| Carboxypeptidase E mediates palmitate-induced beta-cell ER stress and apoptosis. | |
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MedLine Citation:
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PMID: 18550819 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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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Authors:
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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:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2008-06-11 |
Journal Detail:
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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:
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Created Date: 2008-06-19 Completed Date: 2008-07-18 Revised Date: 2009-11-18 |
Medline Journal Info:
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Nlm Unique ID: 7505876 Medline TA: Proc Natl Acad Sci U S A Country: United States |
Other Details:
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Languages: eng Pagination: 8452-7 Citation Subset: IM |
Affiliation:
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Diabetes Research Group, Laboratory of Molecular Signalling in Diabetes, Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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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:
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DK31842/DK/NIDDK NIH HHS; P41RR00954/RR/NCRR NIH HHS |
| Chemical | |
Reg. No./Substance:
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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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