Gender Dimorphism in Nonalcoholic Fatty Liver Disease: from the Viewpoint of Adiponectin

Nonalcoholic fatty liver disease (NAFLD) is defined by a non-alcoholic nature in the presence of fatty liver, and is currently the most common liver disease with increasing importance globally (2300 million individuals worldwide). The 3 major causes of NAFLD-related mortality include cardiovascular disease, all-cause malignancy, and liver-related death. Currently, diet and exercise are the mainstay treatment for the majority of patients with NAFLD and no specific medication for NAFLD is available. Several clinical studies show a profound gender dimorphism in liver diseases. In general, men are 2-fold more likely to die from chronic liver disease and cirrhosis than are women. Interestingly, NAFLD is twice as common in postmenopausal women as in premenopausal women. Substantially, interactions between sex hormones and adipose distribution may explain the differences in the sex-specific liver diseases. However, the precise therapy to probe the gender dimorphism in NAFLD remained unidentified. Secretory proteins derived from adipose tissue are collectively called adipokines. Ectopic fat accumulation, including visceral obesity and fatty liver, can be considered a consequence of adipose tissue dysfunction and results in altered adipokine levels. Increasing evidence indicates that adipkines regulate steatosis and inflammation in NAFLD. The pattern of adipokine alterations are distinct between the men and women. Adiponectin, a 30-kDa adipokine, is highly expressed in adipocytes and is also expressed in hepatocytes. Adiponectin and its receptors might protect hepatocytes from triglyceride accumulation by increasing β-oxidation, decreasing the de novo synthesis of fatty acids, and promoting the uptake and inhibiting the production of glucose in the liver. Thus, hepatitis steatosis is usually associated with low levels of adiponectin. Some animal studies had showed the beneficial effect of adiponectin in protecting obesity-related NAFLD. In human studies, adiponectin had been documented as biomarkers for NAFLD, nonalcoholic steatohepatitis, fibrosis, and insulin resistance. Higher adiponectin levels are usually noted in females than age-matched males. Taken together, targeting the adiponectin-associated pathway has the potentiality to dissect the gender-dimorphism basis in NAFLD. By using conditional transgenic mice that over-express the hepatitis C virus (HCV) core in the liver, we had developed three transgenic mouse lines with core expression under the control of the tetracycline transactivator, those mice exhibited non-obese NAFLD. While well-established commercialized db/db mutant mice may serve as a suitable animal model of obese NAFLD. Thus, based on the results our previous studies investigating the roles of adiponectin in mice with hepatic steatosis, in human with NAFLD and chronic HCV infection; and surveying the adipokine and metabolic profiles in chronic liver diseases, the present proposal is designed to dissect the impact of gender on NAFLD by conducting a prospective case-control cohort of NAFLD, with 3-year follow-up of hepatic and extra-hepatic manifestations, stratified by the menstruation period and the presence of menopause in women, and focused on the adiponectin-associated pathway. In parallel, the associated basis will be probed by using the aforementioned mice with equivalent phenotypes for human NAFLD. The current proposal holds promise to provide therapeutic interventions targeting crucial gender factors to control NAFLD-associated complications in Taiwan.

Project ID:PF10907-2407
External Project ID:MOST109-2629-B182-002