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

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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124 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)8452-8457
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number24
StatePublished - Jun 17 2008


  • 2D difference gel electrophoresis proteomics
  • Free fatty acids
  • Hyperproinsulinemia
  • Mechanisms of β-cell lipotoxicity
  • Type 2 diabetes


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