卵泡刺激素及其受体介导绝经后女性脂质代谢紊乱的作用及其分子机制

绝经后女性常见脂质代谢紊乱，但其机制不明。卵泡刺激素（FSH）在卵子发生中起关键作用，但近年发现FSH可能与绝经后女性多系统功能紊乱密切相关。以往认为仅有卵巢颗粒细胞和睾丸支持细胞表达FSH 受体（FSHR），但我们前期研究中发现人肝脏组织及肝细胞株均可表达FSHR，绝经后女性高水平FSH与绝经后胆固醇（TC）、低密度脂蛋白（LDL）升高密切相关，FSH抑制肝细胞中胆固醇代谢关键因子LDL受体（LDLR）表达，而对合成相关因子影响不明显。本项目拟在前期研究基础上，阐明女性绝经后高水平FSH与肝细胞FSHR结合后与G蛋白偶联，经分子信号通路活化转录因子SREBP2下调LDLR表达，使LDL在肝细胞内降解及胆固醇储存或再利用显著减少，导致血中LDL和胆固醇等脂质水平升高而发生血脂代谢紊乱的分子机制，同时也可以为临床诊治和新药研制提供科学依据，具有很高的创新性及临床意义。

Lipid metabolic disorder frequently occurs in post-menopause women, but its mechanism remains unknown. Follicle stimulating hormone (FSH) plays a critical role in ovogenesis. However, in recent years FSH has been found to display a close correlation with multisystem metabolic disorders in post-menopause women. In previous knowledge, only granular cells of ovaries and sustentacular cell of testis express FSH receptor (FSHR). However, our recent study found that human hepatic tissue and hepatic cell lines expressed FSHR, the high level of FSH in post-menopause women was closely relative to lipid metabolic disorder and FSH inhibited the expression of low-density lipoprotein (LDL) and its receptor (LDLR) in hepatic cells. This project is based on our previous research work to elucidate that the FSH with high level in post-menopause women binds to the FSHR on hepatic cells and then couple with G protein which activates PKA pathway through cAMP and ERK1/2 pathway through Ras protein, evokes the inflow of extracellular Ca2+ and the release of Ca2+ in endocytoplasmic reticulum. Subsequently, the transcription factor SREBP2 is activated to down-regulate the expression of LDLR, which causing the decrease of LDL degradation, cholesterin storage and salvage in hepatic cells. As a result, the elevation of lipids such as LDL and cholesterin in blood as well as lipid metabolic disorder occur in post-menopause women. All the results of this research project not only elucidate the molecular mechanism of lipid metabolic disorder occur in post-menopause women, but also provide evidence to improve clinical diagnosis and therapy, and to develope new drugs for the lipid metabolic disorder, which display great academic finding and clinical significance.