| Title: | Lipotoxic Stress Induces Pancreatic beta-Cell Apoptosis through Modulation of Bcl-2 Proteins by the Ubiquitin-Proteasome System |
| Authors: | Litwak, SA Wali, JA Pappas, EG Saadi, H Stanley, WJ Varanasi, LC Kay, TWH Thomas, HE Gurzov, EN |
| Issue Year: | 2015 |
| Publisher | HINDAWI PUBLISHING CORPORATION |
| Series | JOURNAL OF DIABETES RESEARCH: (): - |
| Abstract | Pancreatic beta-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 precisemechanism of beta-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 beta-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 beta-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 beta-cell demise in type 2 diabetes. |
| URI: | https://publications.svi.edu.au/publications/1816 |
| Other Identifiers | 10.1155/2015/280615 |
| Publication type | Article |
| Grant ID | GNT1071350;GNT1037321; GNT1042735; |
| Find it online | http://www.hindawi.com/journals/jdr/2015/280615/ |