaires Rares, Hôpital Louis Pradel [CHU - HCL], UMR U1125 Service rhumatologie, service de rhumatologie, CHU Clermont-Ferrand, Unité de Nutrition Humaine (UNH), Institut National de la Recherche Agronomique (INRA)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne), Hôpital Avicenne [AP-HP], service de génétique, Societe Francaise de Rhumatologie, Club Rhumatismes Inflammation, la Chancellerie des Universites de Paris (legs Poix), Sorbonne Paris Cite (FPI-SPC Program), Agence Nationale de la Recherche ANR-10-LABX-46 ANR-10-EQPX-07-01 ANR-14-CE10-0006 ANR-10-INBS-09, France Genomique National Infrastructure, Pfizer, Chugai, Centre de Resources Biologiques Hopital Bichat Paris France, ANR-14-CE10-0006,GENEXGERTEL,Rôles génomiques et extragénomiques de RTEL1(2014), Hôpital Bichat - Claude Bernard, Assistance Publique - Hôpitaux de Paris ( AP-HP ), Université Paris Diderot (Paris 7), Université Sorbonne Paris Cité ( USPC ), Centre Hospitalier Lyon Sud [CHU - HCL] ( CHLS ), Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ), Institut National de la Santé et de la Recherche Médicale ( INSERM ), CHU Saint-Etienne, UMR 1137, Fac Sci, Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Service de Pneumologie et Immuno-Allergologie, Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Hospices Civils de Lyon ( HCL ), Service de Pneumologie Pédiatrique, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Trousseau [APHP], Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Pierre et Marie Curie (Paris 6), Centre National de la Recherche Scientifique ( CNRS ), Université de Bordeaux ( UB ), Sorbonne Universités, Institut de minéralogie, de physique des matériaux et de cosmochimie ( IMPMC ), Muséum National d'Histoire Naturelle ( MNHN ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut de recherche pour le développement [IRD] : UR206-Centre National de la Recherche Scientifique ( CNRS ), Institut de Recherche pour le Développement ( IRD [France-Ouest] ), Muséum National d’Histoire Naturelle ( MNHN ), Laboratoire de cristallographie et RMN biologiques ( LCRB - UMR 8015 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Centre National de la Recherche Scientifique ( CNRS ), Université Paris Descartes - Paris 5 ( UPD5 ), Université Droit et Santé (Lille 2) ( UDSL ), European Genomic Institute for Diabetes ( EGID ), Génétique Médicale et Génomique Fonctionnelle ( GMGF ), Aix Marseille Université ( AMU ) -Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Hôpital Lariboisière, Génomique Intégrative et Modélisation des Maladies Métaboliques ( EGID ), Université de Lille-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut Pasteur de Lille, Réseau International des Instituts Pasteur ( RIIP ) -Réseau International des Instituts Pasteur ( RIIP ) -Centre National de la Recherche Scientifique ( CNRS ) -Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), CHU Cochin [AP-HP], Institut Cochin ( UM3 (UMR 8104 / U1016) ), Centre Hospitalier Universitaire de Lille ( CHU de Lille ), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques, Université Montpellier 1 ( UM1 ) -IFR3-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), Hôpital La Rabta [Tunis), Université de Strasbourg ( UNISTRA ), Rétrovirus et Pathologie Comparée ( RPC ), Institut National de la Recherche Agronomique ( INRA ) -École pratique des hautes études ( EPHE ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Ecole Nationale Vétérinaire de Lyon ( ENVL ), Département Génétique, Institut de l'Elevage, Centre Reference Maladies Respiratoires Rares, Hôpital Armand Trousseau, Assistance Publique - Hôpitaux de Paris ( AP-HP ), Centre Hospitalier Universitaire de Clermont-Ferrand, Unité de Nutrition Humaine - Clermont Auvergne ( UNH ), Université Clermont Auvergne ( UCA ) -Institut national de la recherche agronomique [Auvergne/Rhône-Alpes] ( INRA Auvergne/Rhône-Alpes ), Centre de Recherche en Nutrition Humaine d'Auvergne ( CRNH d'Auvergne ), Hôpital Avicenne, Assistance Publique - Hôpitaux de Paris ( AP-HP ), European Genomic Institute for Diabetes - FR 3508 (EGID), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Centre National de la Recherche Scientifique (CNRS), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Recherche Agronomique (INRA)-École pratique des hautes études (EPHE), Institut de l'élevage (IDELE), ProdInra, Archive Ouverte, Centre de référence national pour les maladies respiratoires rares de l’enfant RespiRare [CHU Trousseau], Service de Pneumologie pédiatrique [CHU Trousseau], 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 Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de génétique et embryologie médicales [CHU Trousseau], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Institut de recherche pour le développement [IRD] : UR206-Centre National de la Recherche Scientifique (CNRS)-Muséum national d'Histoire naturelle (MNHN)-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), European Genomic Institute for Diabetes [Lille] (EGID), Génomique Intégrative et Modélisation des Maladies Métaboliques (EGID), Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut National de la Recherche Agronomique (INRA)-École pratique des hautes études (EPHE)-Université Claude Bernard Lyon 1 (UCBL), Hôpital Armand Trousseau, Assistance Publique - Hôpitaux de Paris (AP-HP), Unité de Nutrition Humaine - Clermont Auvergne (UNH), Institut National de la Recherche Agronomique (INRA)-Université Clermont Auvergne (UCA), Hôpital Avicenne, Assistance Publique - Hôpitaux de Paris (AP-HP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de recherche pour le développement [IRD] : UR206-Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université Paris Descartes - Paris 5 (UPD5), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, IFR3, Université Montpellier 1 (UM1)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS)
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Male ,Pathology ,medicine.disease_cause ,Arthritis, Rheumatoid ,0302 clinical medicine ,Risk Factors ,Pulmonary fibrosis ,Exome ,Telomerase ,Exome sequencing ,Mutation ,[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology ,Interstitial lung disease ,Middle Aged ,3. Good health ,Europe ,Polyarthrite rhumatoïde ,maladie pulmonaire ,Phenotype ,Rheumatoid arthritis ,Female ,Pulmonary and Respiratory Medicine ,Adult ,medicine.medical_specialty ,Heterozygote ,fibrose pulmonaire ,03 medical and health sciences ,[ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology ,medicine ,Genetic predisposition ,Humans ,Genetic Predisposition to Disease ,respiratory system diseases ,Genetic Association Studies ,Aged ,030203 arthritis & rheumatology ,pulmonary fibrosis ,business.industry ,Case-control study ,DNA Helicases ,Sequence Analysis, DNA ,medicine.disease ,030228 respiratory system ,Case-Control Studies ,Immunology ,business ,Lung Diseases, Interstitial ,Software ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology - Abstract
Despite its high prevalence and mortality, little is known about the pathogenesis of rheumatoid arthritis-associated interstitial lung disease (RA-ILD). Given that familial pulmonary fibrosis (FPF) and RA-ILD frequently share the usual pattern of interstitial pneumonia and common environmental risk factors, we hypothesised that the two diseases might share additional risk factors, including FPF-linked genes. Our aim was to identify coding mutations of FPF-risk genes associated with RA-ILD.We used whole exome sequencing (WES), followed by restricted analysis of a discrete number of FPF-linked genes and performed a burden test to assess the excess number of mutations in RA-ILD patients compared to controls.Among the 101 RA-ILD patients included, 12 (11.9%) had 13 WES-identified heterozygous mutations in the TERT, RTEL1, PARN or SFTPC coding regions. The burden test, based on 81 RA-ILD patients and 1010 controls of European ancestry, revealed an excess of TERT, RTEL1, PARN or SFTPC mutations in RA-ILD patients (OR 3.17, 95% CI 1.53–6.12; p=9.45×10−4). Telomeres were shorter in RA-ILD patients with a TERT, RTEL1 or PARN mutation than in controls (p=2.87×10−2).Our results support the contribution of FPF-linked genes to RA-ILD susceptibility.
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- 2017
9. Inactivation of the Nuclear Orphan Receptor COUP-TFII by Small Chemicals
- Author
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Gilles Salbert, François F. Firmin, Bart Staels, Iannis Talianidis, Philippe Lefebvre, Frédérik Oger, Miroslava Kretova, Maheul Ploton, Jérôme Eeckhoute, Celia P. Martinez-Jimenez, Gaëlle Palierne, Maud Bizot, Rémy Le Guével, Céline Gheeraert, Peter Barath, Jonchère, Laurent, EGID Diabetes Pole - - EGID2010 - ANR-10-LABX-0046 - LABX - VALID, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), European Genomic Institute for Diabetes (EGID), Faculté de Médecine-Université de Lille, Droit et Santé, Institute of Immunology, Biomedical Sciences Research Center Al. Fleming, Slovak Academy of Science [Bratislava] (SAS), This work was funded by the European Community (QLG1-CT-2001-01513), the Centre National pour la Recherche Scientifique and the Ministère de l’Enseignement Supérieur et de la Recherche. This work was also supported by grants from 'European Genomic Institute for Diabetes' (E.G.I.D., ANR-10-LABX-46). F.O. and C.G. were supported by OSEO-ANVAR (IT-DIAB). B.S. is a member of the Institut Universitaire de France., ANR-10-LABX-0046,EGID,EGID Diabetes Pole(2010), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut Européen de Génomique du Diabète - European Genomic Institute for Diabetes - FR 3508 (EGID), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM)
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0301 basic medicine ,[CHIM.THER] Chemical Sciences/Medicinal Chemistry ,[SDV.GEN] Life Sciences [q-bio]/Genetics ,[CHIM.THER]Chemical Sciences/Medicinal Chemistry ,Biochemistry ,COUP Transcription Factor II ,Small Molecule Libraries ,Mice ,03 medical and health sciences ,0302 clinical medicine ,3T3-L1 Cells ,Adipocytes ,Animals ,Humans ,Binding site ,Transcription factor ,COUP-TFII ,Orphan receptor ,[SDV.GEN]Life Sciences [q-bio]/Genetics ,Binding Sites ,biology ,Cell Differentiation ,Hep G2 Cells ,General Medicine ,Small molecule ,3. Good health ,Neuron-derived orphan receptor 1 ,Ovalbumin ,030104 developmental biology ,Nuclear receptor ,biology.protein ,Molecular Medicine ,030217 neurology & neurosurgery - Abstract
International audience; Chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII/NR2F2) is an orphan member of the nuclear receptor family of transcription factors whose activities are modulated upon binding of small molecules into an hydrophobic ligand-binding pocket (LBP). Although the LBP of COUP-TFII is filled with aromatic amino-acid side chains, alternative modes of ligand binding could potentially lead to regulation of the orphan receptor. Here, we screened a synthetic and natural compound library in a yeast one-hybrid assay and identified 4-methoxynaphthol as an inhibitor of COUP-TFII. This synthetic inhibitor was able to counteract processes either positively or negatively regulated by COUP-TFII in different mammalian cell systems. Hence, we demonstrate that the true orphan receptor COUP-TFII can be targeted by small chemicals which could be used to study the physiological functions of COUP-TFII or to counteract detrimental COUP-TFII activities in various pathological conditions.
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- 2017
10. Peroxisome Proliferator-activated Receptor γ Regulates Genes Involved in Insulin/Insulin-like Growth Factor Signaling and Lipid Metabolism during Adipogenesis through Functionally Distinct Enhancer Classes
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Stéphane Avner, Philippe Froguel, Bart Staels, Gilles Salbert, Philippe Lefebvre, Frédérik Oger, Jérôme Eeckhoute, Julie Dubois-Chevalier, Emmanuelle Durand, Céline Gheeraert, Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut Européen de Génomique du Diabète - European Genomic Institute for Diabetes - FR 3508 (EGID), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM), European Genomic Institute for Diabetes (EGID), Faculté de Médecine-Université de Lille, Droit et Santé, Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur de Lille, and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)
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Epigenomics ,MESH: Signal Transduction ,Muscle Fibers, Skeletal ,Peroxisome proliferator-activated receptor ,Enhancer RNAs ,Biochemistry ,Mice ,chromatin modification ,Transcrip tion regulation ,MESH: Reverse Transcriptase Polymerase Chain Reaction ,DNA methylat ion ,MESH: Gene Expression Regulation, Developmental ,Adipocytes ,Insulin ,MESH: Animals ,insulin/insulin-like growth factor signalling ,MESH: Lipid Metabolism ,MESH: Chromatin Immunoprecipitation ,chemistry.chemical_classification ,Adipogenesis ,MESH: Muscle Fibers, Skeletal ,Reverse Transcriptase Polymerase Chain Reaction ,Gene Expression Regulation, Developmental ,Enhancer Elements, Genetic ,Signal transduction ,Transcription enhancers ,Protein Binding ,Signal Transduction ,Chromatin Immunoprecipitation ,MESH: Insulin ,Biology ,Cell Line ,Somatomedins ,3T3-L1 Cells ,Animals ,MESH: Protein Binding ,Gene Regulation ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,MESH: Somatomedins ,Enhancer ,MESH: Mice ,Molecular Biology ,Transcription factor ,MESH: Adipocytes ,MESH: Transcriptome ,Lipid metabolism ,Cell Biology ,Lipid Metabolism ,MESH: 3T3-L1 Cells ,MESH: Cell Line ,PPAR gamma ,MESH: PPAR gamma ,Nuclear receptor ,chemistry ,Peroxisome proliferator-activated receptor (PPAR) ,MESH: Enhancer Elements, Genetic ,Transcriptome ,MESH: Adipogenesis - Abstract
International audience; The nuclear receptor peroxisome proliferator-activated receptor (PPAR) is a transcription factor whose expression is induced during adipogenesis and that is required for the acquisition and control of mature adipocyte functions. Indeed, PPAR induces the expression of genes involved in lipid synthesis and storage through enhancers activated during adipocyte differentiation. Here, we show that PPAR also binds to enhancers already active in preadipocytes as evidenced by an active chromatin state including lower DNA methylation levels despite higher CpG content. These constitutive enhancers are linked to genes involved in the insulin/insulin-like growth factor signaling pathway that are transcriptionally induced during adipogenesis but to a lower extent than lipid metabolism genes, because of stronger basal expression levels in preadipocytes. This is consistent with the sequential involvement of hormonal sensitivity and lipid handling during adipocyte maturation and correlates with the chromatin structure dynamics at constitutive and activated enhancers. Interestingly, constitutive enhancers are evolutionary conserved and can be activated in other tissues, in contrast to enhancers controlling lipid handling genes whose activation is more restricted to adipocytes. Thus, PPAR utilizes both broadly active and cell type-specific enhancers to modulate the dynamic range of activation of genes involved in the adipogenic process.
