Selective Inhibition of Eukaryotic Translation Initiation Factor 2α Dephosphorylation Potentiates Fatty Acid-induced Endoplasmic Reticulum Stress and Causes Pancreatic β-Cell Dysfunction and Apoptosis

• Published in: The Journal of biological chemistry Vol. 282; no. 6; p. 3989
• Main Authors: Miriam Cnop, Laurence Ladriere, Paul Hekerman, Fernanda Ortis, Alessandra K. Cardozo, Zeynep Dogusan, Daisy Flamez, Michael Boyce, Junying Yuan, Decio L. Eizirik
• Format: Journal Article
• Language: English
• Published: American Society for Biochemistry and Molecular Biology 09-02-2007
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M607627200

Free fatty acids cause pancreatic β-cell apoptosis and may contribute to β-cell loss in type 2 diabetes via the induction
of endoplasmic reticulum stress. Reductions in eukaryotic translation initiation factor (eIF) 2α phosphorylation trigger β-cell
failure and diabetes. Salubrinal selectively inhibits eIF2α dephosphorylation, protects other cells against endoplasmic reticulum
stress-mediated apoptosis, and has been proposed as a β-cell protector. Unexpectedly, salubrinal induced apoptosis in primary
β-cells, and it potentiated the deleterious effects of oleate and palmitate. Salubrinal induced a marked eIF2α phosphorylation
and potentiated the inhibitory effects of free fatty acids on protein synthesis and insulin release. The synergistic activation
of the PERK-eIF2α branch of the endoplasmic reticulum stress response, but not of the IRE1 and activating transcription factor-6
pathways, led to a marked induction of activating transcription factor-4 and the pro-apoptotic transcription factor CHOP.
Our findings demonstrate that excessive eIF2α phosphorylation is poorly tolerated by β-cells and exacerbates free fatty acid-induced
apoptosis. This modifies the present paradigm regarding the beneficial role of eIF2α phosphorylation in β-cells and must be
taken into consideration when designing therapies to protect β-cells in type 2 diabetes.