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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 beta-cell apoptosis.

par Andrade Da Cunha, Daniel ;Igoillo Esteve, Mariana ;Gurzov, Esteban Nicolas ;Germano, Carla Maria Ramos C.M.;Naamane, Najib ;Marhfour, Ihsane ;Fukaya, Makiko ;Vanderwinden, Jean-Marie ;Gysemans, Conny;Mathieu, Chantal;Marselli, Lorella;Marchetti, Piero;Harding, Heather HP;Ron, David;Eizirik, Decio ;Cnop, Miriam
Référence Diabetes (New York, N.Y.), 61, 11, page (2763-2775)
Publication Publié, 2012-11

Article révisé par les pairs

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Résumé :

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.