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Molecular and Cellular Biology, September 2006, p. 6786-6798, Vol. 26, No. 18
0270-7306/06/$08.00+0     doi:10.1128/MCB.00077-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Stearoyl-Coenzyme A Desaturase 1 Deficiency Protects against Hypertriglyceridemia and Increases Plasma High-Density Lipoprotein Cholesterol Induced by Liver X Receptor Activation

Kiki Chu,1 Makoto Miyazaki,1* Weng Chi Man,1 and James M. Ntambi1,2*

Department of Biochemistry,1 Department of Nutritional Sciences, University of Wisconsin—Madison, Madison, Wisconsin 537062

Received 12 January 2006/ Returned for modification 16 February 2006/ Accepted 29 June 2006

Stearoyl-coenzyme A desaturase (SCD) is the rate-limiting enzyme necessary for the biosynthesis of monounsaturated fatty acids. In this study, we investigated the regulation of mouse SCD1 by liver X receptor (LXR) and its role in plasma lipoprotein metabolism upon LXR activation. In vivo, the SCD1 gene remained induced upon LXR activation in the absence of sterol regulatory element-binding protein 1c (SREBP-1c), a known transcriptional regulator of SCD1. Serial deletion and point mutation analyses in reporter gene assays, as well as a gel mobility shift assay, identified an LXR response element in the mouse SCD1 promoter. In addition, SCD1 deficiency prevented the hypertriglyceridemic effect and reduced hepatic triglyceride accumulation associated with LXR activation despite induced hepatic expression of SREBP-1c protein and several SREBP1c and LXR target genes involved in lipoprotein metabolism. Unlike wild-type mice, SCD1-deficient mice failed to elevate the hepatic triglyceride monounsaturated acid (MUFA)/saturated fatty acid (SFA) ratio despite induction of the SCD2 gene. Together, these findings suggest that SCD1 plays a pivotal role in the regulation of hepatic and plasma triglyceride accumulation, possibly by modulating the MUFA-to-SFA ratio. In addition, SCD1 deficiency also increased plasma high-density lipoprotein cholesterol levels induced by LXR activation.

* Corresponding author. Mailing address: Department of Biochemistry, University of Wisconsin—Madison, 433 Babcock Drive, Madison, WI 53706. Phone: (608) 265-3700. Fax: (608) 265-3272. E-mail for Makoto Miyazaki: miyazakim{at}biochem.wisc.edu. E-mail for James M. Ntambi: ntambi{at}biochem.wisc.edu.

Molecular and Cellular Biology, September 2006, p. 6786-6798, Vol. 26, No. 18
0270-7306/06/$08.00+0     doi:10.1128/MCB.00077-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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