Role of microRNAs in lipid metabolism and cardiovascular disease

描述（由申请人提供）：胆固醇和脂质稳态的异常调节导致代谢综合征和心血管疾病。microRNA（miRNA）是一种短的非编码RNA，主要通过转录后抑制来调控基因表达。它们涉及多种生理和病理过程的控制。然而，miRNAs在调节胆固醇和脂蛋白代谢中的具体作用才刚刚开始探索。我们先前的工作已经表明，hsa-miR-33 a/B及其小鼠同源物mmu-miR-33（下文称为miR-33），分别位于人类固醇调节元件结合蛋白（SREBP）2和1基因内的内含子miRNA，与SREBP宿主基因一起调节胆固醇稳态。MiR-33抑制ATP结合盒（ABC）转运蛋白ABCA 1的表达，从而减弱胆固醇流出至apoA 1和高密度脂蛋白（HDL）生物合成。相反，体内miR-33的沉默增加了肝脏ABCA 1和血浆HDL。此外，我们最近的初步数据表明，miR-33还协调调节脂肪酸代谢和胰岛素信号传导的基因。例如，miR-33靶向肉毒碱O-辛醇转移酶（CROT）、肉毒碱棕榈酰转移酶1A（CPT 1a）和羟酰基-CoA-脱氢酶（HADHB）（参与调节脂肪酸氧化的关键酶）以及调节胰岛素信号传导的胰岛素受体底物2（IRS 2）。因此，我们假设抑制miR-33可能是改善心脏代谢疾病（包括动脉粥样硬化和代谢综合征）的治疗靶点。本提案的目的是确定心脏代谢疾病中miR-33介导的反应的分子机制。我们提出以下具体目标：目标1。阐明miR-33在体内调节胆固醇代谢、脂肪酸氧化和胰岛素信号传导中的作用，目的2。明确miR-33在体内脂质代谢、胰岛素信号传导和动脉粥样硬化中的作用。

DESCRIPTION (provided by applicant): Aberrant regulation of cholesterol and lipid homeostasis leads to metabolic syndrome and cardiovascular diseases. microRNAs (miRNA) are short non-coding RNAs that control gene expression predominantly through post-transcriptional repression. They are implicated in the control of multiple physiological and pathological processes. However the specific roles of miRNAs in regulating cholesterol and lipoprotein metabolism are just beginning to be explored. Our previous work has shown that hsa-miR- 33a/b and its mouse homologue mmu-miR-33 (herein after referred to as miR-33), intronic miRNAs located within the sterol-regulatory element-binding protein (SREBP) 2 and 1 genes, respectively, in humans; regulate cholesterol homeostasis in concert with the SREBP host gene. MiR-33 inhibits the expression of the ATP-binding cassette (ABC) transporter, ABCA1, thereby attenuating cholesterol efflux to apoA1 and high-density lipoprotein (HDL) biogenesis. Conversely, silencing of miR-33 in vivo increased hepatic ABCA1 and plasma HDL. In addition, our recent preliminary data suggest that miR-33 also coordinates genes regulating fatty acid metabolism and insulin signaling. For example, miR-33 targets carnitine O- octaniltransferase (CROT), Carnitine palmitoyltransferase 1A (CPT1a) and hydroxyacyl-CoA- dehydrogenase (HADHB), key enzymes involved in the regulation of fatty acid oxidation, and insulin receptor substrate 2 (IRS2), which regulates insulin signaling. Thus, we hypothesize that inhibition of miR-33 may represent a therapeutic target for ameliorating cardiometabolic disease, including atherosclerosis and metabolic syndrome. The objective of this proposal is to determine the molecular mechanism underlying the miR-33-mediated responses in cardiometabolic disease. We propose the following specific Aims: Aim 1. To delineate the role of miR-33 in regulating cholesterol metabolism, - oxidation of fatty acid and insulin signaling in vivo and Aim 2. To define the role of miR-33 in lipid metabolism, insulin signaling, and atherosclerosis in vivo.