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Papers In Press, published online ahead of print February 24, 2003
Division de Biochimie Clinique, Centre Médical Universitaire, Geneva, GE CH-11
Corresponding Author: Haiyan.Wang{at}medecine.unige.ch
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. In fact, the SREBP-1c maturation could be implicated in the pathogenesis of beta-cell glucolipotoxicity.
J. Biol. Chem, 10.1074/jbc.M212488200
Submitted on December 9, 2002
Revised on February 21, 2003
Accepted on February 24, 2003
The transcription factor SREBP-1c is instrumental in the development of beta-cell dysfunction
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