Regulation of Lipid and Lipoprotein Metabolism by Nuclear Receptors

项目概要 项目摘要：动脉粥样硬化性心血管疾病 (CVD) 是导致死亡和死亡的最常见原因。 发达国家的残疾。动脉粥样硬化是一种慢性炎症性疾病，其特征是脂质 积聚在动脉壁的巨噬细胞中。 ATP 结合盒 (ABC) 转运蛋白 A1 (ABCA1) 和 G1 (ABCG1) 对于通过促进胆固醇防止巨噬细胞发育成“泡沫”细胞至关重要 流出为无脂 apoA-I 或 HDL，随后将巨噬细胞衍生的胆固醇输送至肝脏， 肠腔用于排泄粪便。胆固醇流出缺陷导致泡沫形成 巨噬细胞，在动脉粥样硬化形成过程中被激活促进炎症反应。 MicroRNA (miRNA) 是短的非编码 RNA，可在转录后与 mRNA 的 3'UTR 结合 调节基因表达。最近的研究证明 miRNA 是脂质的重要调节因子 新陈代谢。我们培育了 miR-34aApoe 双敲除 (DKO) 小鼠。接受西方饮食后， 与对照组相比，DKO 小鼠的主动脉和主动脉根部的动脉粥样硬化病变均显着减少。 Apoe---小鼠，其血浆 LDL-C 或 HDL-C 水平未发生变化。进一步的研究表明 miR-34a 巨噬细胞 Abca1 和 Abcg1 表达显着增加，并且具有保护作用 炎症反应。根据我们的初步研究，我们假设抑制 miR-34a 可保护 通过增加巨噬细胞逆转胆固醇转运和抑制炎症来对抗动脉粥样硬化。至 检验这一假设，我们提出了三个具体目标来确定巨噬细胞 miR-34a 是否调节 胆固醇外流并逆转胆固醇转运、炎症和动脉粥样硬化。我们将利用基因 改良小鼠和药理操作以及最先进的技术来完成这一任务 项目。完成拟议的研究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，也可能导致 miR-34a 被鉴定为新靶点 用于预防和/或消退动脉粥样硬化。

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.