MiR-33 and Aging: Implications for Metabolic Syndrome

描述(申请人提供)：胆固醇和脂肪酸的新陈代谢，许多生化途径的基本成分，在细胞水平上受到严格的调控。水平不足或过高可能对细胞有害，并与动脉粥样硬化、2型糖尿病和代谢综合征等与衰老相关的疾病有关。有许多调节途径可以确保胆固醇和脂肪酸水平达到平衡。尤其是最近 研究结果表明，小的非编码RNA(MiRNAs)在胆固醇和脂蛋白相关基因的转录后控制中发挥着至关重要的作用。值得注意的是microRNA-33(miR-33)，它是位于固醇调节元件结合蛋白(SREBP)基因内的一种内含子miRNA，SREBP基因是胆固醇和脂肪酸代谢的主要调节者之一。MiR-33与SREBP宿主基因一起调节胆固醇外流和高密度脂蛋白(HDL)的形成，表明miRNAs在调节胆固醇代谢中发挥着重要作用。最近，MIR-33也被证明可以调节脂肪酸代谢和胰岛素信号。MIR-33结合并抑制参与调节脂肪酸氧化的关键酶，包括肉碱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)。此外，miR-33还针对胰岛素受体底物2(IRS2)，这是胰岛素信号通路的重要组成部分。MiR-33的过表达减少了肝细胞系的脂肪酸氧化和胰岛素信号转导，而内源性抑制miR-33则增加了这两条代谢途径。在这项提议中，我们假设miR-33调节控制代谢综合征的三个危险因素的途径，包括高密度脂蛋白、甘油三酯和胰岛素信号转导水平，并且miR-33可能作为治疗靶点来治疗这一日益增长的健康问题。

DESCRIPTION (provided by applicant): The metabolism of cholesterol and fatty acids, essential components of many biochemical pathways, is tightly regulated at the cellular level. Insufficient or excess levels can be detrimental to cells and are associated with aging-related diseases such as atherosclerosis, type 2 diabetes, and metabolic syndrome. Many regulatory pathways exist to ensure that cholesterol and fatty acid levels are balanced. In particular, recent findings have revealed a crucial role for small non-coding RNAs (miRNAs) in the post-transcriptional control of cholesterol and lipoprotein-related genes. Of note is microRNA-33 (miR-33), an intronic miRNA located within the sterol regulatory element-binding protein (SREBP) gene, one of the master regulators of cholesterol and fatty acid metabolism. miR-33 regulates cholesterol efflux and high density lipoprotein (HDL) formation in concert with the SREBP host genes, suggesting an important role for miRNAs in the regulation of cholesterol metabolism. miR-33 has also recently been to shown to regulate fatty acid metabolism and insulin signaling. miR-33 binds and represses key enzymes involved in the regulation of fatty acid oxidation, including carnitine O-octaniltransferase (CROT), carnitine palmitoyltransferase 1A (CPT1a), and hydroxyacyl-CoA-dehydrogenase (HADHB). In addition, miR-33 also targets the insulin receptor substrate 2 (IRS2), an essential component of the insulin- signaling pathway. Overexpression of miR-33 reduces both fatty acid oxidation and insulin signaling in hepatic cell lines, whereas endogenous inhibition of miR-33 increases these two metabolic pathways. In this proposal, we hypothesize that miR-33 regulates pathways controlling three of the risk factors of metabolic syndrome, including levels of HDL, triglycerides, and insulin signaling and that miR-33 may be useful as a therapeutic target to treat this growing health concern.