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Journal of Lipid Research, Vol. 48, 1885-1896, August 2007
Copyright © 2007 by American Society for Biochemistry and Molecular Biology

Polyunsaturated fat in the methionine-choline-deficient diet influences hepatic inflammation but not hepatocellular injury^1,

Gene S. Lee^*,, Jim S. Yan^*,, Raymond K. Ng^*,, Sanjay Kakar^*, and Jacquelyn J. Maher^2,*,

^* Liver Center, University of California, San Francisco, San Francisco, CA 94110
Department of Medicine, University of California, San Francisco, San Francisco, CA 94110
Department of Pathology, University of California, San Francisco, San Francisco, CA 94110

¹ A portion of this work appeared previously in abstract form (Hepatology. 2005. 42: 630A).

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

Published, JLR Papers in Press, May 27, 2007.

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

Methionine-choline-deficient (MCD) diets that cause steatohepatitis in rodents are typically enriched in polyunsaturated fat. To determine whether the fat composition of the MCD formula influences the development of liver disease, we manufactured custom MCD formulas with fats ranging in PUFA content from 2% to 59% and tested them for their ability to induce steatohepatitis. All modified-fat MCD formulas caused identical degrees of hepatic steatosis and resulted in a similar distribution of fat within individual hepatic lipid compartments. The fatty acid composition of hepatic lipids, however, reflected the fat composition of the diet. Mice fed a PUFA-rich MCD formula showed extensive hepatic lipid peroxidation, induction of proinflammatory genes, and histologic inflammation. When PUFAs were substituted with more saturated fats, lipid peroxidation, proinflammatory gene induction, and hepatic inflammation all declined significantly. Despite the close relationship between PUFAs and hepatic inflammation in mice fed MCD formulas, dietary fat had no impact on MCD-mediated damage to hepatocytes. Indeed, histologic apoptosis and serum alanine aminotransferase levels were comparable in all MCD-fed mice regardless of dietary fat content. Together, these results indicate that dietary PUFAs promote hepatic inflammation but not hepatotoxicity in the MCD model of liver disease. These findings emphasize that individual dietary nutrients can make specific contributions to steatohepatitis.

Supplementary key words steatohepatitis • fatty liver • lipotoxicity • inflammation • apoptosis

Abbreviations: ALT, alanine aminotransferase; COX-2, cyclooxygenase-2; CXCL-2, CXC chemokine ligand-2; CYP2E1, cytochrome P4502E1; I-kB, inhibitor of NF-B; iNOS, inducible nitric oxide synthase; MCD, methionine-choline-deficient; MCS, methionine-choline-sufficient; MTP, microsomal triglyceride transfer protein; NF-B, nuclear factor-B; PL, phospholipid; SFA, saturated fatty acid; TAG, triacylglycerol; TBARS, thiobarbituric acid-reactive substances; TNF, tumor necrosis factor; TUNEL, terminal deoxynucleotide transferase-mediated deoxyuridine triphosphate nick end-labeling

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