Carboxypeptidase E mediates palmitate-induced beta-cell ER stress and apoptosis |
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Authors: | Jeffrey Kristin D Alejandro Emilyn U Luciani Dan S Kalynyak Tatyana B Hu Xiaoke Li Hong Lin Yalin Townsend R Reid Polonsky Kenneth S Johnson James D |
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Institution: | Diabetes Research Group, Laboratory of Molecular Signalling in Diabetes, Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada. |
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Abstract: | Obesity is a principal risk factor for type 2 diabetes, and elevated fatty acids reduce beta-cell function and survival. An unbiased proteomic screen was used to identify targets of palmitate in beta-cell death. The most significantly altered protein in both human islets and MIN6 beta-cells treated with palmitate was carboxypeptidase E (CPE). Palmitate reduced CPE protein levels within 2 h, preceding endoplasmic reticulum (ER) stress and cell death, by a mechanism involving CPE translocation to Golgi and lysosomal degradation. Palmitate metabolism and Ca(2+) flux were also required for CPE proteolysis and beta-cell death. Chronic palmitate exposure increased the ratio of proinsulin to insulin. CPE null islets had increased apoptosis in vivo and in vitro. Reducing CPE by approximately 30% using shRNA also increased ER stress and apoptosis. Conversely, overexpression of CPE partially rescued beta-cells from palmitate-induced ER stress and apoptosis. Thus, carboxypeptidase E degradation contributes to palmitate-induced beta-cell ER stress and apoptosis. CPE is a major link between hyperlipidemia and beta-cell death pathways in diabetes. |
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Keywords: | 2D difference gel electrophoresis proteomics free fatty acids hyperproinsulinemia mechanisms of β-cell lipotoxicity type 2 diabetes |
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