Immune Mechanisms in Non-alcoholic Steatohepatitis (NASH)

Non-alcoholic fatty liver had been believed to be a non-progressive benign disease. However, Ludwig et al. described some patients who exhibited progressive steatohepatitis without habitual alcohol drinking (Ludwig et al., 1980) and referred to this disease as non-alcoholic steatohepatitis (NASH). Later, NASH and non-progressive simple steatosis patients were included in the single disease entity of non-alcoholic fatty liver disease (NAFLD). Recently, non-progressive simple fatty liver has been renamed as nonalcoholic fatty liver (NAFL). The differential diagnosis of NAFL and NASH requires liver biopsy interpretation, and it is often difficult to clearly distinguish these two disease. NASH is regarded as a more severe form of NAFLD and is broadly defined by the presence of steatosis with inflammation and progressive fibrosis (Matteoni et al., 1999; Brunt et al., 2009), ultimately leading to cirrhosis and hepatocellular carcinoma (HCC) (Yatsuji et al., 2009; Hatanaka et al., 2007; Fassio et al., 2004; Ono & Saibara, 2006). The mechanisms through which the subset of NAFLD patients develops NASH are poorly understood. The development of NASH is generally thought of as a “two hit” process (Day & James, 1998). The first hit is the development of hepatic steatosis due to overeating, lack of exercise, or drug use. The second hit includes hepatic damage inducing cellular stresses such as oxidative stress, apoptosis, and gut-derived signals such as lipopolysaccharide (LPS). However, recently uncovered liver fat deposition and pro-inflammatory