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J. Biol. Chem., Vol. 282, Issue 6, 3989-3997, February 9, 2007

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

Miriam Cnop¹, Laurence Ladriere, Paul Hekerman, Fernanda Ortis, Alessandra K. Cardozo², Zeynep Dogusan, Daisy Flamez, Michael Boyce^¶, Junying Yuan^¶, and Decio L. Eizirik

From the Laboratory of Experimental Medicine, Université Libre de Bruxelles, 1070 Brussels, Belgium, the Division of Endocrinology, Erasmus Hospital, 1070 Brussels, Belgium, and the ^¶Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115

Free fatty acids cause pancreatic -cell apoptosis and may contribute to -cell loss in type 2 diabetes via the induction of endoplasmic reticulum stress. Reductions in eukaryotic translation initiation factor (eIF) 2 phosphorylation trigger -cell failure and diabetes. Salubrinal selectively inhibits eIF2 dephosphorylation, protects other cells against endoplasmic reticulum stress-mediated apoptosis, and has been proposed as a -cell protector. Unexpectedly, salubrinal induced apoptosis in primary -cells, and it potentiated the deleterious effects of oleate and palmitate. Salubrinal induced a marked eIF2 phosphorylation and potentiated the inhibitory effects of free fatty acids on protein synthesis and insulin release. The synergistic activation of the PERK-eIF2 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 eIF2 phosphorylation is poorly tolerated by -cells and exacerbates free fatty acid-induced apoptosis. This modifies the present paradigm regarding the beneficial role of eIF2 phosphorylation in -cells and must be taken into consideration when designing therapies to protect -cells in type 2 diabetes.

Received for publication, August 10, 2006 , and in revised form, November 17, 2006.

^* This work was supported by a grant from the European Foundation for the Study of Diabetes-Novo Nordisk Programme in Diabetes Research, by European Union Integrated Project EuroDia LSHM-CT-2006-518153 in the Framework Programme 6 of the European Community, and a Belgian Lipid Club research fellowship and by grants from the Octave Dupont Foundation (Royal Academy of Science of Belgium), the Fonds National de la Recherche Scientifique, Fonds de la Recherche Scientifique Médicale, and Actions de Recherche Concertées da la Communauté Française, Belgium (to M. C. and D. L. E.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S10.

² Recipient of an Advanced Post-doctoral Fellowship from the Juvenile Diabetes Research Foundation International.

¹ To whom correspondence should be addressed: Laboratory of Experimental Medicine, Université Libre de Bruxelles CP-618, Route de Lennik 808, 1070 Brussels, Belgium. Tel.: 32-2-555-63-05; Fax: 32-2-555-62-39; E-mail: mcnop{at}ulb.ac.be.

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