Journal article

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

Sara A Litwak, Jibran A Wali, Evan G Pappas, Hamdi Saadi, William J Stanley, L Chitra Varanasi, Thomas WH Kay, Helen E Thomas, Esteban N Gurzov



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 prosurvi..

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Awarded by National Health and Medical Research Council of Australia (NHMRC)

Funding Acknowledgements

The authors thank L Elkerbout, S Fynch, S Thorburn, and C Selck for technical assistance, Dr. S Andrikopoulos (University of Melbourne) for assistance with IV-GTTs, Dr. J Allison (St Vincent's Institute) for RIP-Bcl-2 mice, Professor A Strasser(Walter and Eliza Hall Institute) for PUMA-/- mice, and Dr. T Loudovaris and Ms L Mariana (Australian Islet Transplant Consortium, St Vincent's Institute) for human islets. This work was supported by a National Health and Medical Research Council of Australia (NHMRC) Project Grant (APP1071350) and fellowship (Helen E. Thomas). Esteban N. Gurzov is supported by a Juvenile Diabetes Research Foundation (JDRF) fellowship. The St Vincent's Institute receives support from the Operational Infrastructure Support Scheme of the Government of Victoria.