Document Detail


Carboxypeptidase E mediates palmitate-induced beta-cell ER stress and apoptosis.
MedLine Citation:
PMID:  18550819     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Kristin D Jeffrey; Emilyn U Alejandro; Dan S Luciani; Tatyana B Kalynyak; Xiaoke Hu; Hong Li; Yalin Lin; R Reid Townsend; Kenneth S Polonsky; James D Johnson
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2008-06-11
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  105     ISSN:  1091-6490     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2008 Jun 
Date Detail:
Created Date:  2008-06-19     Completed Date:  2008-07-18     Revised Date:  2013-06-05    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  8452-7     Citation Subset:  IM    
Affiliation:
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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MeSH Terms
Descriptor/Qualifier:
Animals
Apoptosis* / genetics
Carboxypeptidase H / genetics,  metabolism*
Cell Survival
Cells, Cultured
Diabetes Mellitus, Type 2 / enzymology,  genetics
Endoplasmic Reticulum / enzymology*
Golgi Apparatus / enzymology
Humans
Hyperglycemia / enzymology,  genetics
Hyperinsulinism / enzymology,  genetics
Insulin-Secreting Cells / drug effects,  enzymology*,  ultrastructure
Mice
Mice, Mutant Strains
Palmitates / metabolism*,  pharmacology
Proteome*
Grant Support
ID/Acronym/Agency:
DK31842/DK/NIDDK NIH HHS; P41RR00954/RR/NCRR NIH HHS
Chemical
Reg. No./Substance:
0/Palmitates; 0/Proteome; EC 3.4.17.10/Carboxypeptidase H
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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