MiR-33 and Aging: Implications for Metabolic Syndrome

描述（由申请人提供）：胆固醇和脂肪酸的代谢是许多生化途径的重要组成部分，在细胞水平受到严格调控。不足或过量的水平可能对细胞有害，并与衰老相关的疾病，如动脉粥样硬化，2型糖尿病和代谢综合征有关。存在许多调节途径以确保胆固醇和脂肪酸水平平衡。特别是最近 研究结果揭示了小的非编码RNA（miRNAs）在胆固醇和脂蛋白相关基因的转录后控制中的关键作用。值得注意的是microRNA-33（miR-33），一种位于固醇调节元件结合蛋白（SREBP）基因内的内含子miRNA，是胆固醇和脂肪酸代谢的主要调节因子之一。miR-33与SREBP宿主基因一起调节胆固醇流出和高密度脂蛋白（HDL）形成，表明miRNA在胆固醇代谢调节中的重要作用。最近还显示miR-33调节脂肪酸代谢和胰岛素信号传导。miR-33结合并抑制参与调节脂肪酸氧化的关键酶，包括肉毒碱O-辛醇转移酶（CROT）、肉毒碱棕榈酰转移酶1A（CPT 1a）和羟酰辅酶A脱氢酶（HADHB）。此外，miR-33还靶向胰岛素受体底物2（IRS 2），这是胰岛素信号传导途径的重要组成部分。在肝细胞系中，miR-33的过表达减少脂肪酸氧化和胰岛素信号传导，而miR-33的内源性抑制增加这两种代谢途径。在这个提议中，我们假设miR-33调节控制代谢综合征的三个风险因素的途径，包括HDL，甘油三酯和胰岛素信号传导的水平，并且miR-33可能用作治疗这种日益增长的健康问题的治疗靶点。

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.