Perilipin5 protects against lipotoxicity and alleviates endoplasmic reticulum stress in pancreatic β-cells

BackgroundChronic exposure of pancreatic beta-cells to excess free fatty acids is thought to contribute to type 2 diabetes pathogenesis in obesity by impairing beta-cell function and even leading to apoptosis. In beta-cells, lipid droplet-associated protein perilipin 5 (PLIN5) has been shown to enhance insulin secretion by regulating intracellular lipid metabolism; the roles of PLIN5 in response to lipotoxicity remain poorly understood.MethodsINS-1 beta-cells were transfected with PLIN5-overexpression adenovirus (Ad-PLIN5) and treated with palmitate. C57BL/6J male mice were fed with high fat diet and tail intravenous injected with adeno-associated virus overexpressing PLIN5 (AAV-PLIN5) in beta-cells.ResultsOur data showed that palmitate and PPAR agonists including WY14643 (PPAR alpha), GW501516 (PPAR beta/delta), rosiglitazone (PPAR gamma) in vitro all induced PLIN5 expression in INS-1 cells. Under palmitate overload, although upregulating PLIN5 promoted lipid droplet storage, it alleviated lipotoxicity in INS-1 beta-cells with improved cell viability, cell apoptosis and beta-cell function. The protection role of PLIN5 in beta-cell function observed in cell experiments were further verified in in vivo study indicated by mitigated glucose intolerance in high fat diet fed mice with beta-cell-specific overexpression of PLIN5. Mechanistic experiments revealed that enhanced FAO induced by elevation of PLIN5, followed by decreased ER stress may be a major mechanism responsible for alleviation of lipotoxicity observed in the present study.ConclusionsOur finding substantiated the important role of PLIN5 in protection against lipotoxicity in beta-cells.