Subtype Specific LXR Activity Limits Atherosclerosis

亚型特异性 LXR 活性限制动脉粥样硬化

基本信息

批准号：
8432506
负责人：
Ira G Schulman
金额：
$ 36.29万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2014-08-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8432506
关键词：
ADD-1 protein ATP-Binding Cassette Transporters Adult Adverse effects Affect Agonist American Heart Association Amino Acids Animal Model Antiatherogenic Apolipoprotein E Apolipoproteins Atherosclerosis Biochemical Genetics Bone Marrow Transplantation Cardiovascular Diseases Catabolism Cell model Cells Cholesterol Cholesterol Homeostasis Data Development Diet Disease Progression Drug Targeting Enzymes Excretory function Fatty acid glycerol esters Gene Expression Generations Genes Goals Hematopoietic System Hepatic Individual Knock-out Knockout Mice Laboratories Lesion Life Ligand Binding Ligands Lipids Lipoproteins Liver Low Density Lipoprotein Receptor Measures Mediating Molecular Mus Nuclear Hormone Receptors Pathogenesis Pathway interactions Pharmaceutical Preparations Pharmacologic Substance Plasma Play Process Production Proteins Receptor Activation Receptor Gene Research Risk Role Site Sterols Testing Therapeutic Trans-Activators Transcription Coactivator Triglycerides United States Up-Regulation Western World drug development drug discovery genetic analysis improved in vivo innovation interest lipid biosynthesis macrophage member novel novel therapeutics public health relevance receptor research study reverse cholesterol transport small molecule statistics therapy development transcription factor uptake

项目摘要

DESCRIPTION (provided by applicant): The liver X receptors LXR (NR1H3) and LXR (NR1H2), members of the nuclear hormone receptor superfamily of transcription factors, have been identified as important regulators of cholesterol homeostasis. Treatment with LXR agonists promotes the efflux of cholesterol from cells, a process termed reverse cholesterol transport (RCT), by increasing expression of the genes encoding the ATP binding cassette transporters ABCA1 and ABCG1 and the apolipoprotein apoE. The uptake of oxidized cholesterol by macrophages plays a critical role in the development and pathogenesis of atherosclerosis and it has been suggested that enhancing RCT in these cells would retard disease progression. Importantly, treatment with LXR agonists reduces atherosclerosis in animal models of cardiovascular disease at least in part by up- regulation of RCT. Not surprisingly there are intense efforts underway in academic and in pharmaceutical laboratories to identify LXR ligands, however, a major limitation associated with first generation compounds is their propensity to increase plasma lipid levels. A genetic analysis of the individual anti-atherogenic potential of each LXR subtype uncovered a critical therapeutic role for LXR. These studies also demonstrated that activation of LXR in macrophages as well as at a novel non-macrophage site(s) is required for full therapeutic potential. The main goal of this proposal is to define the therapeutic potential of LXR in atherosclerosis, elucidate its underlying mechanism and identify novel therapeutic sites of action. Functional analysis of the two LXR subtypes indicates that LXR is stronger activator of the genes involved in RCT while LXR is a stronger repressor of gene expression. Thus in the absence of LXR RCT is not sufficiently induced when cholesterol levels are high leading to intracellular cholesterol accumulation and an increased risk for atherosclerosis. One goal of the proposed research is to use molecular approaches to identify the trans-acting factors that confer subtype specific differences in anti-atherogenic activity. Molecular and cellular characterization of these trans-acting factors should provide unique entry points for the discovery of novel treatments for atherosclerosis. Additionally, the liver plays a major role in the control of cholesterol homeostasis by serving as the site of lipoprotein production, by synthesizing and secreting the enzymes that remodel lipoproteins, and as the site of lipoprotein-borne sterol clearance. A second goal of the proposed research will be utilize cellular and animal models to define the liver as a novel site of LXR-dependent anti- atherogenic activity. The results of these studies should assist in the identification LXR ligands with minimal side effects and improved anti-atherogenic activity.

描述（由申请人提供）：肝脏 X 受体 LXR (NR1H3) 和 LXR (NR1H2) 是转录因子核激素受体超家族的成员，已被确定为胆固醇稳态的重要调节剂。 LXR 激动剂治疗通过增加编码 ATP 结合盒转运蛋白 ABCA1 和 ABCG1 以及载脂蛋白 apoE 的基因表达，促进胆固醇从细胞中流出，这一过程称为反向胆固醇转运 (RCT)。巨噬细胞对氧化胆固醇的摄取在动脉粥样硬化的发展和发病机制中起着至关重要的作用，并且有人建议增强这些细胞中的 RCT 将延缓疾病进展。重要的是，LXR激动剂治疗至少部分通过上调RCT来减少心血管疾病动物模型中的动脉粥样硬化。毫不奇怪，学术界和制药实验室正在大力努力鉴定 LXR 配体，然而，与第一代化合物相关的主要限制是它们增加血浆脂质水平的倾向。对每种 LXR 亚型的个体抗动脉粥样硬化潜力的遗传分析揭示了 LXR 的关键治疗作用。这些研究还表明，要充分发挥治疗潜力，需要激活巨噬细胞以及新的非巨噬细胞位点的 LXR。该提案的主要目标是确定 LXR 在动脉粥样硬化中的治疗潜力，阐明其潜在机制并确定新的治疗作用位点。两种 LXR 亚型的功能分析表明，LXR 是参与 RCT 的基因的更强激活剂，而 LXR 是基因表达的更强抑制剂。因此，在缺乏 LXR 的情况下，当胆固醇水平较高时，RCT 不会被充分诱导，导致细胞内胆固醇积累并增加动脉粥样硬化的风险。拟议研究的目标之一是使用分子方法来识别反式作用因子，这些因子赋予亚型抗动脉粥样硬化活性的特异性差异。这些反式作用因子的分子和细胞特征应该为发现动脉粥样硬化的新疗法提供独特的切入点。此外，肝脏通过充当脂蛋白生产场所、合成和分泌重塑脂蛋白的酶以及作为脂蛋白携带的甾醇清除场所，在控制胆固醇稳态中发挥着重要作用。拟议研究的第二个目标是利用细胞和动物模型将肝脏定义为 LXR 依赖性抗动脉粥样硬化活性的新位点。这些研究的结果应有助于鉴定具有最小副作用和改善的抗动脉粥样硬化活性的 LXR 配体。