Regulation of Lipid and Lipoprotein Metabolism by Nuclear Receptors

描述（由申请人提供）：核受体超家族包括配体激活的转录因子，在人类和哺乳动物生理中起重要的调节作用。我们对核受体在脂质稳态中的作用很感兴趣。我们的长期目标是阐明核受体控制脂质稳态的调节机制，并确定治疗高脂血症和冠心病的治疗靶点或方法。Farnesoid X受体（FXR）是核受体超家族的成员，在维持胆汁酸、脂质和葡萄糖的稳态中起重要的调节作用。最近的数据表明，FXR的激活可以抑制动脉粥样硬化的发展。与后一项发现一致，FXR的激活已被证明可以降低血浆胆固醇水平。高胆固醇血症是动脉粥样硬化的独立危险因素。然而，激活FXR降低血浆胆固醇水平并防止动脉粥样硬化发展的机制仍有待确定。我们最近的研究表明，FXR的激活i)可能通过一种新的FXR- hnf4a - sr - bi途径降低血浆胆固醇水平，ii)抑制肠道胆固醇吸收，iii)增加逆向胆固醇运输，这是一种将肝外胆固醇运输回肝脏并分泌到胆汁和粪便中的过程。在这项提议中，我们将利用几种转基因小鼠模型，结合分子、细胞和药物方法来确定FXR激活降低血浆胆固醇水平、减少肠道胆固醇吸收和增加逆向胆固醇运输的机制。完成本提案的具体目标将为FXR激活降低血浆胆固醇水平和预防动脉粥样硬化发展的机制提供重要的见解。此外，拟议研究的完成可能为心血管疾病的治疗提供新的治疗方法。

DESCRIPTION (provided by applicant):: 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 (is) for treatment of cardiovascular diseases. PUBLIC HEALTH RELEVANCE: Atherosclerosis is the most common cause for coronary heart disease. Completion of the proposed studies will provide important insights into the mechanisms by which activation of FXR lowers plasma cholesterol levels and prevents the development of atherosclerosis. Thus, the studies proposed in this application are highly relevant to cardiovascular diseases and human health.