Initiation and execution of lipotoxic ER stress in pancreatic beta-cells.
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.
Cunha
Daniel A
DA
Laboratory of Experimental Medicine, Université Libre de Bruxelles, Brussels, Belgium.
Hekerman
Paul
P
Ladrière
Laurence
L
Bazarra-Castro
Angie
A
Ortis
Fernanda
F
Wakeham
Marion C
MC
Moore
Fabrice
F
Rasschaert
Joanne
J
Cardozo
Alessandra K
AK
Bellomo
Elisa
E
Overbergh
Lutgart
L
Mathieu
Chantal
C
Lupi
Roberto
R
Hai
Tsonwin
T
Herchuelz
Andre
A
Marchetti
Piero
P
Rutter
Guy A
GA
Eizirik
Décio L
DL
Cnop
Miriam
M
D051700:Activating Transcription Factor 3 / Q000378:metabolism; D051702:Activating Transcription Factor 6 / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology*; D005230:Fatty Acids, Nonesterified / Q000378:metabolism / Q000633:toxicity*; D005947:Glucose / Q000633:toxicity; D006801:Humans; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008875:Middle Aged; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D051742:Transcription Factor CHOP / Q000378:metabolism; D019892:eIF-2 Kinase / Q000378:metabolism
D051700:Activating Transcription Factor 3; D051702:Activating Transcription Factor 6; D002118:Calcium; D005230:Fatty Acids, Nonesterified; D005947:Glucose; D048031:JNK Mitogen-Activated Protein Kinases; D008565:Membrane Proteins; D017346:Protein Serine-Threonine Kinases; D051742:Transcription Factor CHOP; D019892:eIF-2 Kinase; C490449:ATF3 protein, human; C497108:Atf3 protein, rat; C486557:Ern2 protein, rat