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Originally published In Press as doi:10.1074/jbc.M212488200 on February 24, 2003

J. Biol. Chem., Vol. 278, Issue 19, 16622-16629, May 9, 2003
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The Transcription Factor SREBP-1c Is Instrumental in the Development of beta -Cell Dysfunction*

Haiyan WangDagger , Pierre Maechler§, Peter A. Antinozzi, Laura Herrero||, Kerstin A. Hagenfeldt-Johansson**, Anneli BjörklundDagger Dagger , and Claes B. Wollheim

From the Division of Clinical Biochemistry, Department of Internal Medicine, University Medical Centre, Geneva-4 CH-1211, Switzerland

Accumulation of lipids in non-adipose tissues is often associated with Type 2 diabetes and its complications. Elevated expression of the lipogenic transcription factor, sterol regulatory element binding protein-1c (SREBP-1c), has been demonstrated in islets and liver of diabetic animals. To elucidate the molecular mechanisms underlying SREBP-1c-induced beta -cell dysfunction, we employed the Tet-On inducible system to achieve tightly controlled and conditional expression of the nuclear active form of SREBP-1c (naSREBP-1c) in INS-1 cells. Controlled expression of naSREBP-1c induced massive accumulation of lipid droplets and blunted nutrient-stimulated insulin secretion in INS-1 cells. K+-evoked insulin exocytosis was unaltered. Quantification of the gene expression profile in this INS-1 stable clone revealed that naSREBP-1c induced beta -cell dysfunction by targeting multiple genes dedicated to carbohydrate metabolism, lipid biosynthesis, cell growth, and apoptosis. naSREBP-1c elicits cell growth-arrest and eventually apoptosis. We also found that the SREBP-1c processing in beta -cells was irresponsive to acute stimulation of glucose and insulin, which was distinct from that in lipogenic tissues. However, 2-day exposure to these agents promoted SREBP-1c processing. Therefore, the SREBP-1c maturation could be implicated in the pathogenesis of beta -cell glucolipotoxicity.

* This work was supported by Swiss National Science Foundation Grant 32-49755.96 (to C. B. W.) and the Leenaards Foundation (to P. M.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger To whom correspondence should be addressed. Tel.: 41-22-702-5548; Fax: 41-22-702-5543; E-mail: Haiyan.Wang@medicine.unige.ch.

§ Fellow of the Dr. Max Cloetta Foundation.

Present address: Cellular Biochemistry and Biophysics, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., Box 251, New York, NY 10021.

|| Present address: Dept. of Biochemistry, School of Pharmacy, University of Barcelona, E-08028 Barcelona, Spain.

** Present address: Swiss Institute for Experimental Cancer Research (ISREC), CH-1066 Epalinges, Switzerland.

Dagger Dagger Present address: Rolf Luft Center of Diabetes Research, Endocrine and Diabetes Unit, Dept. of Molecular Medicine, Karolinska Institute, Karolinska Hospital, Stockholm, Sweden.

Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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