Regulation of Lipid and Lipoprotein Metabolism by Nuclear Receptors

项目摘要 项目摘要：动脉粥样硬化性心血管疾病(CVD)是最常见的死亡原因和 发达国家的残疾问题。动脉粥样硬化是一种慢性炎症性疾病，以脂质为特征。 聚集在动脉壁巨噬细胞中。三磷酸腺苷结合盒(ABC)转运蛋白A1(ABCA1)和G1 (Abcg1)是通过促进胆固醇而防止巨噬细胞发育成“泡沫”细胞所必需的 外流到无脂apoA-I或高密度脂蛋白，随后将巨噬细胞衍生的胆固醇输送到肝脏和 肠腔用于排泄到粪便中。胆固醇外流缺陷导致泡沫形成 巨噬细胞，它被激活，在动脉粥样硬化形成过程中参与炎症反应。 MicroRNAs(MiRNAs)是一种短的、非编码的RNA，在转录后结合到mRNAs的3‘端非编码区 调控基因表达。最近的研究证明miRNAs是调节血脂的重要因素 新陈代谢。我们已经产生了MIR-34aAPOE双基因敲除小鼠。在喂食西式饮食后， 与DKO小鼠相比，dKO小鼠主动脉和主动脉根部的动脉粥样硬化病变明显减少 APOE小鼠，伴随着血浆低密度脂蛋白或高密度脂蛋白胆固醇水平的变化。进一步的研究表明， MIR-34a巨噬细胞ABCA1和Abcg1表达显著增加，并具有保护作用 炎症反应。根据我们的初步研究，我们假设抑制miR-34a可以保护 通过增加巨噬细胞的反向胆固醇运输和抑制炎症来抗动脉粥样硬化。至 为了验证这一假设，我们提出了三个特定的目标来确定巨噬细胞miR-34a是否调节 胆固醇外流和逆转胆固醇运输、炎症和动脉粥样硬化。我们将在基因上使用 改良的小鼠和药理操作以及最先进的技术来完成这一点 项目。拟议研究的完成可能会揭示巨噬细胞miR-34a在胆固醇中的新作用。 代谢、炎症和动脉粥样硬化，并可能导致将miR-34a确定为新的靶点 用于预防和/或逆转动脉粥样硬化。

Project Summary Project Summary: Atherosclerotic cardiovascular diseases (CVD) are the most common causes of death and disability in the developed countries. Atherosclerosis is a chronic inflammatory disease, characterized by lipid accumulation in macrophages of arterial walls. ATP-binding cassette (ABC) transporters A1 (ABCA1) and G1 (ABCG1) are essential for preventing macrophages from developing into “foam” cells by promoting cholesterol efflux to lipid-free apoA-I or HDL, which subsequently delivers macrophage-derived cholesterol to the liver and intestinal lumen for excretion to the feces. Defective cholesterol efflux leads to formation of foam macrophages, which are activated to contribute to the inflammatory response during atherogenesis. MicroRNAs (miRNAs) are short, non-coding RNAs that bind to the 3'UTR of mRNAs to post-transcriptionally regulate gene expression. Recent studies have documented miRNAs as important regulators of lipid metabolism. We have generated miR-34aApoe double knockout (DKO) mice. Upon fed a Western diet, the DKO mice have a marked reduction in atherosclerotic lesions in both the aorta and aortic root as compared to Apoemice, which is accompanied by unchanged plasma LDL-C or HDL-C levels. Further studies show that miR-34a macrophages have a striking increase in Abca1 and Abcg1 expression and are protective against inflammatory response. Based on our preliminary studies, we hypothesize that inhibition of miR-34a protects against atherosclerosis by increasing macrophage reverse cholesterol transport and inhibiting inflammation. To test this hypothesis, we propose three specific aims to determine whether macrophage miR-34a regulates cholesterol efflux and reverse cholesterol transport, inflammation and atherosclerosis. We will use genetically modified mice and pharmacological manipulations together with state-of-the-art techniques to complete this project. Completion of the proposed studies may uncover a novel role of macrophage miR-34a in cholesterol metabolism, inflammation and atherosclerosis, and may also lead to identification of miR-34a as a novel target for prevention and/or regression of atherosclerosis.