**6. Gender differences in NASH development**

The prevalence and severity of human NAFLD/NASH varies with gender and age [58]. Yatsuji et al. studied 193 Japanese patients with NASH (86 women and 107 men) and showed a predominance of the disease in women over 50 years old, yet a greater prevalence in men aged 30–40 years [59]. Williams et al. reported that NAFLD patients were more likely to be male, older, and hypertensive [60]. The incidence of NAFLD/NASH is higher in men than premenopausal women (less than 50 years of age), while this immediately increases in women after menopause. Therefore, sex hormones such as estradiol may influence gender differences in NASH. In our study, we regarded female SHRSP5/Dmcr rats aged 12–24 weeks to correspond to the menopausal age in women. We also found female rats were less susceptible to HFC diet-induced liver damage compared with males [61]. Hence, our rat model may be useful for studies into gender differences in HFC-induced NASH. In order to investigate the related mechanisms, mature female and male SHRSP5/Dmcr rats (10 weeks old) were fed either an HFC or control diet for 2, 8, and 14 weeks. The severity of hepatic fibrosis was markedly lower in the female rats compared with the males. Although HFC feeding significantly reduced serum estradiol levels in female rats at 2 weeks, these levels were still much higher in females compared with males during HFC feeding, suggesting that this female hormone may contribute to the gender difference in NASH. In addition, only minor gender differences were noted in the expression of CYP7A1, CYP8B1, CYP27A1, and CYP7B1, the enzymes involved in BA synthesis, as well as MRP3 and BSEP, the proteins associated with BA transport. On the other hand, the enzymes implicated in BA detoxification, UGT and SULT2A1, as well as the nuclear receptors, CAR and PXR, were significantly suppressed in the male rats fed the HFC diet, whereas expression of these proteins was only slightly changed in females following HFC feeding. Since estradiol, which markedly decreases in women after menopause, may stabilize CAR and PXR proteins [61, 62], these results suggested a stronger capacity of BA detoxification associated with higher estradiol levels may be responsible for the resistance to HFC-induced liver damage and hepatic fibrosis in female rats compared with males.
