Environmental factors such as diets rich in saturated fats contribute to dysfunction and death of pancreatic beta-cells in diabetes. Endoplasmic reticulum (ER) stress is elicited in beta-cells by saturated fatty acids. Here we show that palmitate-induced beta-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 beta-cells. DP5 induction depends on inositol-requiring enzyme 1 (IRE1)-dependent c-Jun NH(2)-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 beta-cell mass. This study elucidates the crosstalk between lipotoxic ER stress and the mitochondrial pathway of apoptosis that causes beta-cell death in diabetes.
|Autori:||Cunha Daniel A; Igoillo-Esteve M; Gurzov Esteban N; Germano C; Naamane N; Marhfour I; Fukaya M; Vanderwinden J-M; Gysemans C; Mathieu Cl; Marselli L; Marchetti P; Harding Heather P; Ron D; Eizirik D L; Cnop M|
|Titolo:||Death Protein 5 and p53-Upregulated Modulator of Apoptosis Mediate the Endoplasmic Reticulum Stress-Mitochondrial Dialog Triggering Lipotoxic Rodent and Human beta-Cell Apoptosis.|
|Anno del prodotto:||2012|
|Digital Object Identifier (DOI):||10.2337/db12-0123|
|Appare nelle tipologie:||1.1 Articolo in rivista|