雌激素调节肝脏脂代谢机制研究

With the development of living standard, non-alcoholic fatty liver disease (NAFLD) becomes an increasingly severe health problem. 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. 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 development of metabolic diseases. NRs play important roles in the homeostasis of glucose and lipid, insulin sensitivity, and so on. Farnesoid X receptor (FXR), a bile acid sensor, functions as an important regulator of hepatic glucose and lipid metabolism. Our previous work demonstrated the important role of estrogen in hepatic glucose and lipid metabolism, and also confirmed the central role of FXR/SHP pathway. Based on these results, we will further study (1) the relation of estrogen with hepatic triglyceride contents and further NAFLD; (2) the molecular mechanism of estrogen in the regulation of lipid metabolism in the liver; (3) the crosstalk between FXR/SHP pathway and estrogen in hepatic glucose and lipid metabolism; (4) the improvement of NAFLD by estrogen in vivo. Our study aimed to explore the function of estrogen in hepatic glucose and lipid metabolism from the point of NAFLD. We speculated that estrogen and the downstream molecules might be a potential target for the prevention and treatment of metabolic diseases.

随着人们生活水平的提高，非酒精性脂肪肝病（NAFLD）已经成为一个越来越严重的健康问题。NAFLD与肥胖、胰岛素抵抗等密切相关，然而其发生机制尚未明确，预防和治疗手段更是有限。本项目组前期研究发现雌激素与肝脏脂代谢密切相关，并且初步证实雌激素通过胆汁酸受体FXR通路调节甘油三酯代谢。在这些重要发现的基础上，我们拟进一步研究（1）雌激素水平与肝脏甘油三酯含量的关系，以及雌激素减少与NAFLD发生的关系；（2）雌激素调节肝脏脂代谢的分子机制，尤其调节小二聚体伴侣分子（SHP）表达的分子机制；（3）雌激素与FXR/SHP通路在调控肝脏糖脂代谢中的对话关系；（4）雌激素对于肝脏甘油三酯沉积的改善作用。该项目将从人群、动物、细胞水平，系统地探讨雌激素在肝脏脂代谢中的作用及其机制。本研究不仅有助于阐明NAFLD的发生机制，也为今后针对雌激素信号通路进行肝脏选择性药物开发，提供新的靶点。

随着我国经济的高速发展、人们生活水平的提高，非酒精性脂肪肝病(NAFLD)已经成为一个越来越严重的健康问题。然而其发生机制尚未明确，预防和治疗的手段则更是有限。本课题通过多个动物模型的表型观察，发现：(1) 给予正常雌性小鼠他莫昔芬或卵巢切除处理后，均显著增加肝脏甘油三酯含量；给予肥胖雄性小鼠腹腔注射雌激素后，则可纠正小鼠的脂肪肝、胰岛素抵抗等糖脂代谢紊乱表型。(2) 沉默正常雌性小鼠肝脏中雌激素受体(ERalpha)的表达后，肝脏中甘油三酯含量增加；给予肥胖雌性小鼠肝脏中过表达ERalpha后，则显著改善甘油三酯的过量堆积。(3) 胆汁酸受体(FXR)基因敲除的雄性小鼠表现为肝脏脂质沉积和胰岛素抵抗，而雌性敲除小鼠则无明显表型；而将雌性敲除小鼠卵巢切除后，则呈现肝脏脂质含量增加、胰岛素抵抗等表型。进一步，课题组通过细胞和分子机制的研究，证实：雌激素通过激活ERalpha，通过招募辅因子SRC-1，结合至小二聚体伴侣分子(SHP)的启动子上，进而促进其基因表达，下调SREBP-1c等甘油三酯合成相关基因的表达，抑制甘油三酯的合成和过量堆积，从而改善NAFLD和相关糖脂代谢紊乱。综上所述，本课题系统阐述了雌激素在肝脏甘油三酯代谢中的作用，不仅有助于阐明NAFLD的发生机制，也为今后针对雌激素信号通路进行肝脏选择性药物开发，提供新的靶点。课题资助期间，发表SCI论著3篇(均已标注），应邀撰写SCI综述1篇(已标注)，项目负责人及团队成员在国家级学术会议上开展特邀或专题报告4次，获得国家发明专利1项，培养博士研究生3名，硕士研究生2名。因此，顺利完成了预定的研究计划。