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Journal of Lipid Research, Vol. 49, 217-229, January 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Absence of stearoyl-CoA desaturase-1 ameliorates features of the metabolic syndrome in LDLR-deficient mice

Marcia L. E. MacDonald^*, Roshni R. Singaraja^*, Nagat Bissada^*, Piers Ruddle^*, Russell Watts, Joanna M. Karasinska^*, William T. Gibson^*, Catherine Fievet^,**,, Jean E. Vance, Bart Staels^,**, and Michael R. Hayden^1,*

^* Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia, and Child and Family Research Institute, Vancouver, British Columbia, Canada V5Z 4H4
Canadian Institutes of Health Research Group on the Molecular and Cell Biology of Lipids, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada T6G 2S2
Institut Pasteur de Lille, Département d'Athérosclérose, Lille, F-59019 France
^** Institut National de la Santé et de la Recherche Médicale U545, Lille, F-59019 France
Université de Lille 2, Lille, F-59006 France

Published, JLR Papers in Press, October 24, 2007.

¹ To whom correspondence should be addressed. e-mail: mrh{at}cmmt.ubc.ca

A combination of the interrelated metabolic risk factors obesity, insulin resistance, dyslipidemia, and hypertension, often described as the "metabolic syndrome," is known to increase the risk of developing cardiovascular disease and diabetes. Stearoyl-coenzyme A desaturase (SCD) activity has been implicated in the metabolic syndrome, but detailed studies of the beneficial metabolic effects of SCD deficiency have been limited. Here, we show that absence of the Scd1 gene product reduces plasma triglycerides and reduces weight gain in severely hyperlipidemic low density lipoprotein receptor (LDLR)-deficient mice challenged with a Western diet. Absence of SCD1 also increases insulin sensitivity, as measured by intraperitoneal glucose and insulin tolerance testing. SCD1 deficiency dramatically reduces hepatic lipid accumulation while causing more modest reductions in plasma apolipoproteins, suggesting that in conditions of sustained hyperlipidemia, SCD1 functions primarily to mediate lipid stores. In addition, absence of SCD1 partially ameliorates the undesirable hypertriglyceridemic effect of antiatherogenic liver X receptor agonists. Our results demonstrate that constitutive reduction of SCD activity improves the metabolic phenotype of LDLR-deficient mice on a Western diet.

Supplementary key words monounsaturated fatty acids • very low density lipoprotein • high density lipoprotein • apolipoprotein B • mouse model • liver • atherosclerosis • ATP binding cassette transporter A1 • hyperlipidemia • Western diet • low density lipoprotein receptor • coenzyme A

Abbreviations: ACC-1, acetyl-coenzyme A carboxylase-1; apoE, apolipoprotein E; FH, familial hypercholesterolemia; FPLC, fast-protein liquid chromatography; HTG, hypertriglyceridemia; LDLR, low density lipoprotein receptor; LXR, liver X receptor; SCD, stearoyl-coenzyme A desaturase; SREBP-1, sterol-regulatory element binding protein-1; TC, total cholesterol; TG, triglyceride

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