Subtype Specific LXR Activity Limits Atherosclerosis

描述（由申请人提供）：肝脏X受体LXR （NR1H3）和LXR （NR1H2）是核激素受体转录因子超家族的成员，已被确定为胆固醇稳态的重要调节因子。LXR激动剂通过增加编码ATP结合盒转运体ABCA1和ABCG1以及载脂蛋白apoE的基因的表达，促进胆固醇从细胞外排，这一过程被称为逆向胆固醇转运（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关键作用，研究表明，增强这些细胞的RCT可延缓疾病进展。重要的是，LXR激动剂治疗至少在一定程度上通过上调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努力鉴定LXR配体，然而，与第一代化合物相关的一个主要限制是它们倾向于增加血浆脂质水平。对每个LXR亚型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，巨噬细胞和新的非巨噬细胞位点的LXR激活是充分发挥治疗潜力的必要条件。本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RCT相关基因的较强激活因子，而LXR是基因表达的较强抑制因子。因此，在缺乏LXR的情况下，当胆固醇水平高时，不能充分诱导RCT，导致细胞内胆固醇积累和动脉粥样硬化风险增加。拟议研究的一个目标是使用分子方法来确定赋予抗动脉粥样硬化活性亚型特异性差异的反式作用因子。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治疗方法提供独特的切入点。此外，肝脏在控制胆固醇稳态中发挥着重要作用，它是脂蛋白产生的场所，通过合成和分泌重塑脂蛋白的酶，以及作为脂蛋白携带的固醇清除的场所。该研究的第二个目标是利用细胞和动物模型来确定肝脏作为lxr依赖性抗动脉粥样硬化活性的新部位。这些研究的结果应该有助于鉴别副作用最小、抗动脉粥样硬化活性提高的LXR配体。

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.