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J. Biol. Chem., Vol. 279, Issue 24, 25164-25171, June 11, 2004

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Stearoyl-CoA Desaturase 1 Gene Expression Is Necessary for Fructose-mediated Induction of Lipogenic Gene Expression by Sterol Regulatory Element-binding Protein-1c-dependent and -independent Mechanisms^*

Makoto Miyazaki, Agnieszka Dobrzyn, Weng Chi Man, Kiki Chu, Harini Sampath, Hyoun-Ju Kim¶, and James M. Ntambi||

From the Departments of Biochemistry and Nutritional Sciences, University of Wisconsin, Madison, Wisconsin 53706

Stearoyl-CoA desaturase (SCD) synthesizes oleate necessary for the biosynthesis of triglycerides and other lipids. Mice with a targeted disruption of the SCD1 gene are deficient in tissue oleate and have reduced expression of the sterol regulatory element-binding protein (SREBP) and its target genes. The SREBP-1c isoform is a known mediator of insulin action on hepatic gene expression, but its transcriptional effects due to glucose or fructose are still unclear. We found that fructose compared with glucose is a stronger inducer of SREBP-1c and lipogenic gene expression, causing a dramatic increase in hepatic triglyceride levels. However, when fed to the SCD1–/– mice, fructose failed to induce SREBP-1 or lipogenic genes and the triglyceride levels were not increased. Instead fructose feeding caused a decrease in hepatic glycogen and plasma glucose levels. The induction of SREBP-1 and lipogenic gene expression as well as the levels of liver triglycerides, glycogen, and plasma glucose was partially restored when the fructose diet was supplemented with very high levels of oleate (20% by weight) but not with palmitate, stearate, or linoleate. Fructose in a long term feeding induced the expression of SCD1 and that of other lipogenic genes in the liver of SREBP-1c–/– mice, and a further increase in expression of these genes occurred when the fructose diet was supplemented with oleate. Our observations demonstrated that oleate produced by SCD is necessary for fructose-mediated induction of lipogenic gene expression through SREBP-1c-dependent and -independent mechanisms and suggested that SCD1 gene expression is important in lipid and carbohydrate homeostasis.

Received for publication, March 11, 2004

^* This work has been supported by NIDDK, National Institutes of Health Grant RO162388 (to J. M. N.) and the American Heart Association Postdoctoral Fellowship 0420051Z (to A. D.). 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.

^¶ Present address: Laboratory of Molecular Nutrition, Dept. of Clinical Dietetics and Human Nutrition, Faculty of Pharmaceutical Sciences, Josai University, Saitama 350-0295, Japan.

^|| To whom correspondence should be addressed: Dept. of Biochemistry, University of Wisconsin, 433 Babcock Dr., Madison, WI 53706. Tel.: 608-265-3700; Fax: 608-265-3272; E-mail: ntambi{at}biochem.wisc.edu.

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