Death protein 5 and p53-upregulated modulator of apoptosis mediate the endoplasmic reticulum stress-mitochondrial dialog triggering lipotoxic rodent and human β-cell apoptosis.
In: Diabetes, Jg. 61 (2012-11-01), Heft 11, S. 2763-75
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academicJournal
Zugriff:
Environmental factors such as diets rich in saturated fats contribute to dysfunction and death of pancreatic β-cells in diabetes. Endoplasmic reticulum (ER) stress is elicited in β-cells by saturated fatty acids. Here we show that palmitate-induced β-cell apoptosis is mediated by the intrinsic mitochondrial pathway. By microarray analysis, we identified a palmitate-triggered ER stress gene expression signature and the induction of the BH3-only proteins death protein 5 (DP5) and p53-upregulated modulator of apoptosis (PUMA). Knockdown of either protein reduced cytochrome c release, caspase-3 activation, and apoptosis in rat and human β-cells. DP5 induction depends on inositol-requiring enzyme 1 (IRE1)-dependent c-Jun NH₂-terminal kinase and PKR-like ER kinase (PERK)-induced activating transcription factor (ATF3) binding to its promoter. PUMA expression is also PERK/ATF3-dependent, through tribbles 3 (TRB3)-regulated AKT inhibition and FoxO3a activation. DP5(-/-) mice are protected from high fat diet-induced loss of glucose tolerance and have twofold greater pancreatic β-cell mass. This study elucidates the crosstalk between lipotoxic ER stress and the mitochondrial pathway of apoptosis that causes β-cell death in diabetes.
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Death protein 5 and p53-upregulated modulator of apoptosis mediate the endoplasmic reticulum stress-mitochondrial dialog triggering lipotoxic rodent and human β-cell apoptosis.
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Autor/in / Beteiligte Person: | Cunha, DA ; Igoillo-Esteve, M ; Gurzov, EN ; Germano, CM ; Naamane, N ; Marhfour, I ; Fukaya, M ; Vanderwinden, JM ; Gysemans, C ; Mathieu, C ; Marselli, L ; Marchetti, P ; Harding, HP ; Ron, D ; Eizirik, DL ; Cnop, M |
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Zeitschrift: | Diabetes, Jg. 61 (2012-11-01), Heft 11, S. 2763-75 |
Veröffentlichung: | Alexandria, VA : American Diabetes Association ; <i>Original Publication</i>: [New York, American Diabetes Association], 2012 |
Medientyp: | academicJournal |
ISSN: | 1939-327X (electronic) |
DOI: | 10.2337/db12-0123 |
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