Title: Initiation and execution of lipotoxic ER stress in pancreatic beta-cells
Authors: 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 #
Issue Date: Jul-2008
Publisher: Co. of Biologists
Series Title: Journal of Cell Science vol:121 issue:14 pages:2308-2318
Abstract: 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.
ISSN: 0021-9533
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Clinical and Experimental Endocrinology
× corresponding author
# (joint) last author

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