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J. Biol. Chem., Vol. 277, Issue 38, 35625-35634, September 20, 2002

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Insulin and Sterol-regulatory Element-binding Protein-1c (SREBP-1C) Regulation of Gene Expression in 3T3-L1 Adipocytes
IDENTIFICATION OF CCAAT/ENHANCER-BINDING PROTEIN  AS AN SREBP-1C TARGET^*

Soazig Le Lay, Isabelle Lefrère^§¶, Christian Trautwein, Isabelle Dugail^**, and Stéphane Krief^§¶

From ^§ GlaxoSmithKline Laboratoires Pharmaceutiques, 4 rue du Chesnay-Beauregard, BP 58, 35762 Saint-Grégoire, France and  INSERM Unité 465, Centre de Recherches Biomédicales des Cordeliers, 15 rue de l'École de Médecine, 75270 Paris Cedex 06, France, and the  Department of Gastroenterology, Hepatology, and Endocrinology, Medizinische Hochschule Hannover, 30625 Hannover, Germany

We evaluated the hypothesis of sterol-regulatory element-binding protein (SREBP)-1c being a general mediator of the transcriptional effects of insulin, with a focus on adipocytes, in which insulin profoundly influences specific gene expression. Using real time quantitative reverse transcriptase-PCR to monitor changes in the expression of about 50 genes that cover a wide range of adipocyte functions, we have compared the impact of insulin treatment with that of adenoviral overexpression of either dominant positive or dominant negative SREBP-1c mutants in 3T3-L1 adipocytes. As expected, insulin up-regulated, dominant positive stimulated, and dominant negative decreased previously characterized direct SREBP targets (FAS, SCD-1, and low density lipoprotein receptor). We also identified three novel SREBP-1c transcriptional targets in adipocytes, which were confirmed by run-on assays: plasminogen activator inhibitor 1, CCAAT/enhancer-binding protein  (C/EBP), and C/EBP. Because most insulin-regulated genes were also modulated by SREBP-1c mutants, our data establish that 1) SREBP-1c is an important mediator of insulin transcriptional effects in adipocytes, and 2) C/EBP is under the direct control of SREBP-1c, as demonstrated by the ability of SREBP-1c to activate the transcription from C/EBP promoter through canonical SREBP binding sites. Thus, some of the effects of insulin and/or SREBP-1c in mature fat cells might require C/EBP or C/EBP as transcriptional relays.

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