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- 2014
11. Propriétés anti-inflammatoires des oxylipines dérivées du DHA
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Bosviel, Rémy, Joumard-Cubizolles, Laurie, Chinetti-Gbaguidi, Giulia, Bayle, Dominique, Copin, Corinne, Hennuyer, Nathalie, Staels, Bart, Zanoni, Giuseppe, Porta, A., Balas, Laurence, Galano, Jean-Marie, Oger, Camille, Mazur, André, Durand, Thierry, Gladine, Cécile, Unité de Nutrition Humaine (UNH), Institut National de la Recherche Agronomique (INRA)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Clermont Université, Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Universitaire de Lille (CHU de Lille), European Genomic Institute of Diabetes (EGID), Institute of research on Cancer and Aging (IRCAN), Università degli Studi di Pavia = University of Pavia (UNIPV), Université de Montpellier (UM), Centre de Recherche en Nutrition Humaine (CRNH). FRA., ProdInra, Migration, Université d'Auvergne - Clermont-Ferrand I (UdA)-Clermont Université-Institut National de la Recherche Agronomique (INRA), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Pavia, Institut Européen de Génomique du Diabète - European Genomic Institute for Diabetes - FR 3508 (EGID), and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)
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[SDV.AEN] Life Sciences [q-bio]/Food and Nutrition ,[SDV.AEN]Life Sciences [q-bio]/Food and Nutrition - Abstract
Flash Posters : Axe 2; National audience; Whereas the anti-inflammatory properties and mechanisms of action of long chain. 3 PUFAs have been abundantly investigated, research gaps remain regarding the respective contribution and mechanisms of action of their oxygenated metabolites collectively known as oxylipins. A dose-dependent and comparative study was conducted using human primary macrophages. The aim was to compare the anti-inflammatory activity of two types of DHA- derived oxylipins including protectins (NPD1 and PDX), formed through lipoxygenase pathway and the neuroprostanes (14-A4t- and 4-F4t-NeuroP) formed through free-radical mediated oxygenation and suspected to be new anti-inflammatory mediators. Considering the potential ability of these lipid mediators to bind PPARs and knowing the central role of PPARs in the regulation of macrophage inflammatory response, transactivation assays was performed to compare the ability of protectins and neuroprostanes to activate PPARs. All molecules significantly reduced LPS-stimulated expression of cytokines but not at the same doses. Notably, NPD1 showed the most effect at 0.1 µM (IL-6:-14.9%, p
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- 2016
12. DNA damage and the activation of the p53 pathway mediate alterations in metabolic and secretory functions of adipocytes Running title: DNA damage and p53 in obese adipocytes
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Vergoni, Bastien, Cornejo, Pierre-Jean, Gilleron, Jérôme, Dedjani, Mansour, Ceppo, Franck, Jacquel, Arnaud, Bouget, Gwennaelle, Ginet, Clémence, Gonzalez, Teresa, Maillet, Julie, Dhennin, Véronique, Verbanck, Marie, Auberger, Patrick, Froguel, Philippe, Tanti, Jean-François, Cormont, Mireille, Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie Cellulaire et Moléculaire de l'Obésité et du Diabète (Equipe 7), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Nice Sophia Antipolis (... - 2019) (UNS), Mort cellulaire, différenciation et cancer (Equipe 2), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-C3M - Centre Méditerranéen de Médecine Moléculaire, Hôpital l'Archet - CHU de Nice-Hôpital l'Archet - CHU de Nice, 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), European Genomic Institute for Diabetes (EGID), Faculté de Médecine-Université de Lille, Droit et Santé, Génomique Intégrative et Modélisation des Maladies Métaboliques (EGID), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Department of Genomics of Common Disease [London, UK], Imperial College London-School of public health, The University of Hong Kong (HKU)-The University of Hong Kong (HKU), This work was supported by INSERM, the Université Côte d'Azur, and by grants from the European Foundation for the Study of Diabetes (EFSD/Lilly), SFD-Abbott, Aviesan/AstraZeneca (Diabetes and the Vessel Wall Injury Program), and the French National Research Agency (ANR) through 'Investments for the Future' Labex SIGNALIFE (grant ANR-11-LABX-0028-01). Light microscopy was performed at the C3M Imaging core facility (part of the Microscopy and Imaging platform Côte d’Azur IBISA). The Nikon A1R-FLIM microscope used for this study was funded thanks to Conseil Général Alpes-Maritimes ('Appel à Projets Santé') and by Région Provence-Alpes-Côte d'Azur (PACA) ('Appel à Projets Plateforme'). The UMR 8199 Genotyping and Expression platform (Lille, France) belongs to the 'Federation de Recherche' 3508 funded by Labex EGID (European Genomics Institute for Diabetes, ANR-10-LABX-46) and by the ANR Equipex 2010 session (ANR-10-EQPX-07-01, 'LIGAN-PM'). The LIGAN-PM Genomics platform (Lille, France) is also supported by the Fonds Européen de Développement Régional (FEDR) and the Region Nord-Pas-de-Calais-Picardie. B.V. and P.-J.C. were supported by the French Ministry of Education and Research. J.G. was supported by a fellowship (postdoctoral grant) from the 'Fondation pour la Recherche Médicale.' F.C. was supported by a fellowship from INSERM/Région PACA/FEDER (PhD grant) and by a grant from the Société Francophone du Diabète (SFD/Abbott). G.B. was supported by the Labex SIGNALIFE grant (ANR-11-LABX-0028-01). J.-F.T. is an investigator of the CNRS., The authors thank the animal facility staff for animal care and breeding, Damien Alcor, head of the Cell Imaging core facility (INSERM UMR 1065, C3M, Nice, France), and also Prof. Marino Zerial and Dr. Yannis Lalaiszidis (Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany) for the free access to the motion-tracking software developed in Prof. Zerial’s laboratory., ANR: 11-LABX-0028,SIGNALIFE,Réseau d'Innovation sur les Voies de Signalisation en Sciences de la Vie(2011), ANR-10-LABX-0046/10-LABX-0046,EGID,EGID Diabetes Pole(2010), ANR-10-EQPX-07-01 ,[LIGAN-PM],ANR Equipex 2010 session, 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), 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)-Université Nice Sophia Antipolis (... - 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)-C3M - Centre Méditerranéen de Médecine Moléculaire, Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), ANR-11-LABX-0028,SIGNALIFE,Réseau d'Innovation sur les Voies de Signalisation en Sciences de la Vie(2011), ANR-10-LABX-0046,EGID,EGID Diabetes Pole(2010), ANR-10-EQPX-0007,LIGAN PM,Plate forme Lilloise de séquençage du génome humain pour une médecine personnalisée(2010), ANR-15-IDEX-0001,UCA JEDI,Idex UCA JEDI(2015), 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)-Université Nice Sophia Antipolis (1965 - 2019) (UNS), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Européen de Génomique du Diabète - European Genomic Institute for Diabetes - FR 3508 (EGID), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Cormont, Mireille, Centres d'excellences - Réseau d'Innovation sur les Voies de Signalisation en Sciences de la Vie - - SIGNALIFE2011 - ANR-11-LABX-0028 - LABX - VALID, EGID Diabetes Pole - - EGID2010 - ANR-10-LABX-0046 - LABX - VALID, Plate forme Lilloise de séquençage du génome humain pour une médecine personnalisée - - LIGAN PM2010 - ANR-10-EQPX-0007 - EQPX - VALID, and Idex UCA JEDI - - UCA JEDI2015 - ANR-15-IDEX-0001 - IDEX - VALID
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[SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism ,MESH: Signal Transduction/physiology ,MESH: Humans ,MESH: DNA Damage/genetics ,MESH: Flow Cytometry ,MESH: Chemotaxis/physiology ,[SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism ,MESH: Reactive Oxygen Species/metabolism ,MESH: 3T3-L1 Cells ,MESH: Chemotaxis/genetics ,[SDV.AEN] Life Sciences [q-bio]/Food and Nutrition ,MESH: Glucose Transporter Type 4/metabolism ,MESH: Glucose Transporter Type 4/genetics ,MESH: Telomere/genetics ,MESH: Tumor Suppressor Protein p53/genetics ,MESH: DNA Damage/physiology ,MESH: Blotting, Western ,MESH: RAW 264.7 Cells ,MESH: Animals ,MESH: Signal Transduction/genetics ,MESH: Tumor Suppressor Protein p53/metabolism ,MESH: Adipocytes/metabolism ,MESH: Fluorescent Antibody Technique ,MESH: Mice ,[SDV.AEN]Life Sciences [q-bio]/Food and Nutrition - Abstract
International audience; Activation of the p53 pathway in adipose tissue contributes to insulin resistance associated with obesity. However, the mechanisms of p53 activation and the impact on adipocyte functions are still elusive. Here we found a higher level of DNA oxidation and a reduction in telomere length in adipose tissue of high-fat diet mice and an increase in DNA damage and activation of the p53 pathway in adipocytes. Interestingly, hallmarks of chronic DNA damage are visible at the onset of obesity. Furthermore, treatment of lean mice with doxorubicin, a DNA damage-inducing drug, increased the expression of chemokines in adipose tissue and promoted its infiltration by pro-inflammatory macrophages and neutrophils together with adipocyte insulin resistance. In vitro, DNA damage in adipocytes increased chemokines expression and triggered the production of chemotactic factors for macrophages and neutrophils. Insulin signaling and effect on glucose uptake and Glut4 translocation were decreased while lipolysis was increased. These events were prevented by p53 inhibition whereas its activation by nutlin-3 reproduced the DNA damage-induced adverse effects. This study reveals that DNA damage in obese adipocyte could trigger p53-dependent signals involved in alteration of adipocyte metabolism and secretory function leading to adipose tissue inflammation, adipocyte dysfunction and insulin resistance.
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- 2016
13. Potentiation of Calcium Influx and Insulin Secretion in Pancreatic Beta Cell by the Specific TREK-1 Blocker Spadin
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Hivelin, Céline, Béraud-Dufour, Sophie, Devader, Christelle, Abderrahmani, Amar, Moreno, Sébastien, Moha ou Maati, Hamid, Djillani, Alaeddine, Heurteaux, Catherine, Borsotto, Marc, Mazella, Jean, Coppola, Thierry, Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), This work was supported by the Centre National de la Recherche Scientifique, a grant from the Société Francophone du Diabète (SFD 2011) to Thierry Coppola and a grant from the Agence Nationale de la Recherche (ANR-13-SAMA-0002) to Jean Mazella. Amar Abderrahmani is supported by 'European Genomic Institute for Diabetes' (EGID, ANR-10-LABX-46), European Commission, the Regional Council Nord Pas de Calais and the European Regional Development Fund. Alaeddine Djillani is supported by ICST LabEx., ANR-13-SAMA-0002,VASPAC,Validation du concept spadine pour le traitement de la dépression(2013), ANR-10-LABX-0046,EGID,EGID Diabetes Pole(2010), ANR-11-LABX-0015,ICST,Canaux ioniques d'intérêt thérapeutique(2011), Béraud-Dufour, Sophie, Santé Mentale et Addictions - Validation du concept spadine pour le traitement de la dépression - - VASPAC2013 - ANR-13-SAMA-0002 - SAMENTA - VALID, EGID Diabetes Pole - - EGID2010 - ANR-10-LABX-0046 - LABX - VALID, Laboratoires d'excellence - Canaux ioniques d'intérêt thérapeutique - - ICST2011 - ANR-11-LABX-0015 - LABX - VALID, 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)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)
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Male ,endocrine system ,lcsh:RC648-665 ,Article Subject ,[SDV]Life Sciences [q-bio] ,lcsh:Diseases of the endocrine glands. Clinical endocrinology ,Cell Line ,Membrane Potentials ,[SDV] Life Sciences [q-bio] ,Islets of Langerhans ,Mice ,Cytosol ,Glucose ,Potassium Channels, Tandem Pore Domain ,Insulin-Secreting Cells ,Insulin Secretion ,Animals ,Insulin ,Calcium ,Peptides ,Research Article - Abstract
International audience; Inhibition of the potassium channels TREK-1 by spadin (SPA) is currently thought to be a promising therapeutic target for the treatment of depression. Since these channels are expressed in pancreatic β-cells, we investigated their role in the control of insulin secretion and glucose homeostasis. In this study, we confirmed the expression of TREK-1 channels in the insulin secreting MIN6-B1 β-cell line and in mouse islets. We found that their blockade by SPA potentiated insulin secretion induced by potassium chloride dependent membrane depolarization. Inhibition of TREK-1 by SPA induced a decrease of the resting membrane potential ( mV) and increased the cytosolic calcium concentration. In mice, administration of SPA enhanced the plasma insulin level stimulated by glucose, confirming its secretagogue effect observed in vitro. Taken together, this work identifies SPA as a novel potential pharmacological agent able to control insulin secretion and glucose homeostasis.
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- 2016
14. Fischer 344 Rat: A Preclinical Model for Epithelial Ovarian Cancer Folate-Targeted Therapy
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Nacim Betrouni, Céline Frochot, Meryem Tardivel, Caroline Bonner, Gurvan Queniat, Pierre Collinet, Gulim Jetpisbayeva, Serge Mordon, Olivier Kerdraon, Henri Azaïs, Thérapies Laser Assistées par l'Image pour l'Oncologie - U 1189 (ONCO-THAI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut Européen de Génomique du Diabète - European Genomic Institute for Diabetes - FR 3508 (EGID), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Centre de Biologie Pathologie, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Plateforme BioImaging Center Lille (BICeL), Plateformes Lilloises en Biologie et Santé - UAR 2014 - US 41 (PLBS), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Réactions et Génie des Procédés (LRGP), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), European Genomic Institute for Diabetes (EGID), Faculté de Médecine-Université de Lille, Droit et Santé, Plate-forme d'imagerie cellulaire BICEL-IFR 114, Pôle Recherche, University of Lille, Lille, Thérapies Laser Assistées par l'Image pour l'Oncologie (ONCO-THAI), and MORDON, SERGE
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Pathology ,medicine.medical_specialty ,medicine.medical_treatment ,Fluorescent Antibody Technique ,Ovary ,Apoptosis ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Carcinoma, Ovarian Epithelial ,Targeted therapy ,Immunoenzyme Techniques ,Peritoneal Neoplasm ,Peritoneal cavity ,Folic Acid ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,Tumor Cells, Cultured ,Medicine ,Animals ,Humans ,Folate Receptor 1 ,Neoplasms, Glandular and Epithelial ,Peritoneal Neoplasms ,Cell Proliferation ,Ovarian Neoplasms ,Photosensitizing Agents ,business.industry ,Obstetrics and Gynecology ,medicine.disease ,Xenograft Model Antitumor Assays ,Rats, Inbred F344 ,3. Good health ,Rats ,Disease Models, Animal ,medicine.anatomical_structure ,Oncology ,Folate receptor ,Immunohistochemistry ,Female ,Folate receptor 1 ,business ,Ovarian cancer - Abstract
ObjectiveOvarian cancer prognosis remains dire after primary therapy. Recurrence rates are disappointingly high as 60% of women with advanced epithelial ovarian cancer considered in remission will develop recurrent disease within 5 years. Special attention to undetected peritoneal metastasis and residual tumorous cells during surgery is necessary as they are the main predictive factors of recurrences. Folate receptor α (FRα) shows promising prospects in targeting ovarian cancerous cells. Our aim was to determine if the Fischer model described by Rose et al could be used to evaluate folate-targeted therapies in preclinical studies.MethodsNuTu-19 epithelial ovarian cancer cell line was used to induce peritoneal carcinomatosis in female Fischer 344 rats. FRα expression by NuTu-19 cells was assessed in vitro by immunofluorescence using “Cytospin®” protocol. In vitro folate-targeted compound uptake by NuTu-19 cells was evaluated by incubation of FRα-positive ovarian cancer cell lines (NuTu-19/SKOV-3/OVCAR-3/IGROV-1) with or without (control) a folate-targeted photosensitizer. Intracellular incorporation was assessed by confocal microscopy. Determination of in vivo FRα tissue expression by several organs of the peritoneal cavity was studied by immunohistochemistry.ResultsNuTu-19 cells express FRα which allows intracellular incorporation of folate-targeted compound by endocytosis. FRα is expressed in tumor tissue, ovary, and liver. Peritoneum, colon, small intestine, and kidney do not express the receptor.ConclusionsFemale Fischer 344 rat is an inexpensive reproducible and efficient preclinical model to study ovarian peritoneal carcinomatosis folate-targeted therapies.
