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：
7887172
负责人：
Ira G Schulman
金额：
$ 38.5万
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 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7887172
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 Cells Cholesterol Cholesterol Homeostasis Data Development Diet Disease Progression Drug Delivery Systems Enzymes Excretory function Fatty acid glycerol esters Gene Expression Generations Genes Goals Hematopoietic System Hepatic Individual Knock-out 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 disorder subtype 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. PUBLIC HEALTH RELEVANCE: Cardiovascular disease is the leading killer of adults in the Western world and statistics from the American Heart Association indicate that more than 50% of adults living in the United States have cholesterol levels that put them at risk for atherosclerosis. The liver X receptors (LXRs) are important regulators of cholesterol homeostasis throughout the body and the experimental approaches described in this application will define the factors controlling LXR activity and will describe important sites of LXR action. The results of these studies should provide innovative strategies for the development of therapies for the treatment of cardiovascular disease.

描述（由申请人提供）：肝X受体LXR（NR1H3）和LXR（NR1H2），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。用LXR激动剂治疗通过增加编码ATP结合盒转运蛋白ABCA1和ABCG1和载脂蛋白APOE的基因的表达来促进细胞中胆固醇的外流，该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育和发病机理中起着至关重要的作用，并且已经提出，增强这些细胞中的RCT会阻碍疾病进展。重要的是，用LXR激动剂治疗减少心血管疾病动物模型的动脉粥样硬化，至少部分通过RCT的调节。毫不奇怪，在学术和制药实验室中，正在进行巨大的努力来识别LXR配体，但是，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发现了LXR的关键治疗作用。这些研究还表明，巨噬细胞中LXR的激活以及新型的非巨噬细胞位点的激活是充分的治疗潜力所必需的。该提案的主要目的是确定LXR在动脉粥样硬化中的治疗潜力，阐明其潜在的机制并确定新型的治疗作用部位。对两个LXR亚型的功能分析表明，LXR是RCT中涉及的基因的更强活化剂，而LXR是基因表达的更强的抑制剂。因此，在没有LXR的情况下，当胆固醇水平高导致细胞内胆固醇积累并增加动脉粥样硬化的风险时，无法充分诱导RCT。拟议的研究的目标之一是使用分子方法来识别赋予抗动脉粥样硬化活性特异性差异的跨作用因子。这些跨作用因子的分子和细胞表征应为发现动脉粥样硬化的新疗法提供独特的入口点。此外，肝脏通过合成和分泌重塑脂蛋白的酶以及作为脂蛋白 - 荷氨基固醇清除的酶，通过合成和分泌重塑脂蛋白的酶来控制胆固醇稳态的主要作用。拟议的研究的第二个目标将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部位。这些研究的结果应有助于鉴定LXR配体具有最小的副作用并改善抗动脉粥样硬化活性。公共卫生相关性：心血管疾病是西方世界成年人的主要杀手，美国心脏协会的统计数据表明，居住在美国的成年人中有50％以上患有胆固醇水平，使他们有动脉粥样硬化的风险。肝X受体（LXR）是整个身体胆固醇稳态的重要调节剂，本应用中描述的实验方法将定义控制LXR活性的因素，并将描述LXR作用的重要部位。这些研究的结果应为开发心血管疾病的疗法提供创新的策略。