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 β-cell function and survival. An unbiased proteomic screen was used to identify targets of palmitate in β-cell death. The most significantly altered protein in both human islets and MIN6 β-cells treated with palm...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2008-06, Vol.105 (24), p.8452
Main Authors: Jeffrey, Kristin D, Alejandro, Emilyn U, Luciani, Dan S, Kalynyak, Tatyana B, Hu, Xiaoke, Li, Hong, Lin, Yalin, Townsend, R Reid, Polonsky, Kenneth S, Johnson, James D
Format: Article
Language:English
Subjects:
Apoptosis
Cells
Diabetes
Obesity
Peptides
Proteins
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Summary:Obesity is a principal risk factor for type 2 diabetes, and elevated fatty acids reduce β-cell function and survival. An unbiased proteomic screen was used to identify targets of palmitate in β-cell death. The most significantly altered protein in both human islets and MIN6 β-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... flux were also required for CPE proteolysis and β-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 ...30% using shRNA also increased ER stress and apoptosis. Conversely, overexpression of CPE partially rescued β-cells from palmitate-induced ER stress and apoptosis. Thus, carboxypeptidase E degradation contributes to palmitate-induced β-cell ER stress and apoptosis. CPE is a major link between hyperlipidemia and β-cell death pathways in diabetes. (ProQuest: ... denotes formulae/symbols omitted.)
ISSN:0027-8424
1091-6490