Lipotoxic Stress Induces Pancreatic β-Cell Apoptosis through Modulation of Bcl-2 Proteins by the Ubiquitin-Proteasome System
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 pati...
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| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2015-01-01
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| Series: | Journal of Diabetes Research |
| Online Access: | http://dx.doi.org/10.1155/2015/280615 |
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| author | Sara A. Litwak Jibran A. Wali Evan G. Pappas Hamdi Saadi William J. Stanley L. Chitra Varanasi Thomas W. H. Kay Helen E. Thomas Esteban N. Gurzov |
| author_facet | Sara A. Litwak Jibran A. Wali Evan G. Pappas Hamdi Saadi William J. Stanley L. Chitra Varanasi Thomas W. H. Kay Helen E. Thomas Esteban N. Gurzov |
| author_sort | Sara A. Litwak |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-cc42862cb1e94bc789cf5a2f5e4bdf7c |
| institution | OA Journals |
| issn | 2314-6745 2314-6753 |
| language | English |
| publishDate | 2015-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Diabetes Research |
| spelling | doaj-art-cc42862cb1e94bc789cf5a2f5e4bdf7c2025-08-20T02:19:57ZengWileyJournal of Diabetes Research2314-67452314-67532015-01-01201510.1155/2015/280615280615Lipotoxic Stress Induces Pancreatic β-Cell Apoptosis through Modulation of Bcl-2 Proteins by the Ubiquitin-Proteasome SystemSara A. Litwak0Jibran A. Wali1Evan G. Pappas2Hamdi Saadi3William J. Stanley4L. Chitra Varanasi5Thomas W. H. Kay6Helen E. Thomas7Esteban N. Gurzov8St Vincent’s Institute of Medical Research, Melbourne, VIC 3065, AustraliaSt Vincent’s Institute of Medical Research, Melbourne, VIC 3065, AustraliaSt Vincent’s Institute of Medical Research, Melbourne, VIC 3065, AustraliaSt Vincent’s Institute of Medical Research, Melbourne, VIC 3065, AustraliaSt Vincent’s Institute of Medical Research, Melbourne, VIC 3065, AustraliaSt Vincent’s Institute of Medical Research, Melbourne, VIC 3065, AustraliaSt Vincent’s Institute of Medical Research, Melbourne, VIC 3065, AustraliaSt Vincent’s Institute of Medical Research, Melbourne, VIC 3065, AustraliaSt Vincent’s Institute of Medical Research, Melbourne, VIC 3065, AustraliaPancreatic 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.http://dx.doi.org/10.1155/2015/280615 |
| spellingShingle | Sara A. Litwak Jibran A. Wali Evan G. Pappas Hamdi Saadi William J. Stanley L. Chitra Varanasi Thomas W. H. Kay Helen E. Thomas Esteban N. Gurzov Lipotoxic Stress Induces Pancreatic β-Cell Apoptosis through Modulation of Bcl-2 Proteins by the Ubiquitin-Proteasome System Journal of Diabetes Research |
| title | Lipotoxic Stress Induces Pancreatic β-Cell Apoptosis through Modulation of Bcl-2 Proteins by the Ubiquitin-Proteasome System |
| title_full | Lipotoxic Stress Induces Pancreatic β-Cell Apoptosis through Modulation of Bcl-2 Proteins by the Ubiquitin-Proteasome System |
| title_fullStr | Lipotoxic Stress Induces Pancreatic β-Cell Apoptosis through Modulation of Bcl-2 Proteins by the Ubiquitin-Proteasome System |
| title_full_unstemmed | Lipotoxic Stress Induces Pancreatic β-Cell Apoptosis through Modulation of Bcl-2 Proteins by the Ubiquitin-Proteasome System |
| title_short | Lipotoxic Stress Induces Pancreatic β-Cell Apoptosis through Modulation of Bcl-2 Proteins by the Ubiquitin-Proteasome System |
| title_sort | lipotoxic stress induces pancreatic β cell apoptosis through modulation of bcl 2 proteins by the ubiquitin proteasome system |
| url | http://dx.doi.org/10.1155/2015/280615 |
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