biostudies-literatureJeffrey KDNIDDK NIH HHSNCRR NIH HHS8452-7https://www.ebi.ac.uk/biostudies/studies/S-EPMC2448857biostudies-literatureUnknown105(24)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% uProceedings of the National Academy of Sciences of the United States of AmericaCarboxypeptidase E mediates palmitate-induced beta-cell ER stress and apoptosis.PMC2448857P41RR00954R37 DK031842DK31842F31 DK079346R01 DK031842P30 DK052574P41 RR000954Li HJeffrey KDTownsend RRPolonsky KSKalynyak TBHu XLuciani DSJohnson JDLin YAlejandro EUfalseCarboxypeptidase E mediates palmitate-induced beta-cell ER stress and apoptosis.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% u2008-01-01T00:00:00Z2008 Jun2025-04-04T18:33:56.984Z2019-03-27T00:15:46ZS-EPMC24488571855081910.1073/pnas.0711232105