MiR-33 and Aging: Implications for Metabolic Syndrome

MiR-33 和衰老：对代谢综合征的影响

基本信息

批准号：
8536576
负责人：
Leigh Goedeke
金额：
$ 4.22万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-02 至 2015-07-01
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8536576
关键词：
3&apos Untranslated Regions ATP-Binding Cassette Transporters Accounting Address Aging Antisense Oligonucleotides Apoptosis Atherosclerosis Attention Base Pairing Binding Binding Proteins Biochemical Pathway Biology Cardiology Cardiovascular Diseases Cardiovascular system Carnitine Carnitine O-Palmitoyltransferase Carrier Proteins Cell Line Cells Cellular biology Cessation of life Cholesterol Cholesterol Homeostasis Coenzyme A Data Development Diet Disease Down-Regulation Dyslipidemias Ensure Enzyme Inhibition Enzymes Equilibrium Essential Fatty Acids Fatty Acids Fatty acid glycerol esters Functional RNA Gene Expression Gene Expression Regulation Gene Targeting Genes Growth Health Heart Diseases Hepatocyte High Density Lipoproteins Human Hypertension Hypertriglyceridemia In Vitro Individual Insulin Insulin Resistance Insulin Signaling Pathway Laboratories Lipids Liver Mediating Metabolic Diseases Metabolic Pathway Metabolic syndrome Metabolism MicroRNAs Molecular Molecular Biology Mus Non-Insulin-Dependent Diabetes Mellitus Nucleotides Obesity Oxidoreductase Pathway interactions Pharmaceutical Preparations Play Post-Transcriptional Regulation Process Publishing Quality of life Regulation Regulatory Element Regulatory Pathway Research Risk Factors Role SRE-1 binding protein SRE-2 binding protein Sterols Stroke Syndrome Therapeutic Very low density lipoprotein Work age related aged base blood glucose regulation cholesterol trafficking fatty acid metabolism fatty acid oxidation feeding glucose metabolism human IRS2 protein in vivo insulin sensitivity insulin signaling interest lipid metabolism lipoprotein cholesterol lipoprotein triglyceride mortality novel novel therapeutic intervention overexpression oxidation phosphorothioate prevent therapeutic target

项目摘要

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.

描述（由申请人提供）：胆固醇和脂肪酸是许多生化途径的重要组成部分，其代谢在细胞水平上受到严格调节。水平不足或过量都可能对细胞有害，并与动脉粥样硬化、2 型糖尿病和代谢综合征等衰老相关疾病有关。存在许多调节途径来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非编码 RNA (miRNA) 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)，这是一种位于甾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 宿主基因协同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发挥着重要作用。最近还显示 miR-33 可以调节脂肪酸代谢和胰岛素信号传导。 miR-33 结合并抑制参与脂肪酸氧化调节的关键酶，包括肉碱 O-辛基转移酶 (CROT)、肉碱棕榈酰转移酶 1A (CPT1a) 和羟酰基辅酶 A 脱氢酶 (HADHB)。此外，miR-33 还靶向胰岛素受体底物 2 (IRS2)，这是胰岛素信号传导通路的重要组成部分。 miR-33 的过度表达会减少肝细胞系中的脂肪酸氧化和胰岛素信号传导，而 miR-33 的内源性抑制会增加这两种代谢途径。在本提案中，我们假设 miR-33 调节控制代谢综合征三个危险因素的途径，包括 HDL、甘油三酯和胰岛素信号传导水平，并且 miR-33 可能可作为治疗靶点来治疗这一日益严重的健康问题。