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Role of MicroRNA mi R-33 in Controlling Cholesterol/Lipid Homeostasis

MicroRNA miR-33 在控制胆固醇/脂质稳态中的作用

基本信息

批准号：
7905935
负责人：
ANDERS M NAAR
金额：
$ 26.55万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-05 至 2012-01-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7905935
关键词：
ATP binding cassette transporter 1 ATP-Binding Cassette Transporters Alzheimer&apos s Disease Anabolism Arterial Fatty Streak Atherosclerosis Binding Proteins Bioinformatics Biological Blood Cardiovascular Diseases Cause of Death Cells Cholesterol Cholesterol Homeostasis Complement component C1s Coupling Cues DNA Microarray Chip Data Development Diabetes Mellitus Disease Down-Regulation Fatty Acids Feedback Foam Cells Gene Expression Gene Expression Regulation Genes Glucose Health Heart Diseases High Density Lipoprotein Cholesterol High Density Lipoproteins Homeostasis Human Hypertension In Vitro Insulin Knowledge Link Lipids Lipodystrophy Lipoproteins Liver Low Density Lipoprotein Receptor Low-Density Lipoproteins Luciferases Malignant Neoplasms Mammals Mediating Membrane Fluidity Metabolic Metabolic syndrome MicroRNAs Modeling Molecular Mus Mutation Nicotinic Acids Non-Insulin-Dependent Diabetes Mellitus Obesity Pathway interactions Patients Peripheral Physiological Processes Physiology Play Production Proteins Receptor Gene Regulation Regulator Genes Regulatory Element Response Elements Role Series Signaling Molecule Sterols Supplementation Switch Genes Therapeutic Tissues Transactivation Transcription factor genes Transcriptional Regulation Translational Repression Triglycerides Untranslated Regions cholesterol biosynthesis cholesterol control cholesterol trafficking cholesterol transporters gene interaction in vivo inhibitor/antagonist insight lipid biosynthesis lipid transport macrophage new therapeutic target nonhuman primate novel therapeutics particle prevent public health relevance research study reverse cholesterol transport therapeutic target trafficking transcription factor uptake

项目摘要

DESCRIPTION (provided by applicant): The sterol response element binding protein (SREBP) transcription factors have been identified as key regulators of genes involved in both cholesterol and lipid homeostasis. Because of the prominence of aberrant cholesterol and lipid homeostasis in the metabolic dysregulation underpinning cardiovascular disease and diabetes, transcriptional regulators of cholesterol/lipids such as SREBPs could potentially represent important therapeutic targets to ameliorate these diseases. Interestingly, small regulatory RNAs termed microRNAs (miRNAs) have recently also been found to represent important regulators of eukaryotic gene expression. One miRNA, miR-122, was shown in recent studies to modulate cholesterol levels in mice and non-human primates. These studies have highlighted the critical role played by miRNAs in mammalian physiology with relevance to human health. Intriguingly, we have obtained preliminary data suggesting that miR-33a/b, miRNAs that are embedded within intronic sequences in both SREBP-1 and -2 genes in humans, regulate cholesterol homeostasis in mammals in coordination with the SREBP host gene products. Our results show that miR-33 miRNAs target the ABCA1 cholesterol transporter for translational repression, resulting in lowered ABCA1 protein levels and decreased cholesterol efflux. As SREBPs promote cholesterol uptake and synthesis through the transactivation of the LDL receptor gene and cholesterol biosynthesis genes, inhibition of cholesterol efflux by miR-33-dependent down-regulation of ABCA1 acts in cooperation with SREBPs to effectively boost intracellular cholesterol levels. We propose a series of in vitro and in vivo studies to further determine the functional role of miR-33 in controlling cholesterol and lipid homeostasis in cooperation with SREBPs. These studies could have important ramifications for our understanding of the integration and coordination of miRNA and transcription factor gene regulation and will facilitate novel therapeutic strategies to increase HDL synthesis and reverse cholesterol transport in patients with cardiovascular disease. The Specific Aims are: 1. To examine the co-expression of miR-33 and its host gene SREBP in cells and tissues. 2. To determine the role of miR-33 in regulation of cholesterol trafficking. PUBLIC HEALTH RELEVANCE: Cholesterol and fatty acids play critical functional roles in many physiological processes in metazoans, such as modulating membrane fluidity, serving as signaling molecules, and providing energy storage in the form of triglycerides. Abnormal cholesterol and lipid levels have been linked to increasingly prevalent diseases, including atherosclerosis, obesity, type II diabetes, and hypertension (all associated with metabolic syndrome), as well as lipodystrophy, Alzheimers Disease, and certain cancers, underscoring the importance of understanding fully how cholesterol and lipid homeostasis are regulated and maintained. We and others have investigated cholesterol and lipids are controlled by gene switches termed sterol regulatory element binding protein (SREBP). Intriguingly, we have noted the presence of microRNAs (miR- 33a/b) within intronic sequences in the human SREBP-2 and -1 genes, respectively. Preliminary studies yielded the surprising finding that miR-33a/b appear to repress the cholesterol transporter ABCA1, a key regulator of HDL synthesis that is involved in preventing atherosclerosis. As SREBPs promote cholesterol uptake and synthesis, we predict that miR-33-mediated inhibition of ABCA1 and cholesterol efflux acts in cooperation with SREBPs to boost intracellular cholesterol levels. We propose a series of in vitro and in vivo studies that will delineate the role of miR-33 in controlling cholesterol/lipid homeostasis in cooperation with SREBPs. These studies should provide novel therapeutic strategies aimed at increasing HDL synthesis and cholesterol clearance in patients with cardiovascular disease.

