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

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Journal of Diabetes Research - Volume 2015 2015, Article ID 280615, 16 pages -

Research Article

St Vincent’s Institute of Medical Research, Melbourne, VIC 3065, Australia

Department of Medicine, St. Vincent’s Hospital, The University of Melbourne, Melbourne, VIC 3065, Australia

Received 24 January 2015; Revised 17 April 2015; Accepted 20 April 2015

Academic Editor: Konstantinos Kantartzis

Copyright © 2015 Sara A. Litwak et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


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.

Autor: Sara A. Litwak, Jibran A. Wali, Evan G. Pappas, Hamdi Saadi, William J. Stanley, L. Chitra Varanasi, Thomas W. H. Kay, Hele



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