The endoplasmic reticulum stress/autophagy pathway is involved in cholesterol-induced pancreatic \u03b2-cell injury

Fei-Juan Kong,Shui-Ya Sun,Jia-Qiang Zhou,Jia-Hua Wu

doi:10.1038/srep44746

Abstract

Lipotoxicity has been implicated in pancreatic β-cell dysfunction in type 2 diabetes, but the exact mechanisms remain unknown. The current study explored the role of the endoplasmic reticulum (ER) stress pathway in cholesterol-induced lipotoxicity. Two different insulinoma cell lines were treated with cholesterol with or without inhibitors. ER stress-associated proteins glucose-regulated protein (GRP) 78, activating transcription factor (ATF) 4 and C/EBP homologous protein (CHOP), as was phosphorylation of eukaryotic initiation factor (EIF) 2α, were all up-regulated by cholesterol. Cholesterol also up-regulated microtubule-associated protein 1 light chain 3 (LC3)-II and stimulated the formation of autophagic vacuoles and LC3-II aggregates. Cholesterol-induced autophagy and cell injuries were suppressed by pretreatment with the ER stress inhibitor 4-phenylbutyrate (4-PBA). Pretreatment with autophagy inhibitors E-64d/pepstatin A increased ER stress-induced cell injuries as indicated by increased cell apoptosis and decreased insulin secretion. These results suggest that cholesterol treatment induces apoptosis and dysfunction of β-cells, and enhances autophagy through activation of the ER stress pathway. More importantly, autophagy induced by cholesterol may protect β-cells against ER stress-associated cell damages.

Highlights

The past two decades have witnessed the increasing worldwide prevalence of diabetes mellitus (DM), especially type 2 diabetes mellitus (T2DM)
The results revealed that the expression of endoplasmic reticulum (ER) stress-associated proteins GRP78 (P < 0.05, Fig. 2A,B,F and G) and ATF4 (P < 0.01, Fig. 2D and I), as well as phosphorylation of EIF2α(P < 0.01, Fig. 2C and H), were up-regulated following cholesterol treatment
We investigated the involvement of the ER stress signaling pathway in pancreatic β-cell autophagy and apoptosis induced by cholesterol

Summary

Introduction

The past two decades have witnessed the increasing worldwide prevalence of diabetes mellitus (DM), especially type 2 diabetes mellitus (T2DM). Recent studies have indicated that cholesterol metabolism is closely related to β-cell function. ER stress and/or ER stress-induced apoptosis is increasingly recognized as an important mechanism in the development of DM, for β-cell loss and for insulin resistance[9,10]. Accumulating evidence suggests that ER stress-induced apoptosis may be an important mode of β-cell loss[10]. ER stress has been proposed to be associated with lipotoxicity-induced β-cell apoptosis[11,12]. We hypothesized that ER stress-mediated apoptotic pathways play a role in the mechanisms of cholesterol-induced β-cell apoptosis. We explored the role of the ER stress pathway in cholesterol-induced autophagy and apoptosis in pancreatic β-cells. We investigated the influence of autophagy on ER stress-induced pancreatic β-cell injuries

Methods

Results

Conclusion