Pathogenesis of Non-alcoholic Steatohepatitis and Its Potential Therapeutic Strategies

Non-alcoholic steatohepatitis (NASH) is closely associated with progression to liver cirrhosis and hepatocellular carcinoma. We reported that melanocortin 4 receptor–deficient mice (MC4R-KO mice), when fed a high-fat diet, provide a novel rodent model of NASH. Recently, we have identified a unique histological feature termed “hepatic crown-like structures” (hCLS) in the livers of MC4R-KO mice and NASH patients. In hCLS, CD11c-positive macrophages aggregate to surround hepatocytes with large lipid droplets, similar to the “crown-like structure (CLS)” described in obese adipose tissue. Interestingly, we have recently reported that macrophage-induced C-type lectin (Mincle) is involved in CLS formation and fibrogenic gene expression in obese adipose tissue, suggesting the pathophysiologic role of CLS in obesity-induced adipose tissue fibrosis. Collectively, our data provide evidence that hCLS serves as an origin of hepatic inflammation and fibrosis during the progression from simple steatosis to NASH and thus helps in elucidation of the pathogenesis of NASH, pursuit of specific biomarkers, and evaluation of potential therapeutic strategies.