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JCS ePress online publication date 17 Jun 2008
doi: 10.1242/jcs.026062

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Research Article

Initiation and execution of lipotoxic ER stress in pancreatic {beta}-cells


Daniel A. Cunha, Paul Hekerman, Laurence Ladrière, Angie Bazarra-Castro, Fernanda Ortis, Marion C. Wakeham, Fabrice Moore, Joanne Rasschaert, Alessandra K. Cardozo, Elisa Bellomo, Lutgart Overbergh, Chantal Mathieu, Roberto Lupi, Tsonwin Hai, Andre Herchuelz, Piero Marchetti, Guy A. Rutter, Décio L. Eizirik, and Miriam Cnop*
* Author for correspondence (e-mail: mcnop{at}ulb.ac.be)

Free fatty acids (FFA) cause apoptosis of pancreatic {beta}-cells and might contribute to {beta}-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 {beta}-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 {beta}-cell apoptosis. The FFA-induced ER stress response was not modified by high glucose concentrations, suggesting that ER stress in primary {beta}-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 {beta}-cell apoptosis. In conclusion, saturated FFA induce ER stress via ER Ca2+ depletion. The IRE1 and resulting JNK activation contribute to {beta}-cell apoptosis. PERK activation by palmitate also contributes to {beta}-cell apoptosis via CHOP.


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