Death Protein 5 and p53-Upregulated Modulator of Apoptosis Mediate the Endoplasmic Reticulum Stress–Mitochondrial Dialog Triggering Lipotoxic Rodent and Human β-Cell Apoptosis
- Daniel A. Cunha1,
- Mariana Igoillo-Esteve1,
- Esteban N. Gurzov1,
- Carla M. Germano1,
- Najib Naamane1,
- Ihsane Marhfour1,
- Makiko Fukaya1,
- Jean-Marie Vanderwinden2,
- Conny Gysemans3,
- Chantal Mathieu3,
- Lorella Marselli4,
- Piero Marchetti4,
- Heather P. Harding5,
- David Ron5,
- Décio L. Eizirik1 and
- Miriam Cnop1,6⇓
- 1Laboratory of Experimental Medicine, Université Libre de Bruxelles, Brussels, Belgium
- 2Laboratory of Neurophysiology, Université Libre de Bruxelles, Brussels, Belgium
- 3Laboratory of Experimental Medicine Endocrinology (LEGENDO), Faculty of Medicine, Katholieke Universiteit Leuven, Leuven, Belgium
- 4Department of Endocrinology and Metabolism, University of Pisa, Pisa, Italy
- 5University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Cambridge, U.K.
- 6Division of Endocrinology, Erasmus Hospital, Université Libre de Bruxelles, Brussels, Belgium
- Corresponding author: Miriam Cnop, .
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.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db12-0123/-/DC1.
E.N.G. is currently affiliated with the Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Melbourne, Australia.
- Received February 7, 2012.
- Accepted May 4, 2012.
- © 2012 by the American Diabetes Association.
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