Death Protein 5 and p53-Upregulated Modulator of Apoptosis Mediate the Endoplasmic Reticulum Stress-Mitochondrial Dialog Triggering Lipotoxic Rodent and Human β-Cell Apoptosis
| Autor: | Lorella Marselli, Daniel Andrade Da Cunha, Chantal Mathieu, Conny Gysemans, Decio L. Eizirik, Najib Naamane, Piero Marchetti, David Ron, Carla Maria Ramos C.M. Germano, Jean-Marie Vanderwinden, Mariana Igoillo-Esteve, Esteban Nicolas Gurzov, Ihsane Marhfour, Makiko Fukaya, Heather P. Harding, Miriam Cnop |
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| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Male
Endocrinology Diabetes and Metabolism Palmitic Acid Proto-Oncogene Proteins -- antagonists & inhibitors -- genetics -- metabolism Apoptosis Mitochondrion ACTIVATION Mice Mitochondria -- metabolism Puma Insulin-Secreting Cells Insulin-Secreting Cells -- cytology -- metabolism RNA Small Interfering Cells Cultured Mice Knockout biology FREE FATTY-ACIDS Sciences bio-médicales et agricoles Middle Aged ER STRESS Endoplasmic Reticulum Stress Cell biology Mitochondria RNA Interference Life Sciences & Biomedicine Signal Transduction medicine.medical_specialty Programmed cell death KAPPA-B Cell Line CONTRIBUTES Endocrinology & Metabolism Internal medicine Proto-Oncogene Proteins SELECTIVE-INHIBITION PUMA Internal Medicine medicine Animals Humans p53 upregulated modulator of apoptosis RNA Messenger Protein kinase B INDUCIBLE GENE Aged Science & Technology Endoplasmic reticulum Palmitic Acid -- adverse effects Gene Expression Profiling JNK PHOSPHORYLATION biology.organism_classification RNA Messenger -- metabolism Rats Mice Inbred C57BL Endocrinology DEPENDENT APOPTOSIS biology.protein Unfolded protein response Apoptosis Regulatory Proteins Apoptosis Regulatory Proteins -- antagonists & inhibitors -- genetics -- metabolism |
| Zdroj: | Diabetes Diabetes (New York, N.Y.), 61 (11 |
| Popis: | 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. info:eu-repo/semantics/published |
| Databáze: | OpenAIRE |
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