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

Abstract

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.

Stearoyl CoA desaturase is a gatekeeper that protects human beta cells against lipotoxicity and maintains their identity

“…Live/dead cells were counted following Trypan Blue staining. Caspase 3/7 activity assays were performed using the Promega Apo-ONE Homogenous caspase-3/7 Assay kit as described [36] (Promega, Charbonières-les-Bains, France). As another method for apoptosis detection, cells were stained with the Hoechst 33342 (5 μg/ml, Sigma-Aldrich) and propidium iodide (PI, 5 μg/ml, Sigma-Aldrich) and counted by fluorescence microscopy [37].…”

Use of preclinical models to identify markers of type 2 diabetes susceptibility and novel regulators of insulin secretion – A step towards precision medicine

“…In the present review, we will first, illustrate the mouse studies that we have performed to identify novel biomarkers of diabetes susceptibility and validate them in humans [13] and, second, how this approach led us to uncover the role of a lipid modifying enzyme in protecting beta-cells against glucolipotoxicity [14], [15].…”

Vitamin D and ω-3 Supplementations in Mediterranean Diet During the 1st Year of Overt Type 1 Diabetes: A Cohort Study

“…A plausible explanation of a similar metabolic control with less insulin administration, despite decreased FCP, is probably related to the counteraction of ω-3 on neoglucogenesis, that limits the postprandial glucose increase and reduces insulin need for meals. The lowering of the blood glucose excursions could in turn affect the process of apoptosis of β-cells reducing glucolipotoxicity, and so could preserve REIS, according to findings in translational models [11]. This assumption might be investigated through analysis of stimulated C-peptide (SCP) after standardized mixed-meal tolerance test, that represent a direct measurement of insulin secretion, in future randomized trials.…”

“…Recently in Persian children at onset of overt T1D, Narges Habibian et al provided evidence of vitamin D as an environmental factor decreasing the C-peptide falling in children with recent T1D [9] The ability of ω-3 to counteract the pathogenic pathways of T1D has been highlighted in two translational researches showing that its nutritional intake may reduce blood glucose levels [10] and limit β-cells apoptosis mediated by glucolipotoxicit [11]. Specifically, diet supplementation with ω-3 was found to lead to reduction of postprandial glycemia and improvement of glycemic variability, mediated by inhibition of neoglucogenesis [10], and to counteract β-cell apoptosis through activation of the Eovl2/DHA enzyme axis [11]. These reports suggest both an immunologic and metabolic role of ω-3, limiting the post-prandial blood glucose increase, and protecting β-cell apoptosis induced by glucolipotoxicity.…”