Mouse models of alcohol‐associated liver disease vary greatly in their ease of implementation and the pathology they produce. Effects range from steatosis and mild inflammation with the Lieber–DeCarli liquid diet to severe inflammation, fibrosis, and pyroptosis seen with the Tsukamoto–French intragastric feeding model. Implementation of all of 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 to reproduce features of alcohol‐induced inflammation and fibrosis with minimal operational requirements.

Over a 16‐week period, mice were fed ad libitum with a pelleted high‐fat Western diet (WD; 40% calories from fat) and alcohol added to the drinking water. We found the optimal alcohol consumption to be that at which the alcohol concentration was 20% for 4 days and 10% for 3 days per week. Control mice received WD pellets with water alone.

Alcohol consumption was 18 to 20 g/kg/day in males and 20 to 22 g/kg/day in females. Mice in the alcohol groups developed elevated serum transaminase levels 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 WD without alcohol had mild steatosis only. Alcohol‐fed mice showed reduced HNF4α mRNA and protein expression. HNF4α is a master regulator of hepatocyte differentiation, down‐regulation of which is a known driver of hepatocellular failure in alcoholic hepatitis.

A simple‐to‐administer, 16‐week WD alcohol model recapitulates the inflammatory, fibrotic, and gene expression aspects of human alcohol‐associated steatohepatitis.