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

Abstract

Background Chronic exposure of pancreatic β-cells to excess free fatty acids is thought to contribute to type 2 diabetes pathogenesis in obesity by impairing β-cell function and even leading to apoptosis. In β-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. Methods INS-1 β-cells were transfected with PLIN5-overexpression adenovirus (Ad-PLIN5) and treated with palmitate. C57BL/6 J male mice were fed with high fat diet and tail intravenous injected with adeno-associated virus overexpressing PLIN5 (AAV-PLIN5) in β-cells. Results Our data showed that palmitate and PPAR agonists including WY14643 (PPARα), GW501516 (PPARβ/δ), rosiglitazone (PPARγ) 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 β-cells with improved cell viability, cell apoptosis and β-cell function. The protection role of PLIN5 in β-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 β-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. Conclusions Our finding substantiated the important role of PLIN5 in protection against lipotoxicity in β-cells. Electronic supplementary material The online version of this article (10.1186/s12986-019-0375-2) contains supplementary material, which is available to authorized users.

Perilipin 5 Reduces Oxidative Damage Associated With Lipotoxicity by Activating the PI3K/ERK-Mediated Nrf2-ARE Signaling Pathway in INS-1 Pancreatic β-Cells

“…Our results are consistent with previous studies conducted in not only β-cells (58) but also in other type of cells (59). This phenomenon may be explained by our previous observation that Plin5 expression is also moderately induced by palmitate treatment (26) and hence elevated Plin5 expression may contribute to the antioxidant response in βcells, although the details are still inexplicit. While, this adaptive response which may represent an attempt to minimize palmitate's prooxidant actions is not sufficient to overcome palmitatemediated oxidative damage, which ultimately leads to a dramatic elevation of intracellular ROS levels.…”

“…Plin5 expression and its overexpression or deletion by adenovirus transduction were confirmed by Western blot in INS-1 β-cells ( Figure 1A, the upper side). In the present study, overexpression of Plin5 alleviated palmitateinduced apoptosis, which is consistent with our previous study ( Figure 1A) (26). Interestingly, deletion of Plin5 in INS-1 cells didn't augment lipotoxicity, which may be due to the relatively low expression of Plin5 in pancreatic β-cells compared with other members of Plins family (33).…”

“…However, the regulation of Plin5 in FFA-induced oxidative stress and oxidant damage in pancreatic β-cells, to our knowledge, is not established until now. In previous work including ours' , Plin5 was found to play the pivotal role in β-cell survival and function (26,27). Here, we hypothesize that Plin5 may exert protective effects on pancreatic β-cells under lipotoxic conditions by modulating the cellular oxidative stress levels.…”

“…Recently, Plin5 has been established as a LD protein important for lipid metabolism and insulin secretion in β-cells (27). And our previous data showed that Plin5 alleviated nutrition overload-induced endoplasmic reticulum stress in pancreatic β-cells (26). However, whether Plin5 may also modulate oxidative stress and alleviate oxidative injuries in pancreatic β-cells, the hypersensitive targets of oxidative damage, and the detailed molecular mechanisms involved are not understood.…”

“…Plin5 serves as an LD protein in human islets, mouse islets and pancreatic β-cell lines (MIN6 and INS-1) (26,27), however its concrete role in β-cell's function and survival is rarely defined. We previously reported that upregulation of Plin5 decreased cell apoptosis, and hence protected β-cells from palmitateinduced lipotoxicity by alleviating endoplasmic reticulum stress in pancreatic β-cells (26). Nevertheless, endoplasmic reticulum stress cannot be used to entirely explain the differences in cell apoptosis observed between Plin5-overexpression INS-1 cells and the control cells because its improvement only blunts the lipotoxic effects, not ablates them.…”