Sex difference in the liver of hepatocyte-specific Pten-deficient mice: A model of nonalcoholic steatohepatitis

Nonalcoholic fatty liver disease (NAFLD) is considered to be a public health problem worldwide. NAFLD is more prevalent in men than in women. Tamoxifen, a potent estrogen receptor antagonist, causes nonalcoholic steatohepatitis (NASH), a severe form of NAFLD. Thus, there may be a sex difference that is dependent on estrogens in NAFLD and NASH. Hepatocyte-specific Pten-deficient mice exhibit hepatic lesions analogous to NASH and are considered to be a clinical model of NASH. We aimed to shed light on any sex differences in the hepatic lesions of Pten-deficient mice and the underlying mechanisms. At 40 weeks, livers from male and female Pten-deficient mice were processed for measuring lipid content, genes expression analysis, and histological examination. Level of serum reactive oxygen species (ROS) was also determined. Seventy-six-week-old mice were used in tumor burden experiments. Hepatic steatosis, inflammation, and even carcinogenesis in Pten-deficient mice were attenuated in females compared to males. Attenuated fatty liver in females was ascribed to inactivation of sterol regulatory element binding protein-1c. Hepatic inflammation in females was suppressed via decreased ROS with increased antioxidant gene expression and decreased proinflammatory cytokine production. Anti-cancer effect in female mice was, at least in part, due to the significantly lower ratio of oleic to stearic acid in the liver. Hepatic lesions in Pten-deficient mice were attenuated in females compared to males, as were human NAFLD and NASH. Some of the underlying mechanisms in sex difference appeared to be due to the change of gene expression, dependent on estrogens.