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- 2015
15. Contribution of the low-frequency, loss-of-function p.R270H mutation in FFAR4 (GPR120) to increased fasting plasma glucose levels
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Claire Levy-Marchal, Serge Hercberg, Jacques Weill, Pilar Galan, Michel Marre, Amélie Bonnefond, Philippe Froguel, Amel Lamri, Emmanuel Vaillant, Stéphanie Ragot, Audrey Leloire, Frédéric Fumeron, Beverley Balkau, Samy Hadjadj, Ronan Roussel, Guillaume Charpentier, Université de Lille, Institut Européen de Génomique du Diabète - European Genomic Institute for Diabetes - FR 3508 (EGID), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), McMaster University, Institut National de la Santé et de la Recherche Médicale (INSERM), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), Service de Diabétologie-Endocrinologie-Nutrition, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Centre Hospitalier Universitaire de Lille (CHU de Lille), Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Centre Hospitalier Sud Francilien, Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Endocrinologie Diabétologie et Nutrition, Hôpital Edourad Herriot, Imperial College London, Centre National de la Recherche Scientifique (CNRS), Inserm, European Genomic Institute of Diabetes (EGID), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), EGID, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), and École pratique des hautes études (EPHE)
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Blood Glucose ,Male ,medicine.medical_specialty ,[SDV]Life Sciences [q-bio] ,030209 endocrinology & metabolism ,Type 2 diabetes ,Biology ,Receptors, G-Protein-Coupled ,03 medical and health sciences ,0302 clinical medicine ,Insulin resistance ,Gene Frequency ,Internal medicine ,Diabetes mellitus ,Genetics ,medicine ,Humans ,Point Mutation ,Genetics (clinical) ,030304 developmental biology ,2. Zero hunger ,0303 health sciences ,GPR120 ,Fasting ,Glucose Tolerance Test ,medicine.disease ,Impaired fasting glucose ,Obesity ,Endocrinology ,Diabetes Mellitus, Type 2 ,Case-Control Studies ,Female ,Body mass index ,Homeostasis - Abstract
International audience; Background We previously reported that the low-frequency, loss-of-function variant p.R270H in FFAR4 encoding the lipid sensor GPR120 was associated with obesity. Gpr 120-deficient mice develop obesity and both impaired fasting glucose and glucose intolerance under a high-fat diet. We aimed to assess the contribution of p.R270H to type 2 diabetes (T2D) risk and the variation of glucose-related traits. Methods We genotyped p.R270H in 8996 nondiabetic individuals (among whom 4523 had an oral glucose tolerance test (OGTT)) and in a T2D case-control study including 4725 cases and 4339 controls. The regression models were adjusted for age, sex and body mass index (BMI). Results We found a significant association between p.R270H and increased fasting glucose levels (beta=0.092 +/- 0.05 mmol/L; p=4.13x10(-4)). Furthermore, p.R270H nominally contributed to decreased homeostasis model of pancreatic beta-cell function (HOMA-B; beta=-0.090 +/- 0.06; p=6.01x10(-3)). Despite a high statistical power, we did not find any significant association between p.R270H and T2D risk or the variation of fasting insulin levels, the homeostasis model of insulin resistance or OGTT-derived indices. Conclusions These results suggest that the low-frequency p.R270H variant which inhibits GPR120 activity might influence fasting glucose levels in a normal physiological range. This study does not exclude that other coding mutations in FFAR4 with stronger functional effect than p.R270H may be associated with T2D.
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- 2015
16. Etude de la voie des kynurénines dans l'obésité humaine
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Favennec, Marie, STAR, ABES, European Genomic Institute for Diabetes (EGID), Faculté de Médecine-Université de Lille, Droit et Santé, Université du Droit et de la Santé - Lille II, and Odile Poulain-Godefroy
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Kynurénines ,[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology ,Tryptophan ,Obesity ,Obésité ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology ,Kynurenine ,Tryptophane ,Diabète de type 2 - Abstract
Tryptophan, an essential amino acid, is either used in protein synthesis or metabolized via the serotonin or the kynurenine pathway. The kynurenine pathway is the main route of tryptophan degradation and generates several metabolites collectively called “kynurenines”. The expression of kynurenine pathway enzymes is induced by inflammatory mediators. Consequently kynurenine synthesis could be induced in individuals with obesity. In fact, obesity is characterized by a chronic low grade inflammation of the adipose tissue reflected by increased serum levels of inflammatory factors which are known to contribute to the development of obesity-induced insulino-resistance. Some metabolites of the kynurenine pathway have been proposed to be risk factors for the development of insulin resistance. Bariatric surgery is currently the most effective treatment for severe obesity and results in a significant weight loss, a decreased level of inflammatory factors and an amelioration of glucose homeostasis. The first enzyme of the kynurenine pathway, IDO1, is known to be more expressed in the adipose tissue of individuals with obesity compared to lean individuals. The kynurenine over tryptophan ratio reflects the activity of IDO1 and is also increased in individuals with obesity.Our objective was to characterize the expression of the kynurenine pathway enzymes in the adipose tissue of women with severe obesity and to evaluate serum levels of the kynurenine pathway metabolites to determine whether these factors could be associated with the appearance of diabetes. This study was performed in women with severe obesity with or without type 2 diabetes. Then we investigated the consequences of weight loss induced by bariatric surgery on levels of circulating kynurenines in order to evaluate whether these variations could explain the improvement in glucose control and type 2 diabetes remission after one year follow-up.In this study, we have shown that several kynurenine pathway enzymes were more expressed in the adipose tissue of women with obesity compared to lean controls. This increase is due to the presence of pro-inflammatory macrophages in the adipose tissue and also comes from the adipocyte response to inflammatory stimuli. In addition, we observed that the serum level of kynurenine and kynurenine over tryptophan ratio are higher in women with higher BMI and they both decrease one year after bariatric surgery. In addition, we observed that the serum level of kynurenine and kynurenine over tryptophan ratio are higher in women with higher BMI and they both decrease one year after bariatric surgery. As expected, bariatric surgery is associated with the improvement and even the remission of type 2 diabetes. We have shown that higher levels of kynurenic acid and quinolinic acid one year after the surgery are associated respectively with type 2 diabetes remission and better glucose homeostasis and that lower levels of xanthurenic acid are associated with better glucose homeostasis., Le tryptophane, un acide aminé essentiel, est soit utilisé pour la synthèse protéique et la synthèse de sérotonine, soit dégradé en plusieurs métabolites appelés collectivement les kynurénines. L’expression et l’activité des enzymes de la voie des kynurénines sont stimulées par l’inflammation. La synthèse des kynurénines est donc susceptible d’être augmentée chez les individus obèses. En effet, l’obésité est caractérisée par une inflammation chronique à bas bruit du tissu adipeux, reflétée par l’augmentation de facteurs inflammatoires circulants qui contribuent à l’apparition de l’insulinorésistance et du diabète de type 2. Plusieurs métabolites de la voie des kynurénines pourraient être des facteurs de risque pour le développement de l’insulinorésistance. La chirurgie bariatrique est actuellement le traitement le plus efficace pour l’obésité sévère, elle permet une perte de poids significative ainsi qu’une diminution des facteurs inflammatoires circulantes et une amélioration de l’insulinorésistance et du diabète. Il a été démontré que l’expression d’IDO1, la première enzyme de la voie des kynurénines, est plus élevée dans le tissu adipeux des individus obèses. Le ratio kynurénine sur tryptophane, qui reflète l’activité D’IDO1, est également augmenté chez les individus obèses.Notre objectif a été de caractériser l’expression des enzymes de la voie des kynurénines dans le tissu adipeux et d’évaluer les concentrations des kynurénines dans les sérums de patientes obèses pour rechercher si certains de ces facteurs pouvaient être reliés à l’apparition du diabète. Ces études ont été réalisées dans une cohorte de femmes obèses normoglycémiques et diabétiques. Puis dans un second temps nous avons étudié les conséquences de la perte de poids induite par la chirurgie bariatrique sur les concentrations circulantes des kynurénines et évalué si les variations des concentrations des kynurénines pourraient expliquer en partie l’amélioration du diabète observée après la chirurgie.Dans cette étude, nous avons montré que plusieurs enzymes de la voie sont plus exprimées dans le tissu adipeux des individus obèses que des minces. L’augmentation de l’expression des enzymes dans le tissu adipeux des individus obèses provient d’une part de la présence de macrophages pro-inflammatoires dans le tissu adipeux et également de la réponse des adipocytes aux stimuli pro-inflammatoires. En parallèle, nous avons montré que les concentrations circulantes des kynurénines et le ratio kynurénine sur tryptophane augmentent avec l’IMC et qu’ils diminuent un an après la chirurgie bariatrique. Dans notre étude, comme attendu, la chirurgie bariatrique est associée à une amélioration voire à une rémission du diabète. Nous avons montré également que le maintien des concentrations d’acide kynurénique et d’acide quinolinique sont associés respectivement à la rémission du diabète et à l’amélioration des traits cliniques qui définissent le diabète. La diminution des concentrations en acide xanthurénique après la chirurgie est associée au contraire à une amélioration des traits cliniques qui définissent le diabète.
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- 2015
17. CD3bright signals on γδ T cells identify IL-17A-producing Vγ6Vδ1+ T cells
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François Trottein, Adam P Uldrich, Thierry Mallevaey, Christophe Paget, Paul J Neeson, Dale I. Godfrey, Geoffrey R. Hill, N. A. Gherardin, Paul A. Beavis, David Dombrowicz, Delphine Staumont-Sallé, Maya Hassane, Denis A. Mogilenko, N. K. Escalante, Mark J. Smyth, Fernando Souza-Fonseca-Guimaraes, Melvyn T. Chow, Helene Duret, David Ritchie, Gabrielle T. Belz, Derudas, Marie-Hélène, Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Cancer immunology program, Peter MacCallum Cancer Center, Sir Peter MacCallum Department of Oncology and Department of Pathology, University of Melbourne, Department of Microbiology and Immunology, QIMR Berghofer Medical Research Institute, Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), European Genomic Institute of Diabetes (EGID), Service de dermatologie, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Department of Immunology, University of Toronto, Department of Bone Marrow Transplantation, Royal Brisbane Hospital, Division of Molecular Immunology, The Walter and Eliza Hall Institute of Medical Research (WEHI), School of Medicine, University of Queensland [Brisbane], his work was supported by an NHMRC Program Grant (454569 and 1013367). CP was supported by a postdoctoral fellowship from the US Department of Defense (W81XWH‐11‐1‐0585) and INSERM. MJS and FSFG were supported by a National Health and Medical Research Council of Australia (NHMRC) Australia Fellowship and Program Grant (1013367). MTC was supported by a Cancer Research Institute PhD scholarship. GTB was supported by an ARC Future Fellowship. FT was supported by CNRS. PN was supported by a National Health and Medical Research Council of Australia (NHMRC) Program Grant (1013367). DIG was supported by an NHMRC Senior Principal Research Fellowship (1020770). NAG was supported by a Leukaemia Foundation of Australia postgraduate scholarship. TM is supported by research grants from the Canadian Institutes of Health Research and the Crohn and Colitis Foundation of Canada, as well as a Tier 2 Canada Research Chair. NKE is a recipient of a Vanier Canada Graduate Scholarship. DAM, DS‐S and DD were supported by the Agence Nationale de la Recherche (ANR‐10‐LABX‐46) and the ‘Fondation de France’., We thank Josette Fontaine, Shin‐Foong Ngiow, Deborah Knight, Sébastien Fleury, Julien Wartelle and Kim Steegh for technical assistance. We thank Qerime Mundrea, Ben Venville, Jessica May, Joanne Sutton and Liam Town for maintaining and caring for the mice. We also thank the Peter MacCallum flow cytometry core facility for technical assistance., Institut Européen de Génomique du Diabète - European Genomic Institute for Diabetes - FR 3508 (EGID), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM)
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Male ,CD3 Complex ,Inflammasomes ,T-Lymphocytes ,Interleukin-1beta ,MESH: Amino Acid Sequence ,MESH: Interleukin-1beta/metabolism ,Interleukin-23 ,MESH: Lung/drug effects ,MESH: Skin/immunology ,MESH: Lung/immunology ,MESH: CD3 Complex/chemistry ,MESH: Lymphocyte Subsets/immunology ,Immunology and Allergy ,Homeostasis ,MESH: Animals ,IL-2 receptor ,MESH: Homeostasis/drug effects ,Lung ,MESH: Immunity ,Skin ,MESH: Interleukin-23 ,Orphan receptor ,education.field_of_study ,Imiquimod ,biology ,MESH: Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism ,Interleukin-17 ,Receptors, Antigen, T-Cell, gamma-delta ,MESH: T-Lymphocytes/immunology ,Nuclear Receptor Subfamily 1, Group F, Member 3 ,MESH: CD3 Complex/metabolism ,3. Good health ,MESH: NLR Family, Pyrin Domain-Containing 3 Protein ,medicine.anatomical_structure ,Phenotype ,MESH: Aminoquinolines/pharmacology ,MESH: Carrier Proteins/metabolism ,Aminoquinolines ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,MESH: Interleukin-17/biosynthesis ,[SDV.IMM] Life Sciences [q-bio]/Immunology ,MESH: Skin/drug effects ,CD3 ,T cell ,MESH: T-Lymphocytes/drug effects ,Immunology ,Population ,Molecular Sequence Data ,MESH: Germ Cells/drug effects ,MESH: Imiquimod ,MESH: Phenotype ,Immune system ,Antigen ,MESH: Mice, Inbred C57BL ,NLR Family, Pyrin Domain-Containing 3 Protein ,MESH: Inflammasomes/drug effects ,medicine ,Animals ,Amino Acid Sequence ,education ,MESH: Molecular Sequence Data ,Innate immune system ,MESH: Inflammasomes/metabolism ,Immunity ,Cell Biology ,MESH: Lymphocyte Subsets/drug effects ,MESH: Male ,Lymphocyte Subsets ,Mice, Inbred C57BL ,Germ Cells ,MESH: Receptors, Antigen, T-Cell, gamma-delta/metabolism ,biology.protein ,Carrier Proteins - Abstract
International audience; Interleukin-17A (IL-17A) is a pro-inflammatory cytokine that has an important role at mucosal sites in a wide range of immune responses including infection, allergy and auto-immunity. γδ T cells are recognized as IL-17 producers, but based on the level of CD3 expression, we now define the remarkable ability of a CD3(bright) γδ T-cell subset with an effector memory phenotype to rapidly produce IL-17A, but not interferon-γ. CD3(bright) γδ T cells uniformly express the canonical germline encoded Vγ6/Vδ1(+) T-cell receptor. They are widely distributed with a preferential representation in the lungs and skin are negatively impacted in the absence of retinoic acid receptor-related orphan receptor gammat expression or endogenous flora. This population responded rapidly to various stimuli in a mechanism involving IL-23 and NOD-like receptor family, pyrin domain containing 3 (NLRP3)-inflammasome-dependent IL-1β. Finally, we demonstrated that IL-17-producing CD3(bright) γδ T cells responded promptly and strongly to pneumococcal infection and during skin inflammation. Here, we propose a new way to specifically analyze IL-17-producing Vγ6/Vδ1(+) T cells based on the level of CD3 signals. Using this gating strategy, our data reinforce the crucial role of this γδ T-cell subset in respiratory and skin disorders.