描述（由申请人提供）：甾醇反应元件结合蛋白（SREBP）转录因子已被确定为涉及胆固醇和脂质稳态的基因的关键调节因子。由于异常胆固醇和脂质稳态在心血管疾病和糖尿病的代谢失调中非常突出，胆固醇/脂质的转录调节剂（例如 SREBP）可能成为改善这些疾病的重要治疗靶点。有趣的是，最近还发现称为 microRNA (miRNA) 的小调节 RNA 代表真核基因表达的重要调节因子。最近的研究表明，一种 miRNA，miR-122，可以调节小鼠和非人类灵长类动物的胆固醇水平。这些研究强调了 miRNA 在与人类健康相关的哺乳动物生理学中发挥的关键作用。有趣的是，我们获得的初步数据表明，miR-33a/b（嵌入人类 SREBP-1 和 -2 基因内含子序列中的 miRNA）与 SREBP 宿主基因产物协调调节哺乳动物的胆固醇稳态。我们的结果表明，miR-33 miRNA 以 ABCA1 胆固醇转运蛋白为靶点进行翻译抑制，从而降低 ABCA1 蛋白水平并减少胆固醇流出。由于 SREBP 通过 LDL 受体基因和胆固醇生物合成基因的反式激活来促进胆固醇摄取和合成，因此通过 miR-33 依赖性下调 ABCA1 来抑制胆固醇外流，与 SREBP 协同作用，有效提高细胞内胆固醇水平。我们提出了一系列体外和体内研究，以进一步确定 miR-33 与 SREBP 合作控制胆固醇和脂质稳态的功能作用。这些研究可能对我们理解 miRNA 和转录因子基因调控的整合和协调产生重要影响，并将促进新的治疗策略，以增加心血管疾病患者的 HDL 合成和逆转胆固醇转运。具体目的是： 1. 检测细胞和组织中miR-33及其宿主基因SREBP的共表达。 2.确定miR-33在调节胆固醇运输中的作用。公共健康相关性：胆固醇和脂肪酸在后生动物的许多生理过程中发挥着关键的功能作用，例如调节膜流动性、充当信号分子以及以甘油三酯的形式提供能量储存。胆固醇和脂质水平异常与日益流行的疾病有关，包括动脉粥样硬化、肥胖、II型糖尿病和高血压（均与代谢综合征有关），以及脂肪营养不良、阿尔茨海默病和某些癌症，这凸显了充分了解胆固醇和脂质稳态如何调节和维持的重要性。我们和其他人研究了胆固醇和脂质是由称为甾醇调节元件结合蛋白（SREBP）的基因开关控制的。有趣的是，我们注意到人类 SREBP-2 和 -1 基因的内含子序列中分别存在 microRNA (miR-33a/b)。初步研究得出了令人惊讶的发现，即 miR-33a/b 似乎可以抑制胆固醇转运蛋白 ABCA1，胆固醇转运蛋白 ABCA1 是 HDL 合成的关键调节因子，参与预防动脉粥样硬化。由于 SREBP 促进胆固醇摄取和合成，我们预测 miR-33 介导的 ABCA1 和胆固醇流出抑制作用与 SREBP 协同作用，可提高细胞内胆固醇水平。我们提出了一系列体外和体内研究，这些研究将描述 miR-33 与 SREBP 合作控制胆固醇/脂质稳态的作用。这些研究应该提供新的治疗策略，旨在增加心血管疾病患者的高密度脂蛋白合成和胆固醇清除。