Carboxypeptidase E mediates palmitate-induced β-cell ER stress and apoptosis

被引：119

作者：

Jeffrey, Kristin D. ^{[1
]}

Alejandro, Emilyn U. ^{[1
]}

Luciani, Dan S. ^{[1
]}

Kalynyak, Tatyana B. ^{[1
]}

Hu, Xiaoke ^{[1
]}

Li, Hong ^{[1
]}

Lin, Yalin ^{[1
]}

Townsend, R. Reid ^{[2
,3
]}

Polonsky, Kenneth S. ^{[2
,3
]}

Johnson, James D. ^{[1
]}

机构：

[1] Univ British Columbia, Dept Cellular & Physiol Sci, Lab Mol Signalling Diabet, Diabet Res Grp,Dept Surg, Vancouver, BC V6T 1Z3, Canada

[2] Washington Univ, Sch Med, Dept Internal Med, St Louis, MO 63110 USA

[3] Washington Univ, Sch Med, Dept Cell Biol & Physiol, St Louis, MO 63110 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2008年 / 105卷 / 24期

关键词：

2D difference gel electrophoresis proteomics; free fatty acids; hyperproinsulinemia; mechanisms of beta-cell lipotoxicity; type; 2; diabetes;

D O I：

10.1073/pnas.0711232105

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 Ca2+ flux were also required for CIPE 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 approximate to 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.

引用

页码：8452 / 8457

页数：6

共 58 条

[1] Fatty acids rapidly induce the carnitine palmitoyltransferase I gene in the pancreatic beta-cell line INS-1 [J].