| First Author | Cunha DA | Year | 2012 |
| Journal | Diabetes | Volume | 61 |
| Issue | 11 | Pages | 2763-75 |
| PubMed ID | 22773666 | Mgi Jnum | J:208516 |
| Mgi Id | MGI:5563635 | Doi | 10.2337/db12-0123 |
| Citation | Cunha DA, et al. (2012) Death protein 5 and p53-upregulated modulator of apoptosis mediate the endoplasmic reticulum stress-mitochondrial dialog triggering lipotoxic rodent and human beta-cell apoptosis. Diabetes 61(11):2763-75 |
| abstractText | 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. |
