动脉粥样硬化中法尼酯X受体下调巨噬细胞中肝脂酶表达的分子机制研究

项目名称： 动脉粥样硬化中法尼酯X受体下调巨噬细胞中肝脂酶表达的分子机制研究

项目编号： No.81200219

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 医学一处

项目作者： 申丽丽

作者单位： 中国人民解放军第三军医大学

项目金额： 23万元

中文摘要： 动脉粥样硬化(AS)发病机制之一是巨噬细胞中脂质蓄积，而法尼酯X受体(FXR)能够下调肝脂酶（HL）表达，抑制脂蛋白摄取，减少斑块产生。我们前期研究发现FXR激动剂下调人肝脏HL mRNA、蛋白表达水平及抑制小鼠HL酶活性，并有时间和剂量依赖性。推测FXR可下调巨噬细胞中HL转录。我们通过生物信息学分析发现，FXR与HL启动子-217～-196bp 处存在结合位点。结合上述推测FXR可通过直接途径下调巨噬细胞中HL转录。本课题拟采用：①构建HL基因启动子报告基因载体，明确FXR与HL基因启动子区结合位点；②采用ChIP及EMSA实验，分别从体内、外鉴定 FXR与HL启动子活性区域结合；③巨噬细胞体外实验及构建AS动物模型，验证FXR下调HL表达可减少AS斑块产生。结果将初步阐明FXR调控HL分子机制是直接途径，及这种途径对巨噬细胞中脂蛋白摄取和AS斑块的影响。为研制AS药物提供实验依据。

中文关键词： 法尼酯X受体；肝脂酶；动脉粥样硬化；巨噬细胞；

英文摘要： The pathogenesis of atherosclerosis (AS) is one of the lipid accumulation in macrophages.Atherosclerosis (AS) is a high mortality of cardiovascular and cerebrovascular disease is closely related to the pathogenesis of lipid accumulation in macrophages .farnesoid X receptor(FXR) could be reduced hepatic lipase (HL) expression, inhibition of lipoprotein uptake, reduce plaque produce. Our preliminary studies found that FXR agonists can be time-and dose-dependent down human liver HL mRNA in protein expression and inhibit HL activity,suggesting that FXR can down-regulate HL transcription in macrophages.Bioinformatics analysis of FXR with HL promoter -217 to-196bp at the existence of binding sites. The combination of these speculated that FXR can be reduced through direct channels of HL transcription in macrophages. This project to be adopted: (a) Construction of the HL gene promoter reporter vector, clear FXR binding sites with the HL gene promoter region; (b) using the ChIP and EMSA experiments, respectively, combined from the body, outside identification FXR and HL promoter activity area; (c) macrophages in vitro experiments and build AS animal models, verify FXR lowered HL expression can reduce the AS plaque produce.Results will initially clarify the mechanisms of FXR regulation of HL molecules is a direct way, an

英文关键词： farnesoid X receptor；hepatic lipase；atherosclerosis；macrophage；