Regulation of Lipid and Lipoprotein Metabolism by Nuclear Receptors

项目摘要 项目概述：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。我们对核武器的作用感兴趣 脂质体内平衡中的受体。我们的长期目标是阐明控制脂质的调节机制， 本发明的目的是通过核受体来调节体内平衡，并鉴定用于治疗 高脂血症和冠心病。法尼醇X受体（Farnesoid X receptor，FXR）是核受体的一员 在维持胆汁酸、脂质和葡萄糖稳态中起重要的调节作用。 最近的数据表明，FXR的激活抑制动脉粥样硬化的发展。符合 后一发现表明FXR的激活可降低血浆胆固醇水平。高胆 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和预防动脉粥样硬化的发展仍有待进一步研究。 确立了习我们最近发现，FXR的激活可能通过以下途径降低血浆胆固醇水平： 新的FXR-HNF 4a-SR-BI途径，ii）抑制肠胆固醇吸收和iii）增加逆转录酶活性， 胆固醇转运，肝外胆固醇转运回肝脏分泌的过程 胆汁和粪便在这个建议中，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 FXR可降低血浆胆固醇水平，减少肠道胆固醇吸收，并增加逆转录酶活性。 胆固醇转运实现这一建议中的具体目标将为以下方面提供重要的见解： FXR的激活降低血浆胆固醇水平并防止发展的机制 动脉粥样硬化此外，完成拟定研究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.