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- 2014
18. Low copy number of the salivary amylase gene predisposes to obesity
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Michel Marre, Peter H. Sudmant, Peter Jacobson, Jeannette Lee, Erdal Ozdemir, Mashael Al-Shafai, Philippe Froguel, Odile Poulain-Godefroy, Ruth McPherson, Evan E. Eichler, Hon-Cheong So, Violeta Raverdy, Julia S. El-Sayed Moustafa, Jacques Weill, Emmanuel Vaillant, François Pattou, Francesco Pesce, Panos Deloukas, Johanna C. Andersson-Assarsson, Petros Takousis, Robert Dent, Amélie Bonnefond, Andrew Walley, Leonardo Bottolo, Pirro G. Hysi, Marlène Huyvaert, Massimo Mangino, Robert Sladek, Christopher J Hammond, Lena M. S. Carlsson, Robert W. Davies, Jane Skinner, Rajkumar Dorajoo, Robert Caiazzo, Lars Sjöström, Pak C. Sham, Aurélie Dechaume, Tim D. Spector, E. Shyong Tai, Marie Pigeyre, Sarah Field, Alexandre Patrice, Beverley Balkau, Mario Falchi, Sophie Visvikis-Siest, Department of Genomics of Common Disease [London, UK], Imperial College London-Hammersmith Hospital NHS Imperial College Healthcare, Università degli studi di Bari Aldo Moro = University of Bari Aldo Moro (UNIBA), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Qatar Biomedical Research Institute (QBRI), Institut Européen de Génomique du Diabète - European Genomic Institute for Diabetes - FR 3508 (EGID), Sahlgrenska Academy at University of Gothenburg [Göteborg], University of Washington [Seattle], Genome Institute of Singapore (GIS), Qatar Foundation, Institute for Mathematical Sciences, Imperial College London, City University of Hong Kong [Hong Kong] (CUHK), University of Ottawa Heart Institute, University of Ottawa [Ottawa], Recherche translationnelle sur le diabète - U 1190 (RTD), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), The Ottawa Hospital, Department of Twin Research and Genetic Epidemiology, King's College London, London, Norwich Medical School, University of East Anglia [Norwich] (UEA), The Wellcome Trust Sanger Institute [Cambridge], Epidémiologie cardiovasculaire et métabolique, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'endocrinologie, diabétologie et nutrition [CHU Bichat], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Déterminants génétiques du diabète de type 2 et de ses complications vasculaires ((U 695)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Interactions Gène-Environnement en Physiopathologie Cardio-Vasculaire (IGE-PCV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Service d'endocrinologie pédiatrique [CHU Lille], Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), William Harvey Research Institute, Barts and the London Medical School, Princess Al-Jawhara AlBrahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, The Chinese University of Hong Kong [Hong Kong], National University of Singapore (NUS), Duke-National University of Singapore Graduate Medical School, Department of Human Genetics [Montréal], McGill University = Université McGill [Montréal, Canada], Department of Medecine [Montréal], McGill University and Genome Quebec Innovation Centre, National Heart & Lung Institute, Howard Hughes Medical Institute [Seattle], Howard Hughes Medical Institute (HHMI), University of Bari Aldo Moro (UNIBA), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M), European Genomic Institute for Diabetes (EGID), Faculté de Médecine-Université de Lille, Droit et Santé, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), 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), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), UL, IGEPCV, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur de Lille, and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)
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Gene Dosage ,Biology ,[SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics ,Gene dosage ,Medical and Health Sciences ,Body Mass Index ,Gene mapping ,Gene cluster ,Genetics ,Odds Ratio ,Humans ,Genetic Predisposition to Disease ,Copy-number variation ,Amylase ,Obesity ,Genetic association ,Cancer ,2. Zero hunger ,Genomics ,Biological Sciences ,Microarray Analysis ,[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics ,Salivary alpha-Amylases ,biology.protein ,Carbohydrate Metabolism ,Low copy number ,Overlapping gene ,Developmental Biology - Abstract
International audience; Common multi-allelic copy number variants (CNVs) appear enriched for phenotypic associations compared to their biallelic counterparts1,2,3,4. Here we investigated the influence of gene dosage effects on adiposity through a CNV association study of gene expression levels in adipose tissue. We identified significant association of a multi-allelic CNV encompassing the salivary amylase gene (AMY1) with body mass index (BMI) and obesity, and we replicated this finding in 6,200 subjects. Increased AMY1 copy number was positively associated with both amylase gene expression (P = 2.31 × 10−14) and serum enzyme levels (P < 2.20 × 10−16), whereas reduced AMY1 copy number was associated with increased BMI (change in BMI per estimated copy = −0.15 (0.02) kg/m2; P = 6.93 × 10−10) and obesity risk (odds ratio (OR) per estimated copy = 1.19, 95% confidence interval (CI) = 1.13–1.26; P = 1.46 × 10−10). The OR value of 1.19 per copy of AMY1 translates into about an eightfold difference in risk of obesity between subjects in the top (copy number > 9) and bottom (copy number < 4) 10% of the copy number distribution. Our study provides a first genetic link between carbohydrate metabolism and BMI and demonstrates the power of integrated genomic approaches beyond genome-wide association studies.
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- 2014
19. Peroxisome proliferator-activated receptor γ regulates genes involved in insulin/insulin-like growth factor signaling and lipid metabolism during adipogenesis through functionally distinct enhancer classes
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Oger, Frederik, Dubois-Chevalier, Julie, Gheeraert, Celine, Avner, Stephane, Durand, Emmanuel, Froguel, Philippe, Salbert, Gilles, Staels, Bart, Lefebvre, Philippe, Eeckhoute, Jerome, Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), European Genomic Institute for Diabetes (EGID), Faculté de Médecine-Université de Lille, Droit et Santé, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), and Derudas, Marie-Hélène
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Epigenomics ,MESH: Signal Transduction ,MESH: Insulin ,chromatin modification ,Transcrip tion regulation ,MESH: Reverse Transcriptase Polymerase Chain Reaction ,DNA methylat ion ,MESH: Gene Expression Regulation, Developmental ,[SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology ,MESH: Protein Binding ,MESH: Animals ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,MESH: Somatomedins ,MESH: Mice ,insulin/insulin-like growth factor signalling ,MESH: Adipocytes ,MESH: Lipid Metabolism ,MESH: Chromatin Immunoprecipitation ,Adipogenesis ,MESH: Muscle Fibers, Skeletal ,MESH: Transcriptome ,MESH: 3T3-L1 Cells ,MESH: Cell Line ,MESH: PPAR gamma ,Peroxisome proliferator-activated receptor (PPAR) ,MESH: Enhancer Elements, Genetic ,MESH: Adipogenesis ,Transcription enhancers - Abstract
International audience; The nuclear receptor peroxisome proliferator-activated receptor (PPAR) is a transcription factor whose expression is induced during adipogenesis and that is required for the acquisition and control of mature adipocyte functions. Indeed, PPAR induces the expression of genes involved in lipid synthesis and storage through enhancers activated during adipocyte differentiation. Here, we show that PPAR also binds to enhancers already active in preadipocytes as evidenced by an active chromatin state including lower DNA methylation levels despite higher CpG content. These constitutive enhancers are linked to genes involved in the insulin/insulin-like growth factor signaling pathway that are transcriptionally induced during adipogenesis but to a lower extent than lipid metabolism genes, because of stronger basal expression levels in preadipocytes. This is consistent with the sequential involvement of hormonal sensitivity and lipid handling during adipocyte maturation and correlates with the chromatin structure dynamics at constitutive and activated enhancers. Interestingly, constitutive enhancers are evolutionary conserved and can be activated in other tissues, in contrast to enhancers controlling lipid handling genes whose activation is more restricted to adipocytes. Thus, PPAR utilizes both broadly active and cell type-specific enhancers to modulate the dynamic range of activation of genes involved in the adipogenic process.
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- 2014
20. LXR controls macrophage iron metabolism
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Mehdi Daoudi, Gael Bories, Sophie Colin, Bruno Derudas, Bart Staels, Stéphan Haulon, Brigitte Jude, Corinne Copin, Mélanie Fanchon, Loic Belloy, Christophe Zawadzki, Jonathan Vanhoutte, Giulia Chinetti-Gbaguidi, Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut Européen du Diabète (EGID), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université de Lille, Droit et Santé, and Grants from the Région Nord-Pas de Calais/FEDER (CPER N. 1449), the Agence Nationale de la Recherche, France (AlMHA project), the Fondation de France, the Fondation pour la Recherche Médicale, the transatlantic Leducq HDL Network, the 'European Genomic Institute for Diabetes' (EGID, ANR-10-LABX-46)
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Apolipoprotein E ,Physiology ,Ferroportin ,030204 cardiovascular system & hematology ,0302 clinical medicine ,Homeostasis ,Macrophage ,MESH: Antigens, Differentiation, Myelomonocytic ,MESH: Antigens, CD ,Cells, Cultured ,ATP Binding Cassette Transporter, Subfamily G, Member 1 ,Liver X Receptors ,MESH: Receptors, Cell Surface ,0303 health sciences ,MESH: Iron ,biology ,CD68 ,Orphan Nuclear Receptors ,MESH: Apolipoproteins E ,Plaque, Atherosclerotic ,Cell biology ,Phenotype ,Biochemistry ,MESH: Orphan Nuclear Receptors ,MESH: Homeostasis ,MESH: ATP-Binding Cassette Transporters ,Cardiology and Cardiovascular Medicine ,Mannose Receptor ,Mannose receptor ,ATP Binding Cassette Transporter 1 ,MESH: Cells, Cultured ,Iron ,MESH: Biological Transport ,Antigens, Differentiation, Myelomonocytic ,Receptors, Cell Surface ,In Vitro Techniques ,MESH: Phenotype ,Article ,03 medical and health sciences ,Apolipoproteins E ,Antigens, CD ,Hepcidin ,MESH: Mannose-Binding Lectins ,Humans ,Lectins, C-Type ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,MESH: ATP Binding Cassette Transporter 1 ,MESH: Plaque, Atherosclerotic ,Liver X receptor ,030304 developmental biology ,MESH: Humans ,Macrophages ,MESH: Macrophages ,Biological Transport ,Mannose-Binding Lectins ,Nuclear receptor ,biology.protein ,ATP-Binding Cassette Transporters ,MESH: Lectins, C-Type - Abstract
Rationale: In atherosclerotic plaques, iron preferentially accumulates in macrophages where it can exert pro-oxidant activities. Objective: The objective of this study was, first, to better characterize the iron distribution and metabolism in macrophage subpopulations in human atherosclerotic plaques and, second, to determine whether iron homeostasis is under the control of nuclear receptors, such as the liver X receptors (LXRs). Methods and Results: Here we report that iron depots accumulate in human atherosclerotic plaque areas enriched in CD68 and mannose receptor (MR)-positive (CD68 + MR + ) alternative M2 macrophages. In vitro IL-4 polarization of human monocytes into M2 macrophages also resulted in a gene expression profile and phenotype favoring iron accumulation. However, M2 macrophages on iron exposure acquire a phenotype favoring iron release, through a strong increase in ferroportin expression, illustrated by a more avid oxidation of extracellular low-density lipoprotein by iron-loaded M2 macrophages. In line, in human atherosclerotic plaques, CD68 + MR + macrophages accumulate oxidized lipids, which activate LXRα and LXRβ, resulting in the induction of ABCA1, ABCG1, and apolipoprotein E expression. Moreover, in iron-loaded M2 macrophages, LXR activation induces nuclear factor erythroid 2-like 2 expression, thereby increasing ferroportin expression, which, together with a decrease of hepcidin mRNA levels, promotes iron export. Conclusions: These data identify a role for M2 macrophages in iron handling, a process regulated by LXR activation.
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- 2013
21. Liver X receptor activation stimulates iron export in human alternative macrophages
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Bories, Gael, Colin, Sophie, Vanhoutte, Jonathan, Derudas, Bruno, Copin, Corinne, Fanchon, Melanie, Daoudi, Mehdi, Belloy, Loic, Haulon, Stephan, Zawadzki, Christophe, Jude, Brigitte, Staels, Bart, Chinetti-Gbaguidi, Giulia, Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut Européen de Génomique du Diabète - European Genomic Institute for Diabetes - FR 3508 (EGID), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université de Lille, Droit et Santé, Grants from the Région Nord-Pas de Calais/FEDER (CPER N. 1449), the Agence Nationale de la Recherche, France (AlMHA project), the Fondation de France, the Fondation pour la Recherche Médicale, the transatlantic Leducq HDL Network, the 'European Genomic Institute for Diabetes' (EGID, ANR-10-LABX-46), Institut Européen du Diabète (EGID), and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)
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MESH: Iron ,MESH: Humans ,MESH: Biological Transport ,MESH: Macrophages ,MESH: Phenotype ,MESH: Apolipoproteins E ,MESH: Orphan Nuclear Receptors ,MESH: Homeostasis ,MESH: Mannose-Binding Lectins ,MESH: ATP-Binding Cassette Transporters ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,MESH: ATP Binding Cassette Transporter 1 ,MESH: Plaque, Atherosclerotic ,MESH: Antigens, Differentiation, Myelomonocytic ,MESH: Antigens, CD ,MESH: Lectins, C-Type ,MESH: Receptors, Cell Surface ,MESH: Cells, Cultured - Abstract
International audience; RATIONALE: In atherosclerotic plaques, iron preferentially accumulates in macrophages where it can exert pro-oxidant activities. OBJECTIVE: The objective of this study was, first, to better characterize the iron distribution and metabolism in macrophage subpopulations in human atherosclerotic plaques and, second, to determine whether iron homeostasis is under the control of nuclear receptors, such as the liver X receptors (LXRs). METHODS AND RESULTS: Here we report that iron depots accumulate in human atherosclerotic plaque areas enriched in CD68 and mannose receptor (MR)-positive (CD68(+)MR(+)) alternative M2 macrophages. In vitro IL-4 polarization of human monocytes into M2 macrophages also resulted in a gene expression profile and phenotype favoring iron accumulation. However, M2 macrophages on iron exposure acquire a phenotype favoring iron release, through a strong increase in ferroportin expression, illustrated by a more avid oxidation of extracellular low-density lipoprotein by iron-loaded M2 macrophages. In line, in human atherosclerotic plaques, CD68(+)MR(+) macrophages accumulate oxidized lipids, which activate LXRα and LXRβ, resulting in the induction of ABCA1, ABCG1, and apolipoprotein E expression. Moreover, in iron-loaded M2 macrophages, LXR activation induces nuclear factor erythroid 2-like 2 expression, thereby increasing ferroportin expression, which, together with a decrease of hepcidin mRNA levels, promotes iron export. CONCLUSIONS: These data identify a role for M2 macrophages in iron handling, a process regulated by LXR activation.
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- 2013
22. Genetics brings new insight to β-cell function.
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Bonnefond A and Froguel P
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- 2024
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23. First fragment-based screening identifies new chemotypes inhibiting ERAP1-metalloprotease.
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Fougiaxis V, Barcherini V, Petrovic MM, Sierocki P, Warenghem S, Leroux F, Bou Karroum N, Petit-Cancelier F, Rodeschini V, Roche D, Deprez B, and Deprez-Poulain R
- Abstract
Inhibition of endoplasmic reticulum aminopeptidase 1 (ERAP1) by small-molecules is being eagerly investigated for the treatment of various autoimmune diseases and in the field of immuno-oncology after its active involvement in antigen presentation and processing. Currently, ERAP1 inhibitors are at different stages of clinical development, which highlights its significance as a promising drug target. In the present work, we describe the first-ever successful identification of several ERAP1 inhibitors derived from a fragment-based screening approach. We applied an enzymatic activity assay to a large library of ∼3000 fragment entries in order to retrieve 32 hits. After a multi-faceted selection process, we prioritized 3 chemotypes for SAR optimization and strategic modifications provided 2 series (2-thienylacetic acid and rhodanine scaffolds) with improved analogues at the low micromolar range of ERAP1 inhibition. We report also evidence of selectivity against homologous aminopeptidase IRAP, combined with complementary in silico docking studies to predict the binding mode and site of inhibition. Our compounds can be the starting point for future fragment growing and rational drug development, incorporating new chemical modalities., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Rebecca Deprez-Poulain reports financial support was provided by European Commission. Vasileios Fougiaxis reports financial support was provided by European Commission. Rebecca Deprez-Poulain reports financial support was provided by French National Research Agency. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
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- 2024
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24. Obesity: exploring its connection to brain function through genetic and genomic perspectives.
