Regulation of Lipid and Lipoprotein Metabolism by Nuclear Receptors

描述(申请人提供)：核受体超家族包括配体激活的转录因子，在人类和哺乳动物的生理中发挥重要的调节作用。我们感兴趣的是核受体在脂质动态平衡中的作用。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靶点或方法。法尼醇X受体(FXR)是核受体超家族中的一员，在维持胆汁酸、血脂和血糖的动态平衡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。与后一发现一致的是，激活FXR已被证明可以降低血浆胆固醇水平。已知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和防止动脉粥样硬化发展的机制仍有待确定。我们最近发现，FXR的激活可能通过一条新的FXR-HNF4a-SR-BI途径降低血浆胆固醇水平，ii)抑制肠道胆固醇的吸收，iii)增加胆固醇的反向转运，这是一个将肝外胆固醇输送回肝脏分泌到胆汁和粪便的过程。在这项提案中，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胆固醇反向转运的机制。实现这一建议中的特定目标将为激活FXR降低血浆胆固醇水平和防止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(IS)。 公共卫生相关性： 动脉粥样硬化是导致冠心病的最常见原因。拟议研究的完成将为激活FXR降低血浆胆固醇水平和防止动脉粥样硬化发展的机制提供重要的见解。因此，本申请中提出的研究与心血管疾病和人类健康高度相关。

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.