Figure 1.

The “mutiple-parallel hit” model in the pathogenesis of NASH. Three factors (environmental, metabolic and genetic factors) contribute to the development and progression of NASH by affecting diverse organs such as the liver, the intestine, and adipose tissue. In particular, excess caloric or inappropriate intake (environmental factor) increases toxic free fatty acid (FFA) and lipid metabolites (LPC, cholesterol and ceramide) in hepatocytes, leading to hepatic steatosis and hepatocyte sublethal/lethal injuries. Subsequently, hepatocyte-derived factors (such as cytokines/chemokines, DAMPs and extracellular vesicles) stimulate inflammatory response in Kupffer cell and fibrotic response in HSC, which leads to the development of inflammation and fibrosis in the liver. FFA and lipid metabolites derived from diets or synthesized de novo also activates Kupffer cell and HSC. In addition, insulin resistance and obesity (metabolic factor) influence organ-crosstalk between the intestine/adipose tissue and the liver, contributing to the development and progression of NASH.