Protective role of the ELOVL2/docosahexaenoic acid axis in glucolipotoxicity-induced apoptosis in rodent beta cells and human islets

• Published in: Diabetologia 2018-08, Vol.61 (8), p.1780-1793
• Main Authors: Bellini, Lara, Campana, Mélanie, Rouch, Claude, Chacinska, Marta, Bugliani, Marco, Meneyrol, Kelly, Hainault, Isabelle, Lenoir, Véronique, Denom, Jessica, Véret, Julien, Kassis, Nadim, Thorens, Bernard, Ibberson, Mark, Marchetti, Piero, Blachnio-Zabielska, Agnieszka, Cruciani-Guglielmacci, Céline, Prip-Buus, Carina, Magnan, Christophe, Le Stunff, Hervé
• Format: Article
• Language: English
• Subjects: AMP; AMP-activated protein kinase; Apoptosis; Beta cells; Carnitine palmitoyltransferase; Caspase; Caspase-3; Cell death; Ceramide; Diabetes; Dietary supplements; Diglycerides; Docosahexaenoic acid; Enzyme inhibitors; Enzymes; Esterification; Fatty acids; Glucose; Glucose tolerance; Homeostasis; Human Physiology; Insulin; Insulin secretion; Internal Medicine; Kinases; Labeling; Life Sciences; Medicine; Medicine & Public Health; Metabolic Diseases; Mitochondria; Oxidation; Palmitic acid; Polyunsaturated fatty acids; Secretion; Western blotting
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-018-4629-8

Aims/hypothesis 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. Methods 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- 14 C]palmitate labelling. Results 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. Conclusions/interpretation 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.