1. Lipotoxic Stress Induces Pancreatic β-Cell Apoptosis through Modulation of Bcl-2 Proteins by the Ubiquitin-Proteasome System.
- Author
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Litwak SA, Wali JA, Pappas EG, Saadi H, Stanley WJ, Varanasi LC, Kay TW, Thomas HE, and Gurzov EN
- Subjects
- Animals, Cell Line, Cell Survival drug effects, Endoplasmic Reticulum Stress drug effects, Humans, Insulin-Secreting Cells drug effects, Leupeptins pharmacology, Mice, Ubiquitination drug effects, Apoptosis drug effects, Insulin-Secreting Cells metabolism, Palmitic Acid pharmacology, Proteasome Endopeptidase Complex metabolism, Proto-Oncogene Proteins c-bcl-2 metabolism, Ubiquitin metabolism
- Abstract
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.
- Published
- 2015
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