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Papers In Press, published online ahead of print December 1, 2006
J. Lipid Res., doi:10.1194/jlr.M600203-JLR200

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Journal of Lipid Research, Vol. 47, 2668-2680, December 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

Cholestasis and hypercholesterolemia in SCD1-deficient mice fed a low-fat, high-carbohydrate diet

Matthew T. Flowers^*,, Albert K. Groen, Angie Tebon Oler^*, Mark P. Keller^*, YounJeong Choi^**, Kathryn L. Schueler^*, Oliver C. Richards^*, Hong Lan^*, Makoto Miyazaki^*, Folkert Kuipers, Christina M. Kendziorski^**, James M. Ntambi^*, and Alan D. Attie^1,*

^* Department of Biochemistry, University of Wisconsin-Madison, Madison, WI
Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI
^** Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI
Department of Medical Biochemistry, Academic Medical Center, Amsterdam, The Netherlands
Department of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, University Medical Center Groningen, Groningen, The Netherlands

The online version of this article (available at http://www.jlr.org) contains supplemental data in the form of 4 tables and 2 figures.

Published, JLR Papers in Press, September 28, 2006.

¹ To whom correspondence should be addressed. e-mail: attie{at}biochem.wisc.edu

Stearoyl-coenzyme A desaturase 1-deficient (SCD1^–/–) mice have impaired MUFA synthesis. When maintained on a very low-fat (VLF) diet, SCD1^–/– mice developed severe hypercholesterolemia, characterized by an increase in apolipoprotein B (apoB)-containing lipoproteins and the appearance of lipoprotein X. The rate of LDL clearance was decreased in VLF SCD1^–/– mice relative to VLF SCD1^+/+ mice, indicating that reduced apoB-containing lipoprotein clearance contributed to the hypercholesterolemia. Additionally, HDL-cholesterol was dramatically reduced in these mice. The presence of increased plasma bile acids, bilirubin, and aminotransferases in the VLF SCD1^–/– mice is indicative of cholestasis. Supplementation of the VLF diet with MUFA- and PUFA-rich canola oil, but not saturated fat-rich hydrogenated coconut oil, prevented these plasma phenotypes. However, dietary oleate was not as effective as canola oil in reducing LDL-cholesterol, signifying a role for dietary PUFA deficiency in the development of this phenotype. These results indicate that the lack of SCD1 results in an increased requirement for dietary unsaturated fat to compensate for impaired MUFA synthesis and to prevent hypercholesterolemia and hepatic dysfunction. Therefore, endogenous MUFA synthesis is essential during dietary unsaturated fat insufficiency and influences the dietary requirement of PUFA.

Supplementary key words monounsaturated fatty acids • polyunsaturated fatty acids • lipoprotein X • very low density lipoprotein • high density lipoprotein • apolipoprotein B • apolipoprotein A-I • stearoyl-coenzyme A desaturase 1 • essential fatty acid • bile acids

Abbreviations: apoB, apolipoprotein B; FPLC, fast-protein liquid chromatography; IDL, intermediate density lipoprotein; SCD1, stearoyl-coenzyme A desaturase 1; SREBP-1c, sterol-regulatory element binding protein-1c; VLF, very low-fat

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