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

• 批准号: 7708682
• 负责人: ANDERS M NAAR
• 金额: $ 22.1万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-05 至 2011-07-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7708682
• 关键词: ATP binding cassette transporter 1; ATP-Binding Cassette Transporters; Alzheimer' 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

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）：固醇反应元件结合蛋白（SREBP）转录因子已被确定为参与胆固醇和脂质稳态涉及的基因的关键调节剂。由于代谢失调中异常胆固醇和脂质稳态的突出，因此心血管疾病的基础和糖尿病，胆固醇/脂质（例如SREBPS）的转录调节剂可能会潜在地代表重要的治疗靶点，以减轻这些疾病。有趣的是，最近还发现称为microRNAS（miRNA）的小调节性RNA代表了真核基因表达的重要调节剂。在最近的研究中显示了一种miRNA，miRNA，miRNA，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在哺乳动物生理学中所起的关键作用，与人类健康有关。有趣的是，我们获得了初步数据，表明miR-33a/b，miRNA嵌入了人类SREBP-1和-2基因中内含子序列中，并与SREBP宿主基因产物协调哺乳动物中的胆固醇稳态。我们的结果表明，miR-33 miRNA靶向ABCA1胆固醇转运蛋白进行翻译抑制，从而降低ABCA1蛋白水平并降低胆固醇外排。随着SREBP通过LDL受体基因和胆固醇生物合成基因的反式激活促进胆固醇的摄取和合成，通过miR-33依赖于ABCA1 ABS的ABCA ACT在与SREBPS合作中抑制胆固醇外排抑制胆固醇外排，从我们提出了一系列体外和体内研究，以进一步确定miR-33与SREBPS合作控制胆固醇和脂质稳态在控制胆固醇和脂质稳态中的功能作用。这些研究可能会产生重要的影响，以理解miRNA和转录因子基因调节的整合和协调，并促进新的治疗策略，以增加心血管疾病患者的HDL合成和反向胆固醇的转运。具体目的是：1。检查细胞和组织中miR-33及其宿主基因SREBP的共表达。 2。确定miR-33在调节胆固醇贩运方面的作用。公共卫生相关性：胆固醇和脂肪酸在后生动物的许多生理过程中起关键的功能作用，例如调节膜流动性，作为信号分子，并以甘油三酸酯形式提供储能。 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.我们和其他人研究了胆固醇，脂质由称为固醇调节元素结合蛋白（SREBP）的基因开关控制。有趣的是，我们已经注意到人类SREBP-2和-1基因中内含子序列中存在microRNA（miR-33a/b）。初步研究提出了一个令人惊讶的发现，即miR-33a/b似乎抑制了胆固醇转运蛋白ABCA1，这是HDL合成的关键调节剂，它参与预防动脉粥样硬化。随着SREBPS促进胆固醇的摄取和合成，我们预测miR-33介导的对ABCA1和胆固醇外排的抑制作用与SREBPS合作以提高细胞内胆固醇水平。我们提出了一系列体外研究和体内研究，这些研究将描绘miR-33在控制胆固醇/脂质稳态中与SREBPS合作控制胆固醇/脂质稳态。这些研究应提供新的治疗策略，以增加心血管疾病患者的HDL合成和胆固醇清除率。