MCD-induced steatohepatitis is associated with hepatic adiponectin resistance and adipogenic transformation of hepatocytes

Background/Aims: In these studies, we tested the hypothesis that increased lipid intake would exacerbate the severity of nutritional steatohepatitis. Methods: C57Bl/6J mice were fed methionine-and-choline deficient (MCD) diets containing 20% (high) or 5% (low) fat by weight for 3 weeks and compared to lipid-matched controls. Results: MCD feeding increased serum ALT levels and induced hepatic steatosis, lobular inflammation and ballooning degeneration of hepatocytes, irrespective of dietary fat content. Hepatic triglyceride accumulation was similar between high and low-fat MCD-fed mice, but lipoperoxide levels were ∼3-fold higher in the high-fat MCD-fed animals. Serum adiponectin levels increased in MCD-fed mice, although to a lesser extent in high-fat fed animals. AMPK phosphorylation was correspondingly increased in muscle of MCD-fed mice, but hepatic AMPK phosphorylation decreased, and there was little evidence of PPARα activation, suggesting impaired adiponectin action in the livers of MCD-fed animals. Hepatocyte PPARγ mRNA levels increased in MCD-fed mice, and were associated with increased aP2 expression, indicating adipogenic transformation of hepatocytes. Conclusions: Increased dietary lipid intake did not alter steatohepatitis severity in MCD-fed mice despite increased lipoperoxide accumulation. Instead, steatohepatitis was associated with impaired hepatic adiponectin action, and adipogenic transformation of hepatocytes in both low and high-fat MCD-fed mice.