title: Sex difference in the liver of hepatocyte-specific Pten-deficient mice: A model of nonalcoholic steatohepatitis.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Gastroenterology, Akita University School of Medicine, Akita, Japan.
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Anezaki
authors.forename: Shigetoshi
authors.initials: S
authors.lastname: Ohshima
authors.forename: Hajime
authors.initials: H
authors.lastname: Ishii
authors.forename: Nobukatsu
authors.initials: N
authors.lastname: Kinoshita
authors.forename: Takahiro
authors.initials: T
authors.lastname: Dohmen
authors.forename: Ei
authors.initials: E
authors.lastname: Kataoka
authors.forename: Wataru
authors.initials: W
authors.lastname: Sato
authors.forename: Masahiro
authors.initials: M
authors.lastname: Iizuka
authors.forename: Takashi
authors.initials: T
authors.lastname: Goto
authors.forename: Junko
authors.initials: J
authors.lastname: Sasaki
authors.forename: Takehiko
authors.initials: T
authors.lastname: Sasaki
authors.forename: Akira
authors.initials: A
authors.lastname: Suzuki
authors.forename: Hirohide
authors.initials: H
authors.lastname: Ohnishi
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Horie