TY - JOUR
T1 - Carboxypeptidase E mediates palmitate-induced β-cell ER stress and apoptosis
AU - Jeffrey, Kristin D.
AU - Alejandro, Emilyn U.
AU - Luciani, Dan S.
AU - Kalynyak, Tatyana B.
AU - Hu, Xiaoke
AU - Li, Hong
AU - Lin, Yalin
AU - Townsend, R. Reid
AU - Polonsky, Kenneth S.
AU - Johnson, James D.
PY - 2008/6/17
Y1 - 2008/6/17
N2 - 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 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.
AB - 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 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.
KW - 2D difference gel electrophoresis proteomics
KW - Free fatty acids
KW - Hyperproinsulinemia
KW - Mechanisms of β-cell lipotoxicity
KW - Type 2 diabetes
UR - https://www.scopus.com/pages/publications/46149098906
U2 - 10.1073/pnas.0711232105
DO - 10.1073/pnas.0711232105
M3 - Article
C2 - 18550819
AN - SCOPUS:46149098906
SN - 0027-8424
VL - 105
SP - 8452
EP - 8457
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 24
ER -