Death Protein 5 and p53-Upregulated Modulator of Apoptosis Mediate the Endoplasmic Reticulum Stress–Mitochondrial Dialog Triggering Lipotoxic Rodent and Human β-Cell Apoptosis

  1. Miriam Cnop1,6
  1. 1Laboratory of Experimental Medicine, Université Libre de Bruxelles, Brussels, Belgium
  2. 2Laboratory of Neurophysiology, Université Libre de Bruxelles, Brussels, Belgium
  3. 3Laboratory of Experimental Medicine Endocrinology (LEGENDO), Faculty of Medicine, Katholieke Universiteit Leuven, Leuven, Belgium
  4. 4Department of Endocrinology and Metabolism, University of Pisa, Pisa, Italy
  5. 5University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Cambridge, U.K.
  6. 6Division of Endocrinology, Erasmus Hospital, Université Libre de Bruxelles, Brussels, Belgium
  1. Corresponding author: Miriam Cnop, mcnop{at}ulb.ac.be.

Abstract

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.

Footnotes

  • Received February 7, 2012.
  • Accepted May 4, 2012.

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  1. Diabetes vol. 61 no. 11 2763-2775
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