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

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.

HDL inhibits endoplasmic reticulum stress-induced apoptosis of pancreatic β-cells in vitro by activation of Smoothened

“…Several laboratories provided data indicating that overload of the ER, mitochondria or plasma membrane with cholesterol also limits the survival of pancreatic β-cells (35). Excess cholesterol in ER membranes induces the depletion of calcium stores and subsequent ER stress and apoptosis (45). In mitochondrial membranes, excess cholesterol promotes the release of cytochrome C and hence apoptosis (46,47).…”

Autophagy in Metabolic Age-Related Human Diseases

“…Since pancreatic β-cells undergo extensive proinsulin biosynthesis, a functional endoplasmic reticulum (ER) is critical to convert pro-insulin to the mature form of insulin, facing a high protein-folding burden. Thereby, autophagy through the degradation of misfolded proteins or dysfunctional regions of the ER promotes the homeostasis of β-cells [ 22 , 23 , 24 ]. It should be noted that the unfolded protein response (UPR) is induced when the ER responds to an overload of unfolded proteins.…”

Endoplasmic Reticulum Stress in Metabolic Disorders

“…Beside long-chain fatty acids, other lipids like cholesterol, diacylglycerols, phospholipids and ceramides exert deleterious effects. For example, in beta cells, cholesterol exerts its toxic effects by activating BIP, eIF2α, ATF4 and CHOP and induces autophagy to protect the cells from ER stress-induced damages [75].…”