Carboxypeptidase E mediates palmitate-induced β-cell ER stress and apoptosis
| Autor: | James D. Johnson, Hong Li, Emilyn U. Alejandro, Kenneth S. Polonsky, Kristin D. Jeffrey, Xiaoke Hu, Tatyana B. Kalynyak, Yalin Lin, Raymond R. Townsend, Dan S. Luciani |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2008 |
| Předmět: |
medicine.medical_specialty
Programmed cell death Proteome Cell Survival Proteolysis medicine.medical_treatment Palmitates Golgi Apparatus Apoptosis Endoplasmic Reticulum Mice Internal medicine Hyperinsulinism Insulin-Secreting Cells medicine Animals Humans Cells Cultured Proinsulin Multidisciplinary biology medicine.diagnostic_test Endoplasmic reticulum Insulin Carboxypeptidase H biochemical phenomena metabolism and nutrition Biological Sciences Mice Mutant Strains Cell biology Endocrinology Carboxypeptidase E Diabetes Mellitus Type 2 Hyperglycemia Unfolded protein response biology.protein |
| Popis: | 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 2+ 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. |
| Databáze: | OpenAIRE |
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