A Western diet with alcohol in drinking water model recapitulates features of alcohol-associated liver disease in mice

Background Mouse models of alcohol-associated liver disease vary greatly in their ease of implementation and the pathology they produce. This ranges from steatosis and mild inflammation in Lieber-DeCarli liquid diet, and severe inflammation, fibrosis and pyroptosis seen in the Tsukamoto-French intragastric feeding model. Implementation of all these models is limited by the labor-intensive nature of the protocols and the specialized skills necessary for successful intragastric feeding. We thus sought to develop a new model that would reproduce features of alcohol-induced inflammation and fibrosis with minimal operational requirements. Methods Mice were fed ad libitum with a pelleted high fat western diet (40% calories from fat) and alcohol added to the drinking water. We found that optimal alcohol consumption occurred when alcohol concentration alternated between 20% for 4 days and 10% for 3 days per week. Control mice received western diet pellets with water alone and the total feeding duration was 16 weeks. Results Alcohol consumption was 18-20 g/kg/day in males and 20-22 g/kg/day in females. Mice in the alcohol groups developed elevated serum ALT and AST after 12 weeks in males and 10 weeks in females. At 16 weeks, both males and females developed liver inflammation, steatosis and pericellular fibrosis. Control mice on western diet without alcohol had mild steatosis only. Alcohol fed mice showed reduced mRNA and protein expression of HNF4α, the master regulator of hepatocyte differentiation, downregulation of which is a known driver of hepatocellular failure in alcoholic hepatitis. Conclusion A simple to administer, 16-week western diet alcohol model recapitulates the inflammatory, fibrotic and gene expression aspects of human alcohol-associated steatohepatitis.