Lipotoxic Stress Induces Pancreatic beta-Cell Apoptosis through Modulation of Bcl-2 Proteins by the Ubiquitin-Proteasome System
AuthorLitwak, SA; Wali, JA; Pappas, EG; Saadi, H; Stanley, WJ; Varanasi, LC; Kay, TWH; Thomas, HE; Gurzov, EN
Source TitleJournal of Diabetes Research
University of Melbourne Author/sSAADI, HAMDI; Kay, Thomas; Thomas, Helen; Gurzov, Esteban; WALI, JIBRAN; Stanley, William
AffiliationMedicine and Radiology
Academic Services and Registrar
Melbourne Dental School
Document TypeJournal Article
CitationsLitwak, S. A., Wali, J. A., Pappas, E. G., Saadi, H., Stanley, W. J., Varanasi, L. C., Kay, T. W. H., Thomas, H. E. & Gurzov, E. N. (2015). Lipotoxic Stress Induces Pancreatic beta-Cell Apoptosis through Modulation of Bcl-2 Proteins by the Ubiquitin-Proteasome System. JOURNAL OF DIABETES RESEARCH, 2015, https://doi.org/10.1155/2015/280615.
Access StatusOpen Access
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.
- Click on "Export Reference in RIS Format" and choose "open with... Endnote".
- Click on "Export Reference in RIS Format". Login to Refworks, go to References => Import References