Initiation and execution of lipotoxic ER stress in pancreatic beta-cells
Cunha, Daniel A × Hekerman, Paul Ladriere, Laurence Bazarra-Castro, Angie Ortis, Fernanda Wakeham, Marion C Moore, Fabrice Rasschaert, Joanne Cardozo, Alessandra K Bellomo, Elisa Overbergh, Lutgart Mathieu, Chantal Lupi, Roberto Hai, Tsonwin Herchuelz, Andre Marchetti, Piero Rutter, Guy A Eizirik, Decio L Cnop, Miriam #
Co. of Biologists
Journal of Cell Science vol:121 issue:14 pages:2308-2318
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.