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Journal of Lipid Research, Vol. 49, 1068-1076, May 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Mechanisms of hepatic steatosis in mice fed a lipogenic methionine choline-deficient diet^*

Mary E. Rinella^1,*, Marc S. Elias^*, Robin R. Smolak^*, Tao Fu^*,, Jayme Borensztajn and Richard M. Green^*

^* Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL
Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL

^* These studies were supported by Grant R01 DK-059580 (R.M.G.), by an American Gastroenterological Association Research Scholar Award, National Institutes of Health Grant K08 DK-066032 (M.E.R.), and by the Sidney and Bess Eisenberg Memorial Fund (J.B.).

Published, JLR Papers in Press, January 28, 2008.

¹ To whom correspondence should be addressed. e-mail: m-rinella{at}northwestern.edu

The methionine choline-deficient (MCD) diet results in liver injury similar to human nonalcoholic steatohepatitis (NASH). The aims of this study were to define mechanisms of MCD-induced steatosis in insulin-resistant db/db and insulin-sensitive db/m mice. MCD-fed db/db mice developed more hepatic steatosis and retained more insulin resistance than MCD-fed db/m mice. Both subcutaneous and gonadal fat were reduced by MCD feeding: gonadal fat decreased by 23% in db/db mice and by 90% in db/m mice. Weight loss was attenuated in the db/db mice, being only 13% compared with 35% in MCD-fed db/db and db/m mice, respectively. Both strains had upregulation of hepatic fatty acid transport proteins as well as increased hepatic uptake of [¹⁴C]oleic acid: 3-fold in db/m mice (P < 0.001) and 2-fold in db/db mice (P < 0.01) after 4 weeks of MCD feeding. In both murine strains, the MCD diet reduced triglyceride secretion and downregulated genes involved in triglyceride synthesis. Therefore, increased fatty acid uptake and decreased VLDL secretion represent two important mechanisms by which the MCD diet promotes intrahepatic lipid accumulation in this model. Feeding the MCD diet to diabetic rodents broadens the applicability of this model for the study of human NASH.

Supplementary key words nonalcoholic steatohepatitis • db/db mouse • lipid metabolism • visceral fat

Abbreviations: AOX, acyl-coenzyme A oxidase; apoB, apolipoprotein B; CPT, carnitine palmitoyltransferase; FATP, fatty acid transport protein; FPLC, fast-protein liquid chromatography; MCD, methionine choline-deficient; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; PPAR, peroxisome proliferator-activated receptor; QUICKI, Quantitative Insulin Sensitivity Check Index; RT, real-time; SCD-1, stearoyl-coenzyme A desaturase-1; SREBP, sterol-regulatory element binding protein

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