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Saeed S, Bonnefond A, and Froguel P
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Obesity represents an escalating global health burden with profound medical and economic impacts. The conventional perspective on obesity revolves around its classification as a "pure" metabolic disorder, marked by an imbalance between calorie consumption and energy expenditure. Present knowledge, however, recognizes the intricate interaction of rare or frequent genetic factors that favor the development of obesity, together with the emergence of neurodevelopmental and mental abnormalities, phenotypes that are modulated by environmental factors such as lifestyle. Thirty years of human genetic research has unveiled >20 genes, causing severe early-onset monogenic obesity and ~1000 loci associated with common polygenic obesity, most of those expressed in the brain, depicting obesity as a neurological and mental condition. Therefore, obesity's association with brain function should be better recognized. In this context, this review seeks to broaden the current perspective by elucidating the genetic determinants that contribute to both obesity and neurodevelopmental and mental dysfunctions. We conduct a detailed examination of recent genetic findings, correlating them with clinical and behavioral phenotypes associated with obesity. This includes how polygenic obesity, influenced by a myriad of genetic variants, impacts brain regions associated with addiction and reward, differentiating it from monogenic forms. The continuum between non-syndromic and syndromic monogenic obesity, with evidence from neurodevelopmental and cognitive assessments, is also addressed. Current therapeutic approaches that target these genetic mechanisms, yielding improved clinical outcomes and cognitive advantages, are discussed. To sum up, this review corroborates the genetic underpinnings of obesity, affirming its classification as a neurological disorder that may have broader implications for neurodevelopmental and mental conditions. It highlights the promising intersection of genetics, genomics, and neurobiology as a foundation for developing tailored medical approaches to treat obesity and its related neurological aspects., (© 2024. The Author(s).)
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- 2024
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25. PNLIPRP1 hypermethylation in exocrine pancreas links type 2 diabetes and cholesterol metabolism.
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Maurin L, Marselli L, Boissel M, Ning L, Boutry R, Fernandes J, Suleiman M, De Luca C, Leloire A, Pascat V, Toussaint B, Amanzougarene S, Derhourhi M, Jörns A, Lenzen S, Pattou F, Kerr-Conte J, Canouil M, Marchetti P, Bonnefond A, Froguel P, and Khamis A
- Abstract
We postulated that T2D predisposes to exocrine pancreatic diseases through (epi)genetic mechanisms. We explored the methylome (methylationEPIC arrays) of the exocrine pancreas of 141 donors, assessing the impact of T2D. Epigenome-wide association study (EWAS) for T2D identified a hypermethylation in an enhancer of the Pancreatic-Lipase-Related-Protein 1 (PNLIPRP1) gene, associated with decreased PNLIPRP1 expression. PNLIPRP1 null variants (in 191K participants of the UKbiobank) associated with elevated glycemia and LDL-cholesterol. Mendelian Randomisation using 2.5M SNP OmniArrays in 111 donors evidenced that T2D was causal of PNLIPRP1 hypermethylation, which was causal for LDL-cholesterol. Further AR42J rat exocrine cell studies demonstrated that Pnliprp1 knockdown induced acinar-to-ductal metaplasia, a known pre-pancreatic cancer state, and increased cholesterol levels, reversible with statin. This (epi)genetic study suggests a role for PNLIPRP1 in human metabolism and on exocrine pancreas function with potential implications for pancreatic diseases., (© 2024 by the American Diabetes Association.)
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- 2024
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26. Characteristics and impact of infiltration of B-cells from systemic sclerosis patients in a 3D healthy skin model.
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Le Maître M, Guerrier T, Collet A, Derhourhi M, Meneboo JP, Toussaint B, Bonnefond A, Villenet C, Sebda S, Bongiovanni A, Tardivel M, Simon M, Jendoubi M, Daunou B, Largy A, Figeac M, Dubucquoi S, and Launay D
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- Humans, Female, Cell Communication immunology, Lymphocyte Activation immunology, Middle Aged, Male, Cells, Cultured, Transcriptome, Adult, Keratinocytes immunology, Keratinocytes metabolism, Cytokines metabolism, Scleroderma, Systemic immunology, Scleroderma, Systemic pathology, Scleroderma, Systemic metabolism, Fibroblasts immunology, Fibroblasts metabolism, Skin immunology, Skin pathology, Skin metabolism, B-Lymphocytes immunology, B-Lymphocytes metabolism, Coculture Techniques
- Abstract
Introduction: In systemic sclerosis (SSc), B-cells are activated and present in the skin and lung of patients where they can interact with fibroblasts. The precise impact and mechanisms of the interaction of B-cells and fibroblasts at the tissular level are poorly studied., Objective: We investigated the impact and mechanisms of B-cell/fibroblast interactions in cocultures between B-cells from patients with SSc and 3-dimensional reconstituted healthy skin model including fibroblasts, keratinocytes and extracellular matrix., Methods: The quantification and description of the B-cell infiltration in 3D cocultures were performed using cells imagery strategy and cytometry. The effect of coculture on the transcriptome of B-cells and fibroblasts was studied with bulk and single-cell RNA sequencing approaches. The mechanisms of this interaction were studied by blocking key cytokines like IL-6 and TNF., Results: We showed a significant infiltration of B-cells in the 3D healthy skin model. The amount but not the depth of infiltration was higher with B-cells from SSc patients and with activated B-cells. B-cell infiltrates were mainly composed of naïve and memory cells, whose frequencies differed depending on B-cells origin and activation state: infiltrated B-cells from patients with SSc showed an activated profile and an overexpression of immunoglobulin genes compared to circulating B-cells before infiltration. Our study has shown for the first time that activated B-cells modified the transcriptomic profile of both healthy and SSc fibroblasts, toward a pro-inflammatory (TNF and IL-17 signaling) and interferon profile, with a key role of the TNF pathway., Conclusion: B-cells and 3D skin cocultures allowed the modelization of B-cells infiltration in tissues observed in SSc, uncovering an influence of the underlying disease and the activation state of B-cells. We showed a pro-inflammatory effect on skin fibroblasts and pro-activation effect on infiltrating B-cells during coculture. This reinforces the role of B-cells in SSc and provide potential targets for future therapeutic approach in this disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Le Maître, Guerrier, Collet, Derhourhi, Meneboo, Toussaint, Bonnefond, Villenet, Sebda, Bongiovanni, Tardivel, Simon, Jendoubi, Daunou, Largy, Figeac, Dubucquoi and Launay.)
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- 2024
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27. Functional genetics reveals the contribution of delta opioid receptor to type 2 diabetes and beta-cell function.
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Meulebrouck S, Merrheim J, Queniat G, Bourouh C, Derhourhi M, Boissel M, Yi X, Badreddine A, Boutry R, Leloire A, Toussaint B, Amanzougarene S, Vaillant E, Durand E, Loiselle H, Huyvaert M, Dechaume A, Scherrer V, Marchetti P, Balkau B, Charpentier G, Franc S, Marre M, Roussel R, Scharfmann R, Cnop M, Canouil M, Baron M, Froguel P, and Bonnefond A
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- Humans, Male, Female, Middle Aged, Insulin metabolism, Insulin Secretion drug effects, Insulin Secretion genetics, Adult, Receptors, Opioid, delta metabolism, Receptors, Opioid, delta genetics, Diabetes Mellitus, Type 2 genetics, Diabetes Mellitus, Type 2 metabolism, Insulin-Secreting Cells metabolism
- Abstract
Functional genetics has identified drug targets for metabolic disorders. Opioid use impacts metabolic homeostasis, although mechanisms remain elusive. Here, we explore the OPRD1 gene (encoding delta opioid receptor, DOP) to understand its impact on type 2 diabetes. Large-scale sequencing of OPRD1 and in vitro analysis reveal that loss-of-function variants are associated with higher adiposity and lower hyperglycemia risk, whereas gain-of-function variants are associated with lower adiposity and higher type 2 diabetes risk. These findings align with studies of opium addicts. OPRD1 is expressed in human islets and beta cells, with decreased expression under type 2 diabetes conditions. DOP inhibition by an antagonist enhances insulin secretion from human beta cells and islets. RNA-sequencing identifies pathways regulated by DOP antagonism, including nerve growth factor, circadian clock, and nuclear receptor pathways. Our study highlights DOP as a key player between opioids and metabolic homeostasis, suggesting its potential as a therapeutic target for type 2 diabetes., (© 2024. The Author(s).)
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- 2024
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28. Heterogeneity of glycaemic phenotypes in type 1 diabetes.
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Fagherazzi G, Aguayo GA, Zhang L, Hanaire H, Picard S, Sablone L, Vergès B, Hamamouche N, Detournay B, Joubert M, Delemer B, Guilhem I, Vambergue A, Gourdy P, Hadjadj S, Velayoudom FL, Guerci B, Larger E, Jeandidier N, Gautier JF, Renard E, Potier L, Benhamou PY, Sola A, Bordier L, Bismuth E, Prévost G, Kessler L, Cosson E, and Riveline JP
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- Humans, Female, Male, Adult, Middle Aged, Cluster Analysis, Algorithms, Diabetes Mellitus, Type 1 blood, Blood Glucose metabolism, Phenotype, Glycated Hemoglobin metabolism
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Aims/hypothesis: Our study aims to uncover glycaemic phenotype heterogeneity in type 1 diabetes., Methods: In the Study of the French-speaking Society of Type 1 Diabetes (SFDT1), we characterised glycaemic heterogeneity thanks to a set of complementary metrics: HbA
1c , time in range (TIR), time below range (TBR), CV, Gold score and glycaemia risk index (GRI). Applying the Discriminative Dimensionality Reduction with Trees (DDRTree) algorithm, we created a phenotypic tree, i.e. a 2D visual mapping. We also carried out a clustering analysis for comparison., Results: We included 618 participants with type 1 diabetes (52.9% men, mean age 40.6 years [SD 14.1]). Our phenotypic tree identified seven glycaemic phenotypes. The 2D phenotypic tree comprised a main branch in the proximal region and glycaemic phenotypes in the distal areas. Dimension 1, the horizontal dimension, was positively associated with GRI (coefficient [95% CI]) (0.54 [0.52, 0.57]), HbA1c (0.39 [0.35, 0.42]), CV (0.24 [0.19, 0.28]) and TBR (0.11 [0.06, 0.15]), and negatively with TIR (-0.52 [-0.54, -0.49]). The vertical dimension was positively associated with TBR (0.41 [0.38, 0.44]), CV (0.40 [0.37, 0.43]), TIR (0.16 [0.12, 0.20]), Gold score (0.10 [0.06, 0.15]) and GRI (0.06 [0.02, 0.11]), and negatively with HbA1c (-0.21 [-0.25, -0.17]). Notably, socioeconomic factors, cardiovascular risk indicators, retinopathy and treatment strategy were significant determinants of glycaemic phenotype diversity. The phenotypic tree enabled more granularity than traditional clustering in revealing clinically relevant subgroups of people with type 1 diabetes., Conclusions/interpretation: Our study advances the current understanding of the complex glycaemic profile in people with type 1 diabetes and suggests that strategies based on isolated glycaemic metrics might not capture the complexity of the glycaemic phenotypes in real life. Relying on these phenotypes could improve patient stratification in type 1 diabetes care and personalise disease management., (© 2024. The Author(s).)- Published
- 2024
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29. ERAP Inhibitors in Autoimmunity and Immuno-Oncology: Medicinal Chemistry Insights.
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Fougiaxis V, He B, Khan T, Vatinel R, Koutroumpa NM, Afantitis A, Lesire L, Sierocki P, Deprez B, and Deprez-Poulain R
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- Animals, Humans, Autoimmune Diseases drug therapy, Autoimmune Diseases immunology, Autoimmunity drug effects, Chemistry, Pharmaceutical, Protease Inhibitors pharmacology, Protease Inhibitors chemistry, Protease Inhibitors therapeutic use, Histocompatibility Antigens Class I, Aminopeptidases antagonists & inhibitors, Aminopeptidases metabolism, Minor Histocompatibility Antigens metabolism, Minor Histocompatibility Antigens immunology
- Abstract
Endoplasmic reticulum aminopeptidases ERAP1 and 2 are intracellular aminopeptidases that trim antigenic precursors and generate antigens presented by major histocompatibility complex class I (MHC-I) molecules. They thus modulate the antigenic repertoire and drive the adaptive immune response. ERAPs are considered as emerging targets for precision immuno-oncology or for the treatment of autoimmune diseases, in particular MHC-I-opathies. This perspective covers the structural and biological characterization of ERAP, their relevance to these diseases and the ongoing research on small-molecule inhibitors. We describe the chemical and pharmacological space explored by medicinal chemists to exploit the potential of these targets given their localization, biological functions, and family depth. Specific emphasis is put on the binding mode, potency, selectivity, and physchem properties of inhibitors featuring diverse scaffolds. The discussion provides valuable insights for the future development of ERAP inhibitors and analysis of persisting challenges for the translation for clinical applications.
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- 2024
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30. Proceedings of the annual meeting of the European Consortium of Lipodystrophies (ECLip), Pisa, Italy, 28-29 September 2023.
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Ceccarini G, Akinci B, Araujo-Vilar D, Beghini M, Brown RJ, Carrion Tudela J, Corradin V, Donadille B, Jerez Ruiz J, Jeru I, Lattanzi G, Maffei M, McIlroy GD, Nobécourt E, Perez de Tudela N, Rochford JJ, Sanders R, von Schnurbein J, Tews D, Vantyghem MC, Vatier C, Vigouroux C, and Santini F
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- Humans, Europe, Italy, Lipodystrophy therapy, Lipodystrophy diagnosis
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Lipodystrophy syndromes are rare diseases primarily affecting the development or maintenance of the adipose tissue but are also distressing indirectly multiple organs and tissues, often leading to reduced life expectancy and quality of life. Lipodystrophy syndromes are multifaceted disorders caused by genetic mutations or autoimmunity in the vast majority of cases. While many subtypes are now recognized and classified, the disease remains remarkably underdiagnosed. The European Consortium of Lipodystrophies (ECLip) was founded in 2014 as a non-profit network of European centers of excellence working in the field of lipodystrophies aiming at promoting international collaborations to increase basic scientific understanding and clinical management of these syndromes. The network has developed a European Patient Registry as a collaborative research platform for consortium members. ECLip and ECLip registry activities involve patient advocacy groups to increase public awareness and to seek advice on research activities relevant from the patients perspective. The annual ECLip congress provides updates on the research results of various network groups members., (Copyright © 2024.)
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- 2024
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31. Beyond MEN1, When to Think About MEN4? Retrospective Study on 5600 Patients in the French Population and Literature Review.
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Chevalier B, Coppin L, Romanet P, Cuny T, Maïza JC, Abeillon J, Forestier J, Walter T, Gilly O, Le Bras M, Smati S, Nunes ML, Geslot A, Grunenwald S, Mouly C, Arnault G, Wagner K, Koumakis E, Cortet-Rudelli C, Merlen É, Jannin A, Espiard S, Morange I, Baudin É, Cavaille M, Tauveron I, Teissier MP, Borson-Chazot F, Mirebeau-Prunier D, Savagner F, Pasmant É, Giraud S, Vantyghem MC, Goudet P, Barlier A, Cardot-Bauters C, and Odou MF
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- Humans, Retrospective Studies, France epidemiology, Male, Female, Adult, Middle Aged, Aged, Germ-Line Mutation, Phenotype, Cyclin-Dependent Kinase Inhibitor p27 genetics, Prevalence, Multiple Endocrine Neoplasia genetics, Multiple Endocrine Neoplasia epidemiology, Proto-Oncogene Proteins, Multiple Endocrine Neoplasia Type 1 genetics, Multiple Endocrine Neoplasia Type 1 epidemiology
- Abstract
Context: Germline CDKN1B variants predispose patients to multiple endocrine neoplasia type 4 (MEN4), a rare MEN1-like syndrome, with <100 reported cases since its discovery in 2006. Although CDKN1B mutations are frequently suggested to explain cases of genetically negative MEN1, the prevalence and phenotype of MEN4 patients is poorly known, and genetic counseling is unclear., Objective: To evaluate the prevalence of MEN4 in MEN1-suspected patients and characterize the phenotype of MEN4 patients., Design: Retrospective observational nationwide study. Narrative review of literature and variant class reassessment., Patients: We included all adult patients with class 3/4/5 CDKN1B variants identified by the laboratories from the French Oncogenetic Network on Neuroendocrine Tumors network between 2015 and 2022 through germline genetic testing for MEN1 suspicion. After class reassessment, we compared the phenotype of symptomatic patients with class 4/5 CDKN1B variants (ie, with genetically confirmed MEN4 diagnosis) in our series and in literature with 66 matched MEN1 patients from the UMD-MEN1 database., Results: From 5600 MEN1-suspected patients analyzed, 4 with class 4/5 CDKN1B variant were found (0.07%). They presented with multiple duodenal NET, primary hyperparathyroidism (PHPT) and adrenal nodule, isolated PHPT, PHPT, and pancreatic neuroendocrine tumor. We listed 29 patients with CDKN1B class 4/5 variants from the literature. Compared with matched MEN1 patients, MEN4 patients presented lower NET incidence and older age at PHPT diagnosis., Conclusion: The prevalence of MEN4 is low. PHPT and pituitary adenoma represent the main associated lesions, NETs are rare. Our results suggest a milder and later phenotype than in MEN1. Our observations will help to improve genetic counseling and management of MEN4 families., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
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- 2024
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32. Mitochondrial antiviral signaling protein enhances MASLD progression through the ERK/TNFα/NFκβ pathway.
