雌激素缺乏状态下补钙对肝脏胆固醇代谢的影响及其机制研究

Recently, studies have shown that calcium supplementation (CaS) was associated with the increased incidence of CVD in postmenopausal women. However, the molecular mechanism is still not clear. Our group found that CaS significantly increased serum total cholesterol levels in postmenopausal women based on a large national population-based study. Increased blood cholesterol level is an independent risk factor for CVD. Therefore， We speculate that calcium may regulate cholesterol metabolism to influence CVD risk. In the following vitro studies we found that estrogen receptor G protein coupled receptor 30 (GPR30) was an important target for calcium regulating hepatic cholesterol metabolism under the condition of estrogen deficiency. However, no mechanism has yet been determined. Therefore, the project will focus on the effect of CaS on liver cholesterol metabolism under the condition of estrogen deficiency and the underlying mechanisms. Furthermore, focusing on the effect of GPR30 for CaS changing liver cholesterol metabolism, we will explain the reasons for elevated serum cholesterol. Meanwhile, the project will apply technologies such as gene chips, gene silencing and pathway blockade and studies in vivo and in vitro will be done. The study will offer a theoretical basis for reasonable CaS to reduce the risk of CVD for postmenopausal women, and, provide new targets to prevent cholesterol disorders in postmenopausal women, which would develop a novel method to reduce the risk of CVD in postmenopausal women..

近年研究表明绝经后女性补钙增加心血管疾病（CVD）的发病风险，然其分子机制尚不明确。课题组在大规模人群研究中发现补钙显著增加绝经后女性血中总胆固醇（TC）水平。由于TC升高是CVD发生的独立危险因素，因此，我们推测钙可能通过调节胆固醇代谢影响CVD的发生。在随后的体外研究中我们发现雌激素受体G蛋白偶联受体30（GPR30）是雌激素缺乏下钙调节肝脏胆固醇代谢的重要靶点，然其具体调节机制尚属空白。本项目拟采用体内外相结合的方式，应用基因芯片、基因沉默、通路阻断等多项技术，对雌激素缺乏状态下补钙对肝脏胆固醇代谢的影响及其机制进行深入研究，并探讨GPR30在其中发挥的作用及其调节的信号传导机制，阐明TC升高的原因。本项目实施将为指导绝经女性科学补钙及降低CVD的发生风险奠定理论基础，为膳食干预或临床防治绝经女性胆固醇紊乱提供新的防治靶点。

近年研究表明绝经后女性补钙增加心血管疾病（CVD）的发病风险，然其分子机制尚不明确。课题组在大规模人群研究中发现补钙显著增加绝经后女性血中总胆固醇（TC）水平。由于TC升高是CVD发生的独立危险因素，因此，我们推测钙可能通过调节胆固醇代谢影响CVD的发生。在随后的体外研究中我们发现雌激素受体G蛋白偶联受体30（GPR30）是雌激素缺乏下钙调节肝脏胆固醇代谢的重要靶点，然其具体调节机制尚属空白。本项目采用体内外相结合的方式，对雌激素缺乏状态下补钙对肝脏胆固醇代谢的影响及其机制进行深入研究，并探讨GPR30在其中发挥的作用及其调节的信号传导机制，阐明TC升高的原因。.目前已按计划完成全部研究内容，共发表SCI标注论文1篇，参加学术会议1次。具体研究结果如下：.（1）雌激素缺乏下，补钙引起血清胆固醇升高可能与胆固醇分解代谢受到抑制有关。.（2）雌激素缺乏下，GPR30在补钙引起的血清总胆固醇升高中是一个关键靶点。在雌激素缺乏下，GPR30和补钙对血清胆固醇升高存在交互作用，GPR30对补钙引起的血清胆固醇升高起到拮抗作用。.（3）雌激素缺乏状态下，长期缺钙后补钙仍然会引起血清胆固醇的升高。.（4）雌激素缺乏状态下，机体无论是否处于钙缺乏状态，长期补钙均可能导致血中总胆固醇水平的上升；补钙状态下特异激动雌激素受体GPR30可调节瞬时受体电位Ⅰ型通道的表达，阻断补钙引起的细胞内钙浓度上升，升高胞内cAMP的水平；升高的cAMP依次通过下调固醇调节元件结合蛋白-1c以及SHP的表达而升高CYP7A1的表达，进而促进胆固醇向胆汁酸的转化，从而阻断了补钙引起的细胞内钙浓度上升进而防止了血中总胆固醇水平的上升。.本项目结论为指导绝经女性科学补钙及降低CVD的发生风险奠定理论基础，为膳食干预或临床防治绝经女性胆固醇紊乱提供新的防治靶点。