Open AccessCarboxypeptidase E mediates palmitate-induced β-cell ER stress and apoptosis
Author(s) -
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
Publication year - 2008
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.0711232105
Subject(s) - unfolded protein response , apoptosis , programmed cell death , beta cell , endoplasmic reticulum , proinsulin , microbiology and biotechnology , carboxypeptidase , lipotoxicity , biology , medicine , endocrinology , chemistry , insulin , islet , biochemistry , insulin resistance , enzyme
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 Ca2+ 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 apoptosisin vivo andin 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.