Roles Of Estrogen In The Regulation Of Hepatic Glucose And Lipid Metabolism

With the development of living standard, non-alcoholic fatty liver disease(NAFLD) becomes an increasingly severe health problem. The prevalence of NAFLD has reached 30% in the developed countries, making it as the most common liver condition in the world. NAFLD results from an imbalance in lipid metabolism. NAFLD is characterized by hepatic steatosis, which is caused by excess TG deposite as lipid droplets in hepatocytes. Although NAFLD is strongly associated with obesity and insulin resistance, its molecular mechanisms remains poorly understood and therapeutic options are limited.Several population based epidemiology studies have demonstrated that NAFLD can be affected by gender. Men are significantly more likely to develop steatosis than women, but after menopause, the disorder is more prevalent in women. Furthermore, the prevalence significantly increased among women after menopause.Besides, it is reported that tamoxifen, an estrogen antagonist, which is widely used for the treatment of breast cancer, could lead to hepatosteatosis.Together, these findings suggest that estrogen may play an important role in the development of NAFLD.Increasing evidences indicate that metabolic nuclear receptors(NRs) are involved in the devolpment of metabolic diseases.NRs play important roles in the balance of glucose and lipid metabolism,insulin sensitivity,anti-inflammation process.Farnesoid X receptor(FXR),a bile acid sensor,is not only involved in cholesterol-bile acid metabolism,but also participates in glucose and lipid metabolism.Our previous work found that FXR knockout mice exhibited obvious impairements in glucose and lipid homeostasis, including fatty liver and insulin resistance.FXR regulates hepatic glucose and lipid metabolism via a pathway involving SHP,and SREBP1 c.Activation of FXR increases the expression of its downstream target gene SHP,which inhibits transcription of SREBP1 c,leading to the downregulation of key enzymes involved in the lipogenesis.As a result,the synthesis of triglyceride is reduced.In the present study, we studied the role of estrogen in the process of hepatic glucose and lipid metabolism.Firstly, through population based studies, we found that the prevelance of NAFLD is significantly increased in menopuased women. Our animal studies further confirmed the relationship between estrogen and NAFLD, and also verified the protection effect of estrogen for NAFLD. Furthermore, we treated high fat diet-fed mice with estrogen and analyzed the potential downstream targets of estrogen. The results suggested that SHP is likely to be the target gene of estrogen in liver.SHP is the major downstream gene of nuclear receptor FXR, therefore, we tested the metabolic phenotype of FXR knockout mice.Interestingly, the gender-related defects in glucose and lipid metabolism were observed in FXR knockout mice. Male FXR knockout mice exhibit obvious impairements in glucose and lipid homeostasis, including fatty liver and insulin resistance. Whereas, female FXR knockout mice did not show any obvious difference compared to female wild-type mice.Our further study demonstrated that it is estrogen that influence the gender difference of FXR knockout mice.The gender difference disappeared by ovariectomy of female mice and was reversed by estrogen treatment.This study demonstrate that the estrogen signaling pathway may crosstalk with FXR pathway in liver. To explore this mechanism more fully, we designed experiments in vitro. We demonstrate that SHP, which is the downstream gene of FXR, is also the target of estrogen. Estrogen upregulates the expression of SHP in liver, which then inhibits the transcription of SREBP1 c, leading to the reduction of triglyceride and fatty acid synthesis.In summary, our study explored the function of estrogen in hepatic glucose and lipid metabolism from the point of NAFLD.We analyzed the relationship between estrogen and FXR pathway,and also studied the specific target of estrogen in liver metabolism.Our results defined the crosstalk between estrogen and metabolic nuclear receptor,and explored a brand new endocrine regulation system.At last,we speculated that estrogen might be a potential target for the prevention and treatment of metabolic deseases.