par Andrade Da Cunha, Daniel ;Hekerman, Paul ;Ladrière, Laurence ;Bazarra-Castro, A.;Ortis, Fernanda ;Wakeham, Marion ;Moore, Fabrice ;Rasschaert, Joanne ;Cardozo, Alessandra K ;Bellomo, Elisa;Overbergh, Lutgart;Mathieu, Chantal;Lupi, R.;Hai, Tsonwin;Herchuelz, André ;Marchetti, Piero;Rutter, Guy A;Eizirik, Decio L. ;Cnop, Miriam
Référence Journal of cell science, 121, Pt 14, page (2308-2318)
Publication Publié, 2008
Référence Journal of cell science, 121, Pt 14, page (2308-2318)
Publication Publié, 2008
Article révisé par les pairs
Résumé : | 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 Ca(2+) 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 Ca(2+) depletion. The IRE1 and resulting JNK activation contribute to beta-cell apoptosis. PERK activation by palmitate also contributes to beta-cell apoptosis via CHOP. |