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

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.

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。

绝经后女性常见脂质代谢紊乱，但其机制不明，巨大内分泌激素波动可能参与其中。绝经后女性有害的低密度脂蛋白（LDL-C）升高伴随心血管疾病风险显著增加。本研究拟探究绝经后高卵泡刺激素（FSH）可能参与影响绝经后脂质代谢异常，与LDL-C升高密切相关，以及其可能机制。首先基于浙江省杭州市拱墅区的进行横断面调查提示，相比绝经前期，围绝经期和绝经后女性平均TC、LDL-C上升，胆固醇升高的发生率增加，其中FSH升高可能是胆固醇代谢紊乱的内在机制，降低FSH可作为绝经激素补充治疗的目标和疗效指标。更进一步，招募2010年1月-2013年7月在浙江大学附属妇产科医院妇科内分泌门诊就诊绝经后女性400例，明确适应症，排除禁忌症，所有患者均签署知情同意书。本研究的进行得到浙江大学医学院伦理委员会的批准。所有患者按照指南予以规范的雌激素补充治疗（HRT）12个月。根据患者初诊时FSH水平队列，以FSH中位数为界分为两组，低FSH组（40 IU/L to 78.3 IU/L）和高FSH组（≥ 78.3 IU/L）。比较发现高FSH组其血清TC、LDL-C水平显著高于低FSH组（p<0.01），患者接受HRT后，表现为FSH水平降低以及血脂谱改善，但发现高FSH组其血脂谱改善情况优于低FSH组（p<0.01），而当FSH改善大于30%的患者，其TC、LDL-C改善显著。第三，在肝脏组织、动物肝脏以及肝脏细胞系中验证发现FSH受体的表达。利用在体动物模型，模拟不同内分泌激素状态，研究发现高FSH组小鼠其血脂TC、LDL-C均显著升高，分析其肝脏组织脂质代谢相关基因表达情况，发现LDL-C代谢关键因子LDLR表达下降；最后，细胞模型中验证发现，高FSH能够浓度依赖性和时间依赖性降调肝脏细胞HepG2中LDLR表达下降，这一作用会被siRNA FSHR后削弱。本研究发现，绝经后高FSH可能通过其受体下调肝脏细胞中LDLR表达从而影响LDL-C的代谢，导致循环中LDL-C水平升高，最终引起脂质代谢异常。本研究以FSH/ FSHR 为新切入点的绝经相关脂质代谢紊乱，尤其是对于LDL-C的影响。首次发现和确定高FSH在绝经后妇女LDL代谢过程中的作用。阐述了绝经后脂质代谢紊乱新机制。