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Nóvoa E, da Silva Lima N, Gonzalez-Rellan MJ, Chantada-Vazquez MDP, Verheij J, Rodriguez A, Esquinas-Roman EM, Fondevila MF, Koning M, Fernandez U, Cabaleiro A, Parracho T, Iglesias-Moure J, Seoane S, Porteiro B, Escudero A, Senra A, Perez-Fernandez R, López M, Fidalgo M, Guallar D, Martinez-Chantar ML, Dieguez C, Varela-Rey M, Prevot V, Schwaninger M, Meijnikman A, Bravo SB, Frühbeck G, and Nogueiras R
- Abstract
Background and Aims: Mitochondrial antiviral signaling protein (MAVS) is a critical regulator that activates the host's innate immunity against RNA viruses, and its signaling pathway has been linked to the secretion of proinflammatory cytokines. However, the actions of MAVS on inflammatory pathways during the development of metabolic dysfunction-associated steatotic liver disease (MASLD) have been little studied., Approach and Results: Liver proteomic analysis of mice with genetically manipulated hepatic p63, a transcription factor that induces liver steatosis, revealed MAVS as a target downstream of p63. MAVS was thus further evaluated in liver samples from patients and in animal models with MASLD. Genetic inhibition of MAVS was performed in hepatocyte cell lines, primary hepatocytes, spheroids, and mice. MAVS expression is induced in the liver of both animal models and people with MASLD as compared with those without liver disease. Using genetic knockdown of MAVS in adult mice ameliorates diet-induced MASLD. In vitro, silencing MAVS blunts oleic and palmitic acid-induced lipid content, while its overexpression increases the lipid load in hepatocytes. Inhibiting hepatic MAVS reduces circulating levels of the proinflammatory cytokine TNFα and the hepatic expression of both TNFα and NFκβ. Moreover, the inhibition of ERK abolished the activation of TNFα induced by MAVS. The posttranslational modification O -GlcNAcylation of MAVS is required to activate inflammation and to promote the high lipid content in hepatocytes., Conclusions: MAVS is involved in the development of steatosis, and its inhibition in previously damaged hepatocytes can ameliorate MASLD., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)
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- 2024
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33. LDHB contributes to the regulation of lactate levels and basal insulin secretion in human pancreatic β cells.
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Cuozzo F, Viloria K, Shilleh AH, Nasteska D, Frazer-Morris C, Tong J, Jiao Z, Boufersaoui A, Marzullo B, Rosoff DB, Smith HR, Bonner C, Kerr-Conte J, Pattou F, Nano R, Piemonti L, Johnson PRV, Spiers R, Roberts J, Lavery GG, Clark A, Ceresa CDL, Ray DW, Hodson L, Davies AP, Rutter GA, Oshima M, Scharfmann R, Merrins MJ, Akerman I, Tennant DA, Ludwig C, and Hodson DJ
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- Humans, Animals, Mice, Glucose metabolism, Insulin metabolism, Isoenzymes metabolism, Citric Acid Cycle, Mice, Inbred C57BL, Male, Insulin-Secreting Cells metabolism, L-Lactate Dehydrogenase metabolism, Insulin Secretion, Lactic Acid metabolism
- Abstract
Using
13 C6 glucose labeling coupled to gas chromatography-mass spectrometry and 2D1 H-13 C heteronuclear single quantum coherence NMR spectroscopy, we have obtained a comparative high-resolution map of glucose fate underpinning β cell function. In both mouse and human islets, the contribution of glucose to the tricarboxylic acid (TCA) cycle is similar. Pyruvate fueling of the TCA cycle is primarily mediated by the activity of pyruvate dehydrogenase, with lower flux through pyruvate carboxylase. While the conversion of pyruvate to lactate by lactate dehydrogenase (LDH) can be detected in islets of both species, lactate accumulation is 6-fold higher in human islets. Human islets express LDH, with low-moderate LDHA expression and β cell-specific LDHB expression. LDHB inhibition amplifies LDHA-dependent lactate generation in mouse and human β cells and increases basal insulin release. Lastly, cis-instrument Mendelian randomization shows that low LDHB expression levels correlate with elevated fasting insulin in humans. Thus, LDHB limits lactate generation in β cells to maintain appropriate insulin release., Competing Interests: Declaration of interests G.A.R. has received grant funding from, and is a consultant for, Sun Pharmaceuticals Industries Ltd. D.J.H. receives licensing revenue from Celtarys Research for provision of chemical probes. D.J.H. has filed patents related to type 1 diabetes and type 2 diabetes therapy, unrelated to the present study., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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34. Pathogenic, Total Loss-of-Function DYRK1B Variants Cause Monogenic Obesity Associated With Type 2 Diabetes.
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Folon L, Baron M, Scherrer V, Toussaint B, Vaillant E, Loiselle H, Dechaume A, De Pooter F, Boutry R, Boissel M, Diallo A, Ning L, Balkau B, Charpentier G, Franc S, Marre M, Derhourhi M, Froguel P, and Bonnefond A
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- Humans, Case-Control Studies, Obesity complications, Obesity genetics, Phenotype, Glucose, Diabetes Mellitus, Type 2 genetics
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Objective: Rare variants in DYRK1B have been described in some patients with central obesity, type 2 diabetes, and early-onset coronary disease. Owing to the limited number of conducted studies, the broader impact of DYRK1B variants on a larger scale has yet to be investigated., Research Design and Methods: DYRK1B was sequenced in 9,353 participants from a case-control study for obesity and type 2 diabetes. Each DYRK1B variant was functionally assessed in vitro. Variant pathogenicity was determined using criteria from the American College of Medical Genetics and Genomics (ACMG). The effect of pathogenic or likely pathogenic (P/LP) variants on metabolic traits was assessed using adjusted mixed-effects score tests., Results: Sixty-five rare, heterozygous DYRK1B variants were identified and were not associated with obesity or type 2 diabetes. Following functional analyses, 20 P/LP variants were pinpointed, including 6 variants that exhibited a fully inhibitory effect (P/LP-null) on DYRK1B activity. P/LP and P/LP-null DYRK1B variants were associated with increased BMI and obesity risk; however, the impact was notably more pronounced for the P/LP-null variants (effect of 8.0 ± 3.2 and odds ratio of 7.9 [95% CI 1.2-155]). Furthermore, P/LP-null variants were associated with higher fasting glucose and type 2 diabetes risk (effect of 2.9 ± 1.0 and odds ratio of 4.8 [95% CI 0.85-37]), while P/LP variants had no effect on glucose homeostasis., Conclusions: P/LP, total loss-of-function DYRK1B variants cause monogenic obesity associated with type 2 diabetes. This study underscores the significance of conducting functional assessments in order to accurately ascertain the tangible effects of P/LP DYRK1B variants., (© 2024 by the American Diabetes Association.)
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- 2024
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35. Genetic drivers of heterogeneity in type 2 diabetes pathophysiology.
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Suzuki K, Hatzikotoulas K, Southam L, Taylor HJ, Yin X, Lorenz KM, Mandla R, Huerta-Chagoya A, Melloni GEM, Kanoni S, Rayner NW, Bocher O, Arruda AL, Sonehara K, Namba S, Lee SSK, Preuss MH, Petty LE, Schroeder P, Vanderwerff B, Kals M, Bragg F, Lin K, Guo X, Zhang W, Yao J, Kim YJ, Graff M, Takeuchi F, Nano J, Lamri A, Nakatochi M, Moon S, Scott RA, Cook JP, Lee JJ, Pan I, Taliun D, Parra EJ, Chai JF, Bielak LF, Tabara Y, Hai Y, Thorleifsson G, Grarup N, Sofer T, Wuttke M, Sarnowski C, Gieger C, Nousome D, Trompet S, Kwak SH, Long J, Sun M, Tong L, Chen WM, Nongmaithem SS, Noordam R, Lim VJY, Tam CHT, Joo YY, Chen CH, Raffield LM, Prins BP, Nicolas A, Yanek LR, Chen G, Brody JA, Kabagambe E, An P, Xiang AH, Choi HS, Cade BE, Tan J, Broadaway KA, Williamson A, Kamali Z, Cui J, Thangam M, Adair LS, Adeyemo A, Aguilar-Salinas CA, Ahluwalia TS, Anand SS, Bertoni A, Bork-Jensen J, Brandslund I, Buchanan TA, Burant CF, Butterworth AS, Canouil M, Chan JCN, Chang LC, Chee ML, Chen J, Chen SH, Chen YT, Chen Z, Chuang LM, Cushman M, Danesh J, Das SK, de Silva HJ, Dedoussis G, Dimitrov L, Doumatey AP, Du S, Duan Q, Eckardt KU, Emery LS, Evans DS, Evans MK, Fischer K, Floyd JS, Ford I, Franco OH, Frayling TM, Freedman BI, Genter P, Gerstein HC, Giedraitis V, González-Villalpando C, González-Villalpando ME, Gordon-Larsen P, Gross M, Guare LA, Hackinger S, Hakaste L, Han S, Hattersley AT, Herder C, Horikoshi M, Howard AG, Hsueh W, Huang M, Huang W, Hung YJ, Hwang MY, Hwu CM, Ichihara S, Ikram MA, Ingelsson M, Islam MT, Isono M, Jang HM, Jasmine F, Jiang G, Jonas JB, Jørgensen T, Kamanu FK, Kandeel FR, Kasturiratne A, Katsuya T, Kaur V, Kawaguchi T, Keaton JM, Kho AN, Khor CC, Kibriya MG, Kim DH, Kronenberg F, Kuusisto J, Läll K, Lange LA, Lee KM, Lee MS, Lee NR, Leong A, Li L, Li Y, Li-Gao R, Ligthart S, Lindgren CM, Linneberg A, Liu CT, Liu J, Locke AE, Louie T, Luan J, Luk AO, Luo X, Lv J, Lynch JA, Lyssenko V, Maeda S, Mamakou V, Mansuri SR, Matsuda K, Meitinger T, Melander O, Metspalu A, Mo H, Morris AD, Moura FA, Nadler JL, Nalls MA, Nayak U, Ntalla I, Okada Y, Orozco L, Patel SR, Patil S, Pei P, Pereira MA, Peters A, Pirie FJ, Polikowsky HG, Porneala B, Prasad G, Rasmussen-Torvik LJ, Reiner AP, Roden M, Rohde R, Roll K, Sabanayagam C, Sandow K, Sankareswaran A, Sattar N, Schönherr S, Shahriar M, Shen B, Shi J, Shin DM, Shojima N, Smith JA, So WY, Stančáková A, Steinthorsdottir V, Stilp AM, Strauch K, Taylor KD, Thorand B, Thorsteinsdottir U, Tomlinson B, Tran TC, Tsai FJ, Tuomilehto J, Tusie-Luna T, Udler MS, Valladares-Salgado A, van Dam RM, van Klinken JB, Varma R, Wacher-Rodarte N, Wheeler E, Wickremasinghe AR, van Dijk KW, Witte DR, Yajnik CS, Yamamoto K, Yamamoto K, Yoon K, Yu C, Yuan JM, Yusuf S, Zawistowski M, Zhang L, Zheng W, Raffel LJ, Igase M, Ipp E, Redline S, Cho YS, Lind L, Province MA, Fornage M, Hanis CL, Ingelsson E, Zonderman AB, Psaty BM, Wang YX, Rotimi CN, Becker DM, Matsuda F, Liu Y, Yokota M, Kardia SLR, Peyser PA, Pankow JS, Engert JC, Bonnefond A, Froguel P, Wilson JG, Sheu WHH, Wu JY, Hayes MG, Ma RCW, Wong TY, Mook-Kanamori DO, Tuomi T, Chandak GR, Collins FS, Bharadwaj D, Paré G, Sale MM, Ahsan H, Motala AA, Shu XO, Park KS, Jukema JW, Cruz M, Chen YI, Rich SS, McKean-Cowdin R, Grallert H, Cheng CY, Ghanbari M, Tai ES, Dupuis J, Kato N, Laakso M, Köttgen A, Koh WP, Bowden DW, Palmer CNA, Kooner JS, Kooperberg C, Liu S, North KE, Saleheen D, Hansen T, Pedersen O, Wareham NJ, Lee J, Kim BJ, Millwood IY, Walters RG, Stefansson K, Ahlqvist E, Goodarzi MO, Mohlke KL, Langenberg C, Haiman CA, Loos RJF, Florez JC, Rader DJ, Ritchie MD, Zöllner S, Mägi R, Marston NA, Ruff CT, van Heel DA, Finer S, Denny JC, Yamauchi T, Kadowaki T, Chambers JC, Ng MCY, Sim X, Below JE, Tsao PS, Chang KM, McCarthy MI, Meigs JB, Mahajan A, Spracklen CN, Mercader JM, Boehnke M, Rotter JI, Vujkovic M, Voight BF, Morris AP, and Zeggini E
- Subjects
- Humans, Adipocytes metabolism, Chromatin genetics, Chromatin metabolism, Coronary Artery Disease complications, Coronary Artery Disease genetics, Diabetic Nephropathies complications, Diabetic Nephropathies genetics, Endothelial Cells metabolism, Enteroendocrine Cells, Epigenomics, Islets of Langerhans metabolism, Multifactorial Inheritance genetics, Peripheral Arterial Disease complications, Peripheral Arterial Disease genetics, Single-Cell Analysis, Diabetes Mellitus, Type 2 classification, Diabetes Mellitus, Type 2 complications, Diabetes Mellitus, Type 2 genetics, Diabetes Mellitus, Type 2 pathology, Diabetes Mellitus, Type 2 physiopathology, Disease Progression, Genetic Predisposition to Disease genetics, Genome-Wide Association Study
- Abstract
Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes
1,2 and molecular mechanisms that are often specific to cell type3,4 . Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P < 5 × 10-8 ) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care., (© 2024. The Author(s).)- Published
- 2024
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36. p63 controls metabolic activation of hepatic stellate cells and fibrosis via an HER2-ACC1 pathway.
