Lipotoxic Stress Induces Pancreatic β-Cell Apoptosis through Modulation of Bcl-2 Proteins by the Ubiquitin-Proteasome System

Pancreatic β-cell loss induced by saturated free fatty acids (ffas) is believed to contribute to type 2 diabetes. previous studies have shown induction of endoplasmic reticulum (er) stress,increased ubiquitinated proteins,and deregulation of the bcl-2 family in the pancreas of type 2 diabetic patients. however,the precise mechanism of β-cell death remains unknown. in the present study we demonstrate that the ffa palmitate blocks the ubiquitin-proteasome system (ups) and causes apoptosis through induction of er stress and deregulation of bcl-2 proteins. we found that palmitate and the proteasome inhibitor mg132 induced er stress in β-cells,resulting in decreased expression of the prosurvival proteins bcl-2,mcl-1,and bcl-xl,and upregulation of the prodeath bh3-only protein puma. on the other hand,pharmacological activation of the ups by sulforaphane ameliorated er stress,upregulated prosurvival bcl-2 proteins,and protected β-cells from ffa-induced cell death. furthermore,transgenic overexpression of bcl-2 protected islets from ffa-induced cell death in vitro and improved glucose-induced insulin secretion in vivo. together our results suggest that targeting the ups and bcl-2 protein expression may be a valuable strategy to prevent β-cell demise in type 2 diabetes. © 2015 sara a. litwak et al.