Fig. 2.

The “Multiple Hit Theory”. The “Multiple Hit Theory” that has now superseded the Two Hit Theory is based on the hypothesis that inflammation precedes steatosis in environmentally and genetically predisposed subjects. According to the “Multiple Hit Theory”, numerous insults act together to induce NAFLD. Such hits include insulin resistance, hormones secreted from the adipose tissue, nutritional factors, endotoxins (lipopolysaccharide) released by the gut microbiota, oxidative stress damage, and genetic and epigenetic factors. These insults act on liver parenchymal cells via toll-like receptors to drive the progression of NASH.