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

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    14
    Author
    Litwak, SA; Wali, JA; Pappas, EG; Saadi, H; Stanley, WJ; Varanasi, LC; Kay, TWH; Thomas, HE; Gurzov, EN
    Date
    2015-01-01
    Source Title
    Journal of Diabetes Research
    Publisher
    HINDAWI LTD
    University of Melbourne Author/s
    SAADI, HAMDI; Kay, Thomas; Thomas, Helen; Gurzov, Esteban; WALI, JIBRAN; Stanley, William
    Affiliation
    Medicine and Radiology

    Academic Services and Registrar
    Melbourne Dental School
    Metadata
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    Document Type
    Journal Article
    Citations
    Litwak, 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 Status
    Open Access
    URI
    http://hdl.handle.net/11343/261353
    DOI
    10.1155/2015/280615
    Abstract
    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.

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