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Fondevila MF, Novoa E, Gonzalez-Rellan MJ, Fernandez U, Heras V, Porteiro B, Parracho T, Dorta V, Riobello C, da Silva Lima N, Seoane S, Garcia-Vence M, Chantada-Vazquez MP, Bravo SB, Senra A, Leiva M, Marcos M, Sabio G, Perez-Fernandez R, Dieguez C, Prevot V, Schwaninger M, Woodhoo A, Martinez-Chantar ML, Schwabe R, Cubero FJ, Varela-Rey M, Crespo J, Iruzubieta P, and Nogueiras R
- Subjects
- Humans, Mice, Animals, Activation, Metabolic, Liver Cirrhosis genetics, Liver Cirrhosis chemically induced, Liver Cirrhosis metabolism, Fibrosis, Acetyl-CoA Carboxylase genetics, Acetyl-CoA Carboxylase metabolism, Hepatic Stellate Cells metabolism, Hepatic Stellate Cells pathology, Non-alcoholic Fatty Liver Disease pathology
- Abstract
The p63 protein has pleiotropic functions and, in the liver, participates in the progression of nonalcoholic fatty liver disease (NAFLD). However, its functions in hepatic stellate cells (HSCs) have not yet been explored. TAp63 is induced in HSCs from animal models and patients with liver fibrosis and its levels positively correlate with NAFLD activity score and fibrosis stage. In mice, genetic depletion of TAp63 in HSCs reduces the diet-induced liver fibrosis. In vitro silencing of p63 blunts TGF-β1-induced HSCs activation by reducing mitochondrial respiration and glycolysis, as well as decreasing acetyl CoA carboxylase 1 (ACC1). Ectopic expression of TAp63 induces the activation of HSCs and increases the expression and activity of ACC1 by promoting the transcriptional activity of HER2. Genetic inhibition of both HER2 and ACC1 blunt TAp63-induced activation of HSCs. Thus, TAp63 induces HSC activation by stimulating the HER2-ACC1 axis and participates in the development of liver fibrosis., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
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- 2024
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37. Regulation of Thyroid Hormone Gatekeepers by Thyrotropin in Tanycytes.
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Chandrasekar A, Schmidtlein PM, Neve V, Rivagorda M, Spiecker F, Gauthier K, Prevot V, Schwaninger M, and Müller-Fielitz H
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- Humans, Thyroid Hormones metabolism, Thyroid Gland metabolism, Receptors, Thyrotropin genetics, Receptors, Thyrotropin metabolism, Pituitary Hormone-Releasing Hormones metabolism, Protein Kinase C metabolism, Thyrotropin pharmacology, Thyrotropin metabolism, Ependymoglial Cells metabolism
- Abstract
Background: Tanycytes are specialized glial cells within the mediobasal hypothalamus that have multiple functions, including hormone sensing and regulation of hypophysiotropic hormone secretion. There are ongoing discussions about the role of tanycytes in regulating the supply of hypothalamic thyroid hormones (THs) through the expression of TH transporters ( Slc16a2 , Slco1c1 ) and deiodinases ( Dio2 , Dio3 ). In this study, we investigated the potential feedback effect of thyrotropin (TSH) on the transcription of these gatekeeper genes on tanycytes. Methods: We analyzed the changes in the expression of TH-gatekeeper genes, in TSH-stimulated primary tanycytes, using quantitative polymerase chain reaction (qPCR). We also used RNAScope
® in brain slices to further reveal the local distribution of the transcripts. In addition, we blocked intracellular pathways and used small-interfering RNA (siRNA) to elucidate differences in the regulation of the gatekeeper genes. Results: TSH elevated messenger RNA (mRNA) levels of Slco1c1 , Dio2 , and Dio3 in tanycytes, while Slc16a2 was mostly unaffected. Blockade and knockdown of the TSH receptor (TSHR) and antagonization of cAMP response element-binding protein (CREB) clearly abolished the increased expression induced by TSH, indicating PKA-dependent regulation through the TSHR. The TSH-dependent expression of Dio3 and Slco1c1 was also regulated by protein kinase C (PKC), and in case of Dio3 , also by extracellular signal-regulated kinase (ERK) activity. Importantly, these gene regulations were specifically found in different subpopulations of tanycytes. Conclusions: This study demonstrates that TSH induces transcriptional regulation of TH-gatekeeper genes in tanycytes through the Tshr/Gαq/PKC pathway, in parallel to the Tshr/Gαs/PKA/CREB pathway. These differential actions of TSH on tanycytic subpopulations appear to be important for coordinating the supply of TH to the hypothalamus and aid its functions.- Published
- 2024
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38. Metabolic control of puberty: 60 years in the footsteps of Kennedy and Mitra's seminal work.
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Anderson GM, Hill JW, Kaiser UB, Navarro VM, Ong KK, Perry JRB, Prevot V, Tena-Sempere M, and Elias CF
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- Male, Adult, Humans, Puberty physiology, Sexual Maturation physiology, Obesity genetics, Diabetes Mellitus, Type 2 genetics, Prostatic Neoplasms
- Abstract
An individual's nutritional status has a powerful effect on sexual maturation. Puberty onset is delayed in response to chronic energy insufficiency and is advanced under energy abundance. The consequences of altered pubertal timing for human health are profound. Late puberty increases the chances of cardiometabolic, musculoskeletal and neurocognitive disorders, whereas early puberty is associated with increased risks of adult obesity, type 2 diabetes mellitus, cardiovascular diseases and various cancers, such as breast, endometrial and prostate cancer. Kennedy and Mitra's trailblazing studies, published in 1963 and using experimental models, were the first to demonstrate that nutrition is a key factor in puberty onset. Building on this work, the field has advanced substantially in the past decade, which is largely due to the impressive development of molecular tools for experimentation and population genetics. In this Review, we discuss the latest advances in basic and translational sciences underlying the nutritional and metabolic control of pubertal development, with a focus on perspectives and future directions., (© 2023. Springer Nature Limited.)
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- 2024
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39. Pathogenic monoallelic variants in GLIS3 increase type 2 diabetes risk and identify a subgroup of patients sensitive to sulfonylureas.
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Meulebrouck S, Scherrer V, Boutry R, Toussaint B, Vaillant E, Dechaume A, Loiselle H, Balkau B, Charpentier G, Franc S, Marre M, Baron M, Vaxillaire M, Derhourhi M, Boissel M, Froguel P, and Bonnefond A
- Subjects
- Mice, Animals, Infant, Newborn, Humans, Transcription Factors genetics, Transcription Factors metabolism, Gene Expression Regulation, Mutation, DNA-Binding Proteins metabolism, Repressor Proteins metabolism, Trans-Activators metabolism, Diabetes Mellitus, Type 2 drug therapy, Diabetes Mellitus, Type 2 genetics, Insulin-Secreting Cells metabolism
- Abstract
Aims/hypothesis: GLIS3 encodes a transcription factor involved in pancreatic beta cell development and function. Rare pathogenic, bi-allelic mutations in GLIS3 cause syndromic neonatal diabetes whereas frequent SNPs at this locus associate with common type 2 diabetes risk. Because rare, functional variants located in other susceptibility genes for type 2 diabetes have already been shown to strongly increase individual risk for common type 2 diabetes, we aimed to investigate the contribution of rare pathogenic GLIS3 variants to type 2 diabetes., Methods: GLIS3 was sequenced in 5471 individuals from the Rare Variants Involved in Diabetes and Obesity (RaDiO) study. Variant pathogenicity was assessed following the criteria established by the American College of Medical Genetics and Genomics (ACMG). To address the pathogenic strong criterion number 3 (PS3), we conducted functional investigations of these variants using luciferase assays, focusing on capacity of GLIS family zinc finger 3 (GLIS3) to bind to and activate the INS promoter. The association between rare pathogenic or likely pathogenic (P/LP) variants and type 2 diabetes risk (and other metabolic traits) was then evaluated. A meta-analysis combining association results from RaDiO, the 52K study (43,125 individuals) and the TOPMed study (44,083 individuals) was finally performed., Results: Through targeted resequencing of GLIS3, we identified 105 rare variants that were carried by 395 participants from RaDiO. Among them, 49 variants decreased the activation of the INS promoter. Following ACMG criteria, 18 rare variants were classified as P/LP, showing an enrichment in the last two exons compared with the remaining exons (p<5×10
-6 ; OR>3.5). The burden of these P/LP variants was strongly higher in individuals with type 2 diabetes (p=3.0×10-3 ; OR 3.9 [95% CI 1.4, 12]), whereas adiposity, age at type 2 diabetes diagnosis and cholesterol levels were similar between variant carriers and non-carriers with type 2 diabetes. Interestingly, all carriers with type 2 diabetes were sensitive to oral sulfonylureas. A total of 7 P/LP variants were identified in both 52K and TOPMed studies. The meta-analysis of association studies obtained from RaDiO, 52K and TOPMed showed an enrichment of P/LP GLIS3 variants in individuals with type 2 diabetes (p=5.6×10-5 ; OR 2.1 [95% CI 1.4, 2.9])., Conclusions/interpretation: Rare P/LP GLIS3 variants do contribute to type 2 diabetes risk. The variants located in the distal part of the protein could have a direct effect on its functional activity by impacting its transactivation domain, by homology with the mouse GLIS3 protein. Furthermore, rare P/LP GLIS3 variants seem to have a direct clinical effect on beta cell function, which could be improved by increasing insulin secretion via the use of sulfonylureas., (© 2023. The Author(s).)- Published
- 2024
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40. comorbidPGS: An R Package Assessing Shared Predisposition between Phenotypes Using Polygenic Scores.
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Pascat V, Zudina L, Ulrich A, Maina JG, Kaakinen M, Pupko I, Bonnefond A, Demirkan A, Balkhiyarova Z, Froguel P, and Prokopenko I
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- Humans, Male, Female, Neoplasms genetics, Software, Blood Pressure genetics, Multifactorial Inheritance genetics, Genetic Predisposition to Disease, Phenotype, Polymorphism, Single Nucleotide genetics, Genome-Wide Association Study
- Abstract
Introduction: Polygenic score (PGS) is a valuable method for assessing the estimated genetic liability to a given outcome or genetic variability contributing to a quantitative trait. While polygenic risk scores are widely used for complex traits, their application in uncovering shared genetic predisposition between phenotypes, i.e., when genetic variants influence more than one phenotype, remains limited., Methods: We developed an R package, comorbidPGS, which facilitates a systematic evaluation of shared genetic effects among (cor)related phenotypes using PGSs. The comorbidPGS package takes as input a set of single nucleotide polymorphisms along with their established effects on the original phenotype (Po), referred to as Po-PGS. It generates a comprehensive summary of effect(s) of Po-PGS on target phenotype(s) (Pt) with customisable graphical features., Results: We applied comorbidPGS to investigate the shared genetic predisposition between phenotypes defining elevated blood pressure (systolic blood pressure, SBP; diastolic blood pressure, DBP; pulse pressure) and several cancers (breast cancer; pancreatic cancer, PanC; kidney cancer, KidC; prostate cancer, PrC; colorectal cancer, CrC) using the European ancestry UK Biobank individuals and GWAS meta-analyses summary statistics from independent set of European ancestry individuals. We report a significant association between elevated DBP and the genetic risk of PrC (β [SE] = 0.066 [0.017], p value = 9.64 × 10-5), as well as between CrC PGS and both, lower SBP (β [SE] = -0.10 [0.029], p value = 3.83 × 10-4) and lower DBP (β [SE] = -0.055 [0.017], p value = 1.05 × 10-3). Our analysis highlights two nominally significant relationships for individuals with genetic predisposition to elevated SBP leading to higher risk of KidC (OR [95% CI] = 1.04 [1.0039-1.087], p value = 2.82 × 10-2) and PrC (OR [95% CI] = 1.02 [1.003-1.041], p value = 2.22 × 10-2)., Conclusion: Using comorbidPGS, we underscore mechanistic relationships between blood pressure regulation and susceptibility to three comorbid malignancies. This package offers valuable means to evaluate shared genetic susceptibility between (cor)related phenotypes through polygenic scores., (© 2024 The Author(s). Published by S. Karger AG, Basel.)
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- 2024
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41. Exploring the role of purinergic receptor P2RY1 in type 2 diabetes risk and pathophysiology: Insights from human functional genomics.
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Dance A, Fernandes J, Toussaint B, Vaillant E, Boutry R, Baron M, Loiselle H, Balkau B, Charpentier G, Franc S, Ibberson M, Marre M, Gernay M, Fadeur M, Paquot N, Vaxillaire M, Boissel M, Amanzougarene S, Derhourhi M, Khamis A, Froguel P, and Bonnefond A
- Subjects
- Humans, Insulin metabolism, Genomics, Glucose metabolism, Receptors, Purinergic P2Y1 genetics, Receptors, Purinergic P2Y1 metabolism, Diabetes Mellitus, Type 2 genetics, Diabetes Mellitus, Type 2 metabolism, Islets of Langerhans metabolism
- Abstract
Objective: Human functional genomics has proven powerful in discovering drug targets for common metabolic disorders. Through this approach, we investigated the involvement of the purinergic receptor P2RY1 in type 2 diabetes (T2D)., Methods: P2RY1 was sequenced in 9,266 participants including 4,177 patients with T2D. In vitro analyses were then performed to assess the functional effect of each variant. Expression quantitative trait loci (eQTL) analysis was performed in pancreatic islets from 103 pancreatectomized individuals. The effect of P2RY1 on glucose-stimulated insulin secretion was finally assessed in human pancreatic beta cells (EndoCβH5), and RNA sequencing was performed on these cells., Results: Sequencing P2YR1 in 9,266 participants revealed 22 rare variants, seven of which were loss-of-function according to our in vitro analyses. Carriers, except one, exhibited impaired glucose control. Our eQTL analysis of human islets identified P2RY1 variants, in a beta-cell enhancer, linked to increased P2RY1 expression and reduced T2D risk, contrasting with variants located in a silent region associated with decreased P2RY1 expression and increased T2D risk. Additionally, a P2RY1-specific agonist increased insulin secretion upon glucose stimulation, while the antagonist led to decreased insulin secretion. RNA-seq highlighted TXNIP as one of the main transcriptomic markers of insulin secretion triggered by P2RY1 agonist., Conclusion: Our findings suggest that P2RY1 inherited or acquired dysfunction increases T2D risk and that P2RY1 activation stimulates insulin secretion. Selective P2RY1 agonists, impermeable to the blood-brain barrier, could serve as potential insulin secretagogues., Competing Interests: Declaration of competing interest Authors declare that they have no competing interests., (Copyright © 2023 The Authors. Published by Elsevier GmbH.. All rights reserved.)
- Published
- 2024
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42. Genetic variants of interferon-response factor 5 are associated with the incidence of chronic kidney disease: the D.E.S.I.R. study.
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Fumeron F, Velho G, Alzaid F, El Boustany R, Vandiedonck C, Bonnefond A, Froguel P, Potier L, Marre M, Balkau B, Roussel R, and Venteclef N
- Subjects
- Humans, Factor V, Incidence, Cross-Sectional Studies, Interferons, Interferon Regulatory Factors genetics, Risk Factors, Albuminuria complications, Albuminuria epidemiology, Renal Insufficiency, Chronic epidemiology, Renal Insufficiency, Chronic genetics, Renal Insufficiency, Chronic complications
- Abstract
Inflammation has been associated with renal diseases. The Interferon Regulatory Factor (IRF)-5 is a key transcription factor in the pro-inflammatory polarization of M1-like macrophages. GWAS have reported that the IRF5 locus is associated with autoimmune diseases and with the estimated glomerular filtration rate (eGFR). We study whether allelic variations in IRF5 are associated with the incidence of chronic kidney disease (CKD) in a general population. We genotyped eleven IRF5 SNPs in the French D.E.S.I.R. cohort from the general population (n = 4820). Associations of SNPs with baseline renal parameters were assessed. Data were analyzed for three endpoints during a 9-year follow-up, incidence of:at least stage 3 CKD, the KDIGO criterion "certain drop in eGFR", and incidence of micro/macro albuminuria. In the cross-sectional analysis, rs10954213 and rs10954214 were associated with eGFR and rs1874328 with urinary albumin/creatinine ratio (ACR). Rs3807306, rs11761199, rs78658945, rs1874328, rs10954213 and rs11770589 were associated with the incidence of stage 3 CKD in multi-adjusted models. Rs4731532, rs3807306, and rs11761199 were associated with the incidence of CKD defined by the KDIGO. Rs4731532, rs3807306, rs11761199 and rs79288514 were associated with the incidence of micro/macro albuminuria. Our results support the hypothesis of the importance of IRF5 mediated macrophage polarization in the etiology of CKD., (© 2023. The Author(s).)
