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J. Biol. Chem., Vol. 279, Issue 33, 34380-34387, August 13, 2004

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Insulin Regulation of Sterol Regulatory Element-binding Protein-1 Expression in L-6 Muscle Cells and 3T3 L1 Adipocytes^*

Kristen J. Nadeau, J. Wayne Leitner¶, Inga Gurerich¶, and Boris Draznin¶||

From the Division of Pediatric Endocrinology, Department of Pediatrics, University of Colorado Health Sciences Center and the ^||Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado 80262 and the ^¶Veterans Affairs Research Service, Denver VA Medical Center, Denver, Colorado 80220

Sterol regulatory element-binding proteins (SREBPs) are transcription factors that regulate enzymes required for cholesterol and fatty acid synthesis. Expression of SREBP-1 is enhanced by insulin; however, the actual insulin-signaling cascades employed are yet unclear. We determined the roles of the phosphatidylinositol (PI) 3-kinase and mitogen-activated protein (MAP) kinase-dependent pathways in the effect of mediating insulin on SREBP-1 in L-6 skeletal muscle cells and 3T3 L1 adipocytes, using wortmannin or LY294002 to inhibit the PI 3-kinase pathway, and PD98059 to inhibit the MAP kinase-dependent pathway. In myocytes, insulin increased SREBP-1 protein in a dose-dependent manner. 1 and 10 nM insulin significantly increased expression of total cellular SREBP-1 protein at 24 and 48 h, nuclear SREBP-1 protein at 24 h, and SREBP-1a mRNA at 24 h. Although wortmannin and LY294002 had no effect on this aspect of insulin action, PD98059 completely blocked each of these responses. Transfection of a dominant negative mutant of Ras similarly blocked the insulin effect on SREBP-1. In contrast, in adipocytes, the insulin effect on SREBP-1 was mediated via the PI 3-kinase and not the MAP kinase pathway. In conclusion, although insulin increases skeletal muscle SREBP-1 expression in a dose-dependent fashion via the MAP kinase-dependent signaling pathway, insulin action on adipocyte SREBP-1 is mediated via the PI 3-kinase signaling pathway. In the state of insulin resistance, characterized by selective inhibition of the PI 3-kinase pathway, the usual stimulation of lipogenesis by insulin in adipocytes may be inhibited, whereas intramyocellular lipogenesis via the MAP kinase pathway of insulin may continue unabated.

Received for publication, March 31, 2004 , and in revised form, June 7, 2004.

^* 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.

To whom correspondence should be addressed: Pediatric Endocrinology Box 256, 1056 East 19th Ave., Denver, CO 80218. Tel.: 303-399-8020 (ext. 2368); Fax: 303-864-5679; E-mail: kristen.nadeau{at}UCHSC.edu.

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