Role of microRNAs in lipid metabolism and cardiovascular disease

描述(申请人提供)：胆固醇和脂类平衡的异常调节会导致代谢综合征和心血管疾病。MicroRNAs(MiRNA)是一种短小的非编码RNA，主要通过转录后抑制来控制基因的表达。它们参与了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。我们以前的工作表明，hsa-miR-33a/b及其小鼠同源物MMU-miR-33(以下简称miR-33)，内含子miRNAs分别位于人类的固醇调节元件结合蛋白(SREBP)2和1基因内，与SREBP宿主基因协同调节胆固醇的动态平衡。MIR-33抑制三磷酸腺苷结合盒(ABC)转运体ABCA1的表达，从而减少胆固醇向apoA1的外流和高密度脂蛋白(HDL)的生物生成。相反，体内沉默miR-33会增加肝脏ABCA1和血浆高密度脂蛋白。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的基因。例如，miR-33针对参与脂肪酸氧化调节的关键酶肉碱O-辛基转移酶(CROT)、肉碱棕榈酰转移酶1A(CPT1A)和羟酰辅酶A脱氢酶(HADHB)，以及调节胰岛素信号的胰岛素受体底物2(IRS2)。因此，我们假设抑制miR-33可能是改善心脏代谢性疾病的治疗靶点，包括动脉粥样硬化和代谢综合征。这项建议的目的是确定miR-33介导的心脏代谢性疾病反应的分子机制。目的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转导中的作用；2.明确miR-33在体内脂代谢、胰岛素信号转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.