Submitted on April 13, 2007
Revised on May 25, 2007
Accepted on May 26, 2007
Polyunsaturated fat in the methionine-choline-deficient diet influences hepatic inflammation but not hepatocellular injury
Gene S. Lee, Jim S. Yan, Raymond K. Ng, Sanjay Kakar, and Jacquelyn J. Maher
Medicine, University of California, San Francisco, San Francisco, CA 94110
Corresponding Author: jmaher{at}medsfgh.ucsf.edu
Methionine-and-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 2-59% 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 pro-inflammatory genes, and histologic inflammation. When PUFA were substituted with more saturated fats, lipid peroxidation, pro-inflammatory gene induction and hepatic inflammation all declined significantly. Despite the close relationship between PUFA and hepatic inflammation in mice fed MCD formulas, dietary fat had no impact on MCD-mediated damage to hepatocytes. Indeed, histologic apoptosis and serum ALT levels were comparable in all MCD-fed mice regardless of dietary fat content. Taken together, the results indicate that dietary PUFA 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.
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