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