Regulation of Lipid and Lipoprotein Metabolism by Nuclear Receptors

项目摘要 项目摘要：核受体超家族由配体激活的转录因子组成 在人类和哺乳动物生理学中的重要调节作用。我们对核能的作用很感兴趣 脂类动态平衡的受体。我们的长期目标是阐明控制血脂的调节机制 核受体的动态平衡，并确定治疗靶点或治疗方法 高脂血症和冠心病。法尼醇X受体(FXR)是核受体的一员 它是一个超家族，在维持胆汁酸、脂肪和血糖的稳态方面起着重要的调节作用。 最近的数据表明，FXR的激活抑制了动脉粥样硬化的发展。与一致 后一项发现，激活FXR已被证明可以降低血浆胆固醇水平。高胆固醇血症 已知是动脉粥样硬化的独立危险因素。然而，激活的机制 FXR降低血浆胆固醇水平并防止动脉粥样硬化的发展有待于 已经成立了。我们最近的研究表明，FXR I的激活可能通过 新的FXR-HNF4a-SR-BI途径，II)抑制肠道胆固醇吸收，III)反向增加 胆固醇运输，肝外胆固醇被运输回肝脏进行分泌的过程。 胆汁和粪便。在这项提案中，我们将结合使用几种转基因小鼠模型 用分子、细胞和药物方法来确定激活的机制 FXR降低血浆胆固醇水平，减少肠道胆固醇吸收，并增加反向作用 胆固醇的运输。实现这项提案中的具体目标将为 FXR激活降低血浆胆固醇水平和预防高血压发生的机制 动脉硬化。此外，拟议研究的完成可能会提供新的治疗方法。 用于治疗心血管疾病。

Project Summary Project Summary: The nuclear receptor superfamily comprises ligand-activated transcription factors that play important regulatory roles in human and mammalian physiology. We are interested in the role of nuclear receptors in lipid homeostasis. Our long-term goal is to elucidate the regulatory mechanisms controlling lipid homeostasis by nuclear receptors and to identify therapeutic targets or approaches for treatment of hyperlipidemia and coronary heart disease. Farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily and plays important regulatory roles in maintaining bile acid, lipid and glucose homeostasis. Recent data have shown that activation of FXR inhibits the development of atherosclerosis. Consistent with this latter finding, activation of FXR has been shown to lower plasma cholesterol levels. Hypercholesterolemia is known to be an independent risk factor for atherosclerosis. However, the mechanism by which activation of FXR lowers plasma cholesterol levels and prevents the development of atherosclerosis remains to be established. We have very recently shown that activation of FXR i) lowers plasma cholesterol levels likely via a novel FXR-HNF4a-SR-BI pathway, ii) inhibits intestinal cholesterol absorption and iii) increases reverse cholesterol transport, a process by which extra-hepatic cholesterol is transported back to the liver for secretion to the bile and feces. In this proposal, we will utilize several genetically modified mouse models in combination with molecular, cellular and pharmaceutical approaches to determine the mechanisms by which activation of FXR lowers plasma cholesterol levels, reduces intestinal cholesterol absorption, and increases reverse cholesterol transport. Accomplishing the specific aims in this proposal will provide important insights into the mechanism by which activation of FXR lowers plasma cholesterol levels and prevents the development of atherosclerosis. In addition, completion of the proposed studies may provide novel therapeutic approach(es) for treatment of cardiovascular diseases.