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First published online 17 June 2008
doi: 10.1242/jcs.026062

Journal of Cell Science 121, 2308-2318 (2008)
Published by The Company of Biologists 2008
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Research Article

Initiation and execution of lipotoxic ER stress in pancreatic β-cells

Daniel A. Cunha1,*, Paul Hekerman1,*, Laurence Ladrière1,*, Angie Bazarra-Castro1, Fernanda Ortis1, Marion C. Wakeham1, Fabrice Moore1, Joanne Rasschaert1, Alessandra K. Cardozo1, Elisa Bellomo2, Lutgart Overbergh3, Chantal Mathieu3, Roberto Lupi4, Tsonwin Hai5, Andre Herchuelz6, Piero Marchetti4, Guy A. Rutter2, Décio L. Eizirik1 and Miriam Cnop1,7,{ddagger}

1 Laboratory of Experimental Medicine, Université Libre de Bruxelles CP-618, Route de Lennik 808, 1070 Brussels, Belgium
2 Department of Cell Biology, Division of Medicine, Faculty of Medicine, Imperial College London, London, UK
3 Laboratory for Experimental Medicine and Endocrinology, University Hospital Gasthuisberg, Catholic University of Leuven, Leuven, Belgium
4 Department of Endocrinology and Metabolism, Metabolic Unit, University of Pisa, Pisa, Italy
5 Department of Molecular and Cellular Biochemistry and Center for Molecular Neurobiology, Ohio State University, Columbus, OH, USA
6 Laboratory of Pharmacology, Université Libre de Bruxelles, Brussels, Belgium
7 Division of Endocrinology, Erasmus Hospital, Brussels, Belgium

{ddagger} Author for correspondence (e-mail: mcnop{at}ulb.ac.be)

Accepted 22 April 2008

Free fatty acids (FFA) cause apoptosis of pancreatic β-cells and might contribute to β-cell loss in type 2 diabetes via the induction of endoplasmic reticulum (ER) stress. We studied here the molecular mechanisms implicated in FFA-induced ER stress initiation and apoptosis in INS-1E cells, FACS-purified primary β-cells and human islets exposed to oleate and/or palmitate. Treatment with saturated and/or unsaturated FFA led to differential ER stress signaling. Palmitate induced more apoptosis and markedly activated the IRE1, PERK and ATF6 pathways, owing to a sustained depletion of ER Ca2+ stores, whereas the unsaturated FFA oleate led to milder PERK and IRE1 activation and comparable ATF6 signaling. Non-metabolizable methyl-FFA analogs induced neither ER stress nor β-cell apoptosis. The FFA-induced ER stress response was not modified by high glucose concentrations, suggesting that ER stress in primary β-cells is primarily lipotoxic, and not glucolipotoxic. Palmitate, but not oleate, activated JNK. JNK inhibitors reduced palmitate-mediated AP-1 activation and apoptosis. Blocking the transcription factor CHOP delayed palmitate-induced β-cell apoptosis. In conclusion, saturated FFA induce ER stress via ER Ca2+ depletion. The IRE1 and resulting JNK activation contribute to β-cell apoptosis. PERK activation by palmitate also contributes to β-cell apoptosis via CHOP.

Key words: Pancreatic β-cell, Islet, Endoplasmic reticulum stress, Fatty acid, Oleate, Palmitate, Lipotoxicity, Apoptosis, Type 2 diabetes






© The Company of Biologists Ltd 2008