Explore the Gender-Specific Impacts on the Three Main Chronic Liver Diseases in Taiwan: a Joint Study Based on Human and Animal Models

Several clinical studies show a profound sex dimorphism in liver diseases. Interactions between sex hormones, adipose distribution and sex hormone-binding globulin (SHBG) may explain the sex-dimorphism. Among the sex hormones, estrogen improves hepatic inflammation, regulates adipose development, improves systemic glucose and lipid homeostasis in both males and females. In males, testosterone promotes hepatic cholesterol storage and hepatocellular carcinoma (HCC) formation. Moreover, SHBG is a serum glycoprotein exhibiting the unique feature of binding sex steroids. Its serum levels are regulated by sex hormone and liver. With menopause, the fall of estrogen levels can lead to fibrosis progression, and this represents a negative turning point for women with chronic liver disease. Currently, the three main chronic liver diseases in Taiwan are non-alcoholic fatty liver disease (NAFLD), chronic hepatitis B (CHB) and chronic hepatitis C (CHC). Interestingly, NAFLD is twice as common in postmenopausal women as in premenopausal women. The adipokine alteration patterns are distinct between the men and women with NAFLD. While male sex is a risk factor for reactivation of hepatitis B virus (HBV) infection after HBeAg seroconversion and for the development of cirrhosis and HCC. For CHC, women have milder disease than men during their reproductive years, although postmenopausal women lose this advantage and present with accelerated fibrosis progression in comparison with male patients of comparable ages. In contrast to " sex", the concept of "gender" includes both the biological and social characteristics, while gender-specific medicine is long-term neglected. For example, male but not female sex has favorable posttransplant employment indicates the gender- but not sex-difference in outcomes. There are some intriguing points regarding the gender-impacts on the three main chronic liver diseases: (1). Is there any cut-off level of sex hormone in determining the severity of the NAFLD, CHB and CHC in women according to pre-, peri- and post-menopausal periods (biological) ? (2).What are the specific alteration patterns of the adipokine and SHBG in patients with the NAFLD, CHB and CHC according to gender (biological) ? (3). How to treat and follow up the patients with NAFLD, CHB and CHC according to gender (biological and social) ? Using conditional transgenic mice that over-express the hepatitis C virus core in the liver, we have developed three mouse lines with phenotypes varying from simple hepatic steatosis to steatohepatitis. This may reflect the hepatic histology of humans with CHC. Commercialized db/db mutant mice may serve as an animal model of NAFLD.While mice with tail vein hydrodynamic-injection with HBV plasmid may work as the CHB animal model. Furthermore, by using a consecutive series of NAFLD patients, we had shown that male and female NAFLD patients have distinct adipokine alteration patterns. Thus, based on our previous studies, the present proposal is designed to dissect the intriguing points regarding the impact of gender on the three main chronic liver diseases in Taiwan by conducting prospective cohorts of NAFLD, CHB and CHC with longitudinal follow-up of hepatic and extra-hepatic manifestations, focused on the sex hormones, adipokine and SHBG alteration, and stratified by sex, menstruation duration and the presence of menopause. In parallel, the associated basis will be probed by using the HCV core transgenic mice, db/db mice and hydrodynamic injected HBV mice with equivalent phenotypes. How the sex hormones affect the three chronic liver diseases will be further elucidated not only by comparing male with female mice, but also by comparing normal male with castrated male mice. The current 3-year proposal holds promise to unveil the clinical controversies and may provide therapeutic interventions targeting crucial gender factors to control the three main chronic liver diseases in Taiwan.

Project ID:PF10507-1987
External Project ID:MOST105-2629-B182-001