Group VIA Phospholipase A2 Mitigates Palmitate-induced β-Cell Mitochondrial Injury and Apoptosis

Background: Lipid-induced -cell loss contributes to type 2 diabetes mellitus (T2DM). Results: Palmitate-induced -cell lipid oxidation, mitochondrial dysfunction, and apoptosis correlate inversely with expression of iPLA(2), which associates with mitochondria, generates monolysocardiolipin, and lowers oxidized phospholipid content. Conclusion: iPLA(2) mitigates palmitate-induced -cell mitochondrial injury and apoptosis and may facilitate repair of oxidized lipids. Significance: Understanding lipid-induced -cell loss could lead to T2DM therapies. Palmitate (C16:0) induces apoptosis of insulin-secreting -cells by processes that involve generation of reactive oxygen species, and chronically elevated blood long chain free fatty acid levels are thought to contribute to -cell lipotoxicity and the development of diabetes mellitus. Group VIA phospholipase A(2) (iPLA(2)) affects -cell sensitivity to apoptosis, and here we examined iPLA(2) effects on events that occur in -cells incubated with C16:0. Such events in INS-1 insulinoma cells were found to include activation of caspase-3, expression of stress response genes (C/EBP homologous protein and activating transcription factor 4), accumulation of ceramide, loss of mitochondrial membrane potential, and apoptosis. All of these responses were blunted in INS-1 cells that overexpress iPLA(2), which has been proposed to facilitate repair of oxidized mitochondrial phospholipids, e.g. cardiolipin (CL), by excising oxidized polyunsaturated fatty acid residues, e.g. linoleate (C18:2), to yield lysophospholipids, e.g. monolysocardiolipin (MLCL), that can be reacylated to regenerate the native phospholipid structures. Here the MLCL content of mouse pancreatic islets was found to rise with increasing iPLA(2) expression, and recombinant iPLA(2) hydrolyzed CL to MLCL and released oxygenated C18:2 residues from oxidized CL in preference to native C18:2. C16:0 induced accumulation of oxidized CL species and of the oxidized phospholipid (C18:0/hydroxyeicosatetraenoic acid)-glycerophosphoethanolamine, and these effects were blunted in INS-1 cells that overexpress iPLA(2), consistent with iPLA(2)-mediated removal of oxidized phospholipids. C16:0 also induced iPLA(2) association with INS-1 cell mitochondria, consistent with a role in mitochondrial repair. These findings indicate that iPLA(2) confers significant protection of -cells against C16:0-induced injury.