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Papers In Press, published online ahead of print October 1, 2006
J. Lipid Res., doi:10.1194/jlr.M600198-JLR200

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Journal of Lipid Research, Vol. 47, 2280-2290, October 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

Mice fed a lipogenic methionine-choline-deficient diet develop hypermetabolism coincident with hepatic suppression of SCD-1

Gizem Rizki^*,, Lorenzo Arnaboldi^1,, Bianca Gabrielli, Jim Yan^*,, Gene S. Lee^*,, Ray K. Ng^*,, Scott M. Turner^**, Thomas M. Badger, Robert E. Pitas^, and Jacquelyn J. Maher^2,*,

^* Department of Medicine, University of California, San Francisco, San Francisco, CA
Liver Center, University of California, San Francisco, San Francisco, CA
Gladstone Institute of Cardiovascular and Neurological Disease, San Francisco, CA
^** KineMed, Emeryville, CA
Arkansas Children's Nutrition Center, University of Arkansas, Little Rock, AR
Department of Pathology, University of California, San Francisco, San Francisco, CA

The online version of this article (available at http://www.jlr.org) contains additional table.

Published, JLR Papers in Press, July 8, 2006.

¹ Present address of L. Arnaboldi: Department of Pharmacological Sciences, University of Milan, Italy.

² To whom correspondence should be addressed. e-mail: jmaher{at}medsfgh.ucsf.edu

Lipogenic diets that are completely devoid of methionine and choline (MCD) induce hepatic steatosis. MCD feeding also provokes systemic weight loss, for unclear reasons. In this study, we found that MCD feeding causes profound hepatic suppression of the gene encoding stearoyl-coenzyme A desaturase-1 (SCD-1), an enzyme whose regulation has significant effects on metabolic rate. Within 7 days of MCD exposure, hepatic SCD-1 mRNA decreased to nearly undetectable levels. By day 21, SCD-1 protein was absent from hepatic microsomes and fatty acids showed a decrease in monounsaturated species. These changes in hepatic SCD-1 were accompanied by signs of hypermetabolism. Calorimetry revealed that MCD-fed mice consumed 37% more energy than control mice (P = 0.0003). MCD feeding also stimulated fatty acid oxidation, although fatty oxidation genes were not significantly upregulated. Interestingly, despite their increased metabolic rate, MCD-fed mice did not increase their food consumption, and as a result, they lost 26% of their body weight in 21 days. In summary, MCD feeding suppresses SCD-1 in the liver, which likely contributes to hypermetabolism and weight loss. MCD feeding also induces hepatic steatosis, by an independent mechanism. Viewed together, these two disparate consequences of MCD feeding (weight loss and hepatic steatosis) give the appearance of an unusual form of lipodystrophy.

Supplementary key words liver • fatty liver • steatosis • lipogenesis • fatty acid • oxidation • stearoyl-coenzyme A desaturase-1

Abbreviations: ACC, acetyl-coenzyme A carboxylase; AMPK, AMP-activated protein kinase; BHT, butylated hydroxytoluene; CPT-1, carnitine palmitoyltransferase-1; DNL, de novo lipogenesis; MCD, methionine-choline-deficient; MCS, methionine-choline-sufficient; MTP, microsomal triglyceride transfer protein; SCD-1, stearoyl-coenzyme A desaturase-1; SREBP-1, sterol-regulatory element binding protein-1

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