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

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.

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

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.