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1: Proc Natl Acad Sci U S A. 2008 Jun 17;105(24):8452-7. Epub 2008 Jun 11.
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Carboxypeptidase E mediates palmitate-induced beta-cell ER stress and apoptosis.

Jeffrey KD, Alejandro EU, Luciani DS, Kalynyak TB, Hu X, Li H, Lin Y, Townsend RR, Polonsky KS, Johnson JD.

Diabetes Research Group, Laboratory of Molecular Signalling in Diabetes, Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada.

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.

Publication Types:
PMID: 18550819 [PubMed - indexed for MEDLINE]

PMCID: PMC2448857 [Available on 12/17/08]