1. Protective role of the ELOVL2/docosahexaenoic acid axis in glucolipotoxicity-induced apoptosis in rodent beta cells and human islets
- Author
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Hervé Le Stunff, Kelly Meneyrol, Nadim Kassis, Mark Ibberson, Julien Véret, Christophe Magnan, Lara Bellini, Isabelle Hainault, Jessica Denom, Céline Cruciani-Guglielmacci, Véronique Lenoir, Piero Marchetti, Agnieszka Blachnio-Zabielska, Mélanie Campana, Marta Chacinska, Carina Prip-Buus, Marco Bugliani, Bernard Thorens, Claude Rouch, Unité de Biologie Fonctionnelle et Adaptative (BFA (UMR_8251 / U1133)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Clinical and Experimental Medicine [Pisa, Italy], University of Pisa [Italy], Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), FACULTAD DE CIENCIAS Y FILOSOFIA, Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne (UNIL), Medical University of Bialystok, Université Paris Diderot, Sorbonne Paris Cité, Paris, France, Université Paris Diderot - Paris 7 (UPD7), Laboratoire de physiopathologie de la nutrition (LPN), Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), SIB Swiss Institute of Bioinformatics, and Université de Lausanne
- Subjects
AMPK ,0301 basic medicine ,medicine.medical_specialty ,Ceramide ,Docosahexaenoic Acids ,Fatty Acid Elongases ,Endocrinology, Diabetes and Metabolism ,[SDV]Life Sciences [q-bio] ,Palmitates ,Apoptosis ,030209 endocrinology & metabolism ,Pancreatic beta cells ,Islets of Langerhans ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,Endocrinology ,0302 clinical medicine ,Carnitine palmitoyltransferase 1 ,Downregulation and upregulation ,ELOVL2 ,Acetyltransferases ,Insulin-Secreting Cells ,Internal medicine ,Internal Medicine ,medicine ,Animals ,Glucose homeostasis ,ComputingMilieux_MISCELLANEOUS ,chemistry.chemical_classification ,food and beverages ,Fatty acid ,Type 2 diabetes ,DHA ,Glucolipotoxicity ,Diabetes and Metabolism ,Mitochondrial β-oxidation ,Glucose ,030104 developmental biology ,chemistry ,Docosahexaenoic acid ,Beta cell ,Oxidation-Reduction ,Etomoxir - Abstract
Dietary n-3 polyunsaturated fatty acids, especially docosahexaenoic acid (DHA), are known to influence glucose homeostasis. We recently showed that Elovl2 expression in beta cells, which regulates synthesis of endogenous DHA, was associated with glucose tolerance and played a key role in insulin secretion. The present study aimed to examine the role of the very long chain fatty acid elongase 2 (ELOVL2)/DHA axis on the adverse effects of palmitate with high glucose, a condition defined as glucolipotoxicity, on beta cells. We detected ELOVL2 in INS-1 beta cells and mouse and human islets using quantitative PCR and western blotting. Downregulation and adenoviral overexpression of Elovl2 was carried out in beta cells. Ceramide and diacylglycerol levels were determined by radio-enzymatic assay and lipidomics. Apoptosis was quantified using caspase-3 assays and poly (ADP-ribose) polymerase cleavage. Palmitate oxidation and esterification were determined by [U-14C]palmitate labelling. We found that glucolipotoxicity decreased ELOVL2 content in rodent and human beta cells. Downregulation of ELOVL2 drastically potentiated beta cell apoptosis induced by glucolipotoxicity, whereas adenoviral Elovl2 overexpression and supplementation with DHA partially inhibited glucolipotoxicity-induced cell death in rodent and human beta cells. Inhibition of beta cell apoptosis by the ELOVL2/DHA axis was associated with a decrease in ceramide accumulation. However, the ELOVL2/DHA axis was unable to directly alter ceramide synthesis or metabolism. By contrast, DHA increased palmitate oxidation but did not affect its esterification. Pharmacological inhibition of AMP-activated protein kinase and etomoxir, an inhibitor of carnitine palmitoyltransferase 1 (CPT1), the rate-limiting enzyme in fatty acid β-oxidation, attenuated the protective effect of the ELOVL2/DHA axis during glucolipotoxicity. Downregulation of CPT1 also counteracted the anti-apoptotic action of the ELOVL2/DHA axis. By contrast, a mutated active form of Cpt1 inhibited glucolipotoxicity-induced beta cell apoptosis when ELOVL2 was downregulated. Our results identify ELOVL2 as a critical pro-survival enzyme for preventing beta cell death and dysfunction induced by glucolipotoxicity, notably by favouring palmitate oxidation in mitochondria through a CPT1-dependent mechanism.
- Published
- 2018