- Published
- 2023
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43. A novel pathogenic variant in MRAP2 in an obese patient with successful outcome of bariatric surgery.
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Gatta-Cherifi B, Laboye A, Gronnier C, Monsaingeon-Henry M, Meulebrouck S, Baron M, Bertin F, Pupier E, Cambos S, Poitou C, Beyec-Le Bihan JL, and Bonnefond A
- Subjects
- Humans, Young Adult, Adaptor Proteins, Signal Transducing genetics, Carrier Proteins genetics, Obesity complications, Obesity genetics, Obesity surgery, Receptor, Melanocortin, Type 4 genetics, Receptor, Melanocortin, Type 4 metabolism, Bariatric Surgery, Diabetes Mellitus, Type 2 complications, Diabetes Mellitus, Type 2 genetics, Diabetes Mellitus, Type 2 surgery
- Abstract
Mutations in genes encoding proteins located in the leptin/melanocortin pathway have been identified in the rare cases of genetic obesities. Heterozygous variants of MRAP2, encoding a G coupled-protein receptor accessory protein implicated in energy control notably via the melanocortin-4 receptor, have been recently identified. A 24-year-old patient with early-onset severe obesity (body mass index [BMI]: 64 kg/m2) associated with hypertension, respiratory complications, nonalcoholic fatty liver disease, and type 2 diabetes was referred to our department. Sleeve gastrectomy was successful. A new heterozygous variant in MRAP2 (NM_138409.4: c.154G>C/p.G52R) variant was identified in the patient DNA. Functional assessment confirmed that this new variant was pathogenic. We report a new pathogenic loss-of-function mutation in MRAP2 in a patient suffering from a severe multicomplicated obesity. This confirms the metabolic phenotype in patients with this monogenic form of obesity. Longer follow-up will be necessary. Our finding will allow a personalized medicine., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Endocrinology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2023
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44. Correction: Heimdall, an alternative protein issued from a ncRNA related to kappa light chain variable region of immunoglobulins from astrocytes: a new player in neural proteome.
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Capuz A, Osien S, Cardon T, Karnoub MA, Aboulouard S, Raffo-Romero A, Duhamel M, Cizkova D, Trerotola M, Devos D, Kobeissy F, F VA, Bonnefond A, Fournier I, Rodet F, and Salzet M
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- 2023
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45. Human GLP1R variants affecting GLP1R cell surface expression are associated with impaired glucose control and increased adiposity.
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Gao W, Liu L, Huh E, Gbahou F, Cecon E, Oshima M, Houzé L, Katsonis P, Hegron A, Fan Z, Hou G, Charpentier G, Boissel M, Derhourhi M, Marre M, Balkau B, Froguel P, Scharfmann R, Lichtarge O, Dam J, Bonnefond A, Liu J, and Jockers R
- Subjects
- Humans, Insulin metabolism, Adiposity genetics, Obesity genetics, Blood Glucose, Diabetes Mellitus, Type 2 genetics
- Abstract
The glucagon-like peptide 1 receptor (GLP1R) is a major drug target with several agonists being prescribed in individuals with type 2 diabetes and obesity
1,2 . The impact of genetic variability of GLP1R on receptor function and its association with metabolic traits are unclear with conflicting reports. Here, we show an unexpected diversity of phenotypes ranging from defective cell surface expression to complete or pathway-specific gain of function (GoF) and loss of function (LoF), after performing a functional profiling of 60 GLP1R variants across four signalling pathways. The defective insulin secretion of GLP1R LoF variants is rescued by allosteric GLP1R ligands or high concentrations of exendin-4/semaglutide in INS-1 823/3 cells. Genetic association studies in 200,000 participants from the UK Biobank show that impaired GLP1R cell surface expression contributes to poor glucose control and increased adiposity with increased glycated haemoglobin A1c and body mass index. This study defines impaired GLP1R cell surface expression as a risk factor for traits associated with type 2 diabetes and obesity and provides potential treatment options for GLP1R LoF variant carriers., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2023
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46. High morbidity and mortality in children with untreated congenital deficiency of leptin or its receptor.
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Saeed S, Khanam R, Janjua QM, Manzoor J, Ning L, Hanook S, Canouil M, Ali M, Ayesha H, Khan WI, Farooqi IS, Yeo GSH, O'Rahilly S, Bonnefond A, Butt TA, Arslan M, and Froguel P
- Subjects
- Child, Humans, Cross-Sectional Studies, Morbidity, Retrospective Studies, Leptin, Obesity, Morbid
- Abstract
The long-term clinical outcomes of severe obesity due to leptin signaling deficiency are unknown. We carry out a retrospective cross-sectional investigation of a large cohort of children with leptin (LEP), LEP receptor (LEPR), or melanocortin 4 receptor (MC4R) deficiency (n = 145) to evaluate the progression of the disease. The affected individuals undergo physical, clinical, and metabolic evaluations. We report a very high mortality in children with LEP (26%) or LEPR deficiency (9%), mainly due to severe pulmonary and gastrointestinal infections. In addition, 40% of surviving children with LEP or LEPR deficiency experience life-threatening episodes of lung or gastrointestinal infections. Although precision drugs are currently available for LEP and LEPR deficiencies, as yet, they are not accessible in Pakistan. An appreciation of the severe impact of LEP or LEPR deficiency on morbidity and early mortality, educational attainment, and the attendant stigmatization should spur efforts to deliver the available life-saving drugs to these children as a matter of urgency., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
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47. Neddylation of phosphoenolpyruvate carboxykinase 1 controls glucose metabolism.
- Author
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Gonzalez-Rellan MJ, Fernández U, Parracho T, Novoa E, Fondevila MF, da Silva Lima N, Ramos L, Rodríguez A, Serrano-Maciá M, Perez-Mejias G, Chantada-Vazquez P, Riobello C, Veyrat-Durebex C, Tovar S, Coppari R, Woodhoo A, Schwaninger M, Prevot V, Delgado TC, Lopez M, Diaz-Quintana A, Dieguez C, Guallar D, Frühbeck G, Diaz-Moreno I, Bravo SB, Martinez-Chantar ML, and Nogueiras R
- Subjects
- Mice, Animals, Phosphoenolpyruvate metabolism, Proteins metabolism, Liver metabolism, Lysine metabolism, Glucose metabolism, Diabetes Mellitus, Type 2 metabolism
- Abstract
Neddylation is a post-translational mechanism that adds a ubiquitin-like protein, namely neural precursor cell expressed developmentally downregulated protein 8 (NEDD8). Here, we show that neddylation in mouse liver is modulated by nutrient availability. Inhibition of neddylation in mouse liver reduces gluconeogenic capacity and the hyperglycemic actions of counter-regulatory hormones. Furthermore, people with type 2 diabetes display elevated hepatic neddylation levels. Mechanistically, fasting or caloric restriction of mice leads to neddylation of phosphoenolpyruvate carboxykinase 1 (PCK1) at three lysine residues-K278, K342, and K387. We find that mutating the three PCK1 lysines that are neddylated reduces their gluconeogenic activity rate. Molecular dynamics simulations show that neddylation of PCK1 could re-position two loops surrounding the catalytic center into an open configuration, rendering the catalytic center more accessible. Our study reveals that neddylation of PCK1 provides a finely tuned mechanism of controlling glucose metabolism by linking whole nutrient availability to metabolic homeostasis., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
- Full Text
- View/download PDF
48. Hepatocyte-specific O-GlcNAc transferase downregulation ameliorates nonalcoholic steatohepatitis by improving mitochondrial function.
- Author
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Gonzalez-Rellan MJ, Parracho T, Heras V, Rodriguez A, Fondevila MF, Novoa E, Lima N, Varela-Rey M, Senra A, Chantada-Vazquez MDP, Ameneiro C, Bernardo G, Fernandez-Ramos D, Lopitz-Otsoa F, Bilbao J, Guallar D, Fidalgo M, Bravo S, Dieguez C, Martinez-Chantar ML, Millet O, Mato JM, Schwaninger M, Prevot V, Crespo J, Frühbeck G, Iruzubieta P, and Nogueiras R
- Subjects
- Humans, Mice, Animals, Down-Regulation, Acetylglucosamine metabolism, Mitochondria metabolism, Hepatocytes metabolism, Lipids, Non-alcoholic Fatty Liver Disease metabolism
- Abstract
Objective: O-GlcNAcylation is a post-translational modification that directly couples the processes of nutrient sensing, metabolism, and signal transduction, affecting protein function and localization, since the O-linked N-acetylglucosamine moiety comes directly from the metabolism of glucose, lipids, and amino acids. The addition and removal of O-GlcNAc of target proteins are mediated by two highly conserved enzymes: O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) and O-GlcNAcase (OGA), respectively. Deregulation of O-GlcNAcylation has been reported to be associated with various human diseases such as cancer, diabetes, and cardiovascular diseases. The contribution of deregulated O-GlcNAcylation to the progression and pathogenesis of NAFLD remains intriguing, and a better understanding of its roles in this pathophysiological context is required to uncover novel avenues for therapeutic intervention. By using a translational approach, our aim is to describe the role of OGT and O-GlcNAcylation in the pathogenesis of NAFLD., Methods: We used primary mouse hepatocytes, human hepatic cell lines and in vivo mouse models of steatohepatitis to manipulate O-GlcNAc transferase (OGT). We also studied OGT and O-GlcNAcylation in liver samples from different cohorts of people with NAFLD., Results: O-GlcNAcylation was upregulated in the liver of people and animal models with steatohepatitis. Downregulation of OGT in NAFLD-hepatocytes improved diet-induced liver injury in both in vivo and in vitro models. Proteomics studies revealed that mitochondrial proteins were hyper-O-GlcNAcylated in the liver of mice with steatohepatitis. Inhibition of OGT is able to restore mitochondrial oxidation and decrease hepatic lipid content in in vitro and in vivo models of NAFLD., Conclusions: These results demonstrate that deregulated hyper-O-GlcNAcylation favors NAFLD progression by reducing mitochondrial oxidation and promoting hepatic lipid accumulation., Competing Interests: Declaration of competing interest The authors declare no conflict of interest, (Copyright © 2023 The Author(s). Published by Elsevier GmbH.. All rights reserved.)
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- 2023
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49. Bidirectional Mendelian Randomization and Multiphenotype GWAS Show Causality and Shared Pathophysiology Between Depression and Type 2 Diabetes.
- Author
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Maina JG, Balkhiyarova Z, Nouwen A, Pupko I, Ulrich A, Boissel M, Bonnefond A, Froguel P, Khamis A, Prokopenko I, and Kaakinen M
- Subjects
- Humans, Genome-Wide Association Study methods, Depression genetics, Mendelian Randomization Analysis, Polymorphism, Single Nucleotide genetics, Membrane Proteins genetics, Intracellular Signaling Peptides and Proteins genetics, RNA-Binding Proteins genetics, Diabetes Mellitus, Type 2 genetics, Depressive Disorder, Major genetics
- Abstract
Objective: Depression is a common comorbidity of type 2 diabetes. We assessed the causal relationships and shared genetics between them., Research Design and Methods: We applied two-sample, bidirectional Mendelian randomization (MR) to assess causality between type 2 diabetes and depression. We investigated potential mediation using two-step MR. To identify shared genetics, we performed 1) genome-wide association studies (GWAS) separately and 2) multiphenotype GWAS (MP-GWAS) of type 2 diabetes (19,344 case subjects, 463,641 control subjects) and depression using major depressive disorder (MDD) (5,262 case subjects, 86,275 control subjects) and self-reported depressive symptoms (n = 153,079) in the UK Biobank. We analyzed expression quantitative trait locus (eQTL) data from public databases to identify target genes in relevant tissues., Results: MR demonstrated a significant causal effect of depression on type 2 diabetes (odds ratio 1.26 [95% CI 1.11-1.44], P = 5.46 × 10-4) but not in the reverse direction. Mediation analysis indicated that 36.5% (12.4-57.6%, P = 0.0499) of the effect from depression on type 2 diabetes was mediated by BMI. GWAS of type 2 diabetes and depressive symptoms did not identify shared loci. MP-GWAS identified seven shared loci mapped to TCF7L2, CDKAL1, IGF2BP2, SPRY2, CCND2-AS1, IRS1, CDKN2B-AS1. MDD has not brought any significant association in either GWAS or MP-GWAS. Most MP-GWAS loci had an eQTL, including single nucleotide polymorphisms implicating the cell cycle gene CCND2 in pancreatic islets and brain and the insulin signaling gene IRS1 in adipose tissue, suggesting a multitissue and pleiotropic underlying mechanism., Conclusions: Our results highlight the importance to prevent type 2 diabetes at the onset of depressive symptoms and the need to maintain a healthy weight in the context of its effect on depression and type 2 diabetes comorbidity., (© 2023 by the American Diabetes Association.)
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- 2023
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50. Heimdall, an alternative protein issued from a ncRNA related to kappa light chain variable region of immunoglobulins from astrocytes: a new player in neural proteome.
- Author
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Capuz A, Osien S, Cardon T, Karnoub MA, Aboulouard S, Raffo-Romero A, Duhamel M, Cizkova D, Trerotola M, Devos D, Kobeissy F, Vanden Abeele F, Bonnefond A, Fournier I, Rodet F, and Salzet M
- Subjects
- Animals, Rats, Proteomics, Antibodies, Neurogenesis, 3' Untranslated Regions, Proteome genetics, Astrocytes
- Abstract
The dogma "One gene, one protein" is clearly obsolete since cells use alternative splicing and generate multiple transcripts which are translated into protein isoforms, but also use alternative translation initiation sites (TISs) and termination sites on a given transcript. Alternative open reading frames for individual transcripts give proteins originate from the 5'- and 3'-UTR mRNA regions, frameshifts of mRNA ORFs or from non-coding RNAs. Longtime considered as non-coding, recent in-silico translation prediction methods enriched the protein databases allowing the identification of new target structures that have not been identified previously. To gain insight into the role of these newly identified alternative proteins in the regulation of cellular functions, it is crucial to assess their dynamic modulation within a framework of altered physiological modifications such as experimental spinal cord injury (SCI). Here, we carried out a longitudinal proteomic study on rat SCI from 12 h to 10 days. Based on the alternative protein predictions, it was possible to identify a plethora of newly predicted protein hits. Among these proteins, some presented a special interest due to high homology with variable chain regions of immunoglobulins. We focus our interest on the one related to Kappa variable light chains which is similarly highly produced by B cells in the Bence jones disease, but here expressed in astrocytes. This protein, name Heimdall is an Intrinsically disordered protein which is secreted under inflammatory conditions. Immunoprecipitation experiments showed that the Heimdall interactome contained proteins related to astrocyte fate keepers such as "NOTCH1, EPHA3, IPO13" as well as membrane receptor protein including "CHRNA9; TGFBR, EPHB6, and TRAM". However, when Heimdall protein was neutralized utilizing a specific antibody or its gene knocked out by CRISPR-Cas9, sprouting elongations were observed in the corresponding astrocytes. Interestingly, depolarization assays and intracellular calcium measurements in Heimdall KO, established a depolarization effect on astrocyte membranes KO cells were more likely that the one found in neuroprogenitors. Proteomic analyses performed under injury conditions or under lipopolysaccharides (LPS) stimulation, revealed the expression of neuronal factors, stem cell proteins, proliferation, and neurogenesis of astrocyte convertor factors such as EPHA4, NOTCH2, SLIT3, SEMA3F, suggesting a role of Heimdall could regulate astrocytic fate. Taken together, Heimdall could be a novel member of the gatekeeping astrocyte-to-neuroprogenitor conversion factors., (© 2023. The Author(s).)
- Published
- 2023
- Full Text
- View/download PDF
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