Carboxypeptidase 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% 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.
Jeffrey
Kristin D
KD
Diabetes Research Group, Laboratory of Molecular Signalling in Diabetes, Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada.
Alejandro
Emilyn U
EU
Luciani
Dan S
DS
Kalynyak
Tatyana B
TB
Hu
Xiaoke
X
Li
Hong
H
Lin
Yalin
Y
Townsend
R Reid
RR
Polonsky
Kenneth S
KS
Johnson
James D
JD
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D043423:Carboxypeptidase H / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000201:enzymology*; D006056:Golgi Apparatus / Q000201:enzymology; D006801:Humans; D006943:Hyperglycemia / Q000201:enzymology / Q000235:genetics; D006946:Hyperinsulinism / Q000201:enzymology / Q000235:genetics; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000201:enzymology* / Q000648:ultrastructure; D051379:Mice; D008817:Mice, Mutant Strains; D010168:Palmitates / Q000378:metabolism* / Q000494:pharmacology; D020543:Proteome
D010168:Palmitates; D020543:Proteome; D043423:Carboxypeptidase H