Inflammation, HDL and class B Scavenger Rectors

炎症、HDL 和 B 类清道夫受体

• 批准号: 7219727
• 负责人: Deneys Rem Van Der Westhuyzen
• 金额: $ 30.14万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-01 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7219727
• 关键词: Acute; Acute-Phase Proteins; Acute-Phase Reaction; Affinity; Apolipoproteins; Arterial Fatty Streak; Atherosclerosis; CD36 gene; Cardiovascular Diseases; Catabolism; Cells; Characteristics; Cholesterol; Chronic; Class; Exhibits; Hepatocyte; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Inflammation; Inflammatory; Inflammatory Response; Lipids; Lipopolysaccharides; Liver; Mediating; Mediator of activation protein; Metabolism; Modification; Pathway interactions; Peripheral; Phase; Phospholipase; Play; Post-Translational Protein Processing; Process; Proteins; Recycling; Research Personnel; Risk; Role; SR-B proteins; Serum amyloid A protein; Structure; Testing; Western World; macrophage; mortality; programs; protective effect; receptor; reverse cholesterol transport; therapeutic target; trafficking; uptake

Atherosclerosis is the leading cause of mortality in the western world. HDL, the levels of which are inversely correlated with the risk of atherosclerosis, exerts its protective effect in large part through its ability to mobilize cholesterol from peripheral cells and to stimulate reverse cholesterol transport to the liver. Atherosclerosis and inflammation share many common features and the atherosclerotic process exhibits characteristics of chronic inflammation. Inflammation significantly alters HDL structure, composition and levels, but the underlying mechanisms and the consequences of such modifications are not understood. In studying the impact of HDL on atherosclerosis it is therefore critical to understand how such HDL modifications, that can result both systemically and within the microenvironment of the atherosclerotic lesion, influence HDL metabolism and its role in cholesterol transport. Inflammatory modifications in HDL may also alter the protective effect of HDL in neutralizing the inflammatory effects of bacterial lipopolysaccharides. Inflammation and the acute-phase response results in a marked induction of acute phase proteins including serum amyloid A (SAA), which becomes a major HDL apolipoprotein. Recently, we identified two Class B scavenger receptors, SR-BI and CD36, as high-affinity receptors for SAA and also showed that SAA promotes cellular cholesterol efflux. Further, SR-BI and CD36 were shown to efficiently take up SAA into cells, a process that may be important in the function and metabolism of SAA. In this proposal we will examine the overall hypothesis that HDL cholesterol transport by Class B scavenger receptors is significantly altered during inflammation through the effects of acute phase proteins and modifications in HDL structure. Aim 1 will examine the hypothesis that the Class B scavenger receptors mediate the cellular uptake and catabolism of SAA. Studies will investigate the roles of SR-BI and CD36 in the cellular uptake, recycling and degradation of SAA in hepatocytes and macrophages. Aim 2 will determine how SAA and HDL remodeling during inflammation impacts HDL cholesterol transport by Class B scavenger receptors. Studies will investigate how SAA and acute phase modifications of HDL influence SR-BI-dependent cholesterol efflux from hepatocytes and macrophages and SR-BI-mediated selective lipid uptake into hepatocytes. Aim 3 will test the hypothesis that Class B scavenger receptors and SAA regulate the LPS-induced inflammatory response. Studies will examine the roles of SR-BI and CD36 in LPS- and LTA-induced inflammation and the modulating effects of SAA. These studies are expected to provide greater understanding of how inflammation influences the protective function of HDL.

在西方世界，动脉粥样硬化是导致死亡的主要原因。高密度脂蛋白，其水平与 与动脉粥样硬化的风险相关，在很大程度上通过其能力发挥其保护作用， 从外周细胞动员胆固醇并刺激胆固醇向肝脏的逆向转运。 动脉粥样硬化和炎症有许多共同的特征，动脉粥样硬化过程表现为 慢性炎症的特征。炎症显著改变HDL结构、组成和 这些变化的潜在机制和后果尚不清楚。在 因此，研究HDL对动脉粥样硬化的影响至关重要， 可以在全身和动脉粥样硬化病变的微环境内引起的改变， 影响HDL代谢及其在胆固醇转运中作用。HDL中的炎症修饰也可能 改变HDL在中和细菌脂多糖的炎症作用中的保护作用。 炎症和急性期反应导致急性期蛋白的显著诱导，包括 血清淀粉样蛋白A（SAA），其成为主要的HDL载脂蛋白。最近，我们发现了两个B类 清道夫受体SR-BI和CD 36作为SAA的高亲和力受体，也表明SAA 促进细胞胆固醇流出。此外，SR-BI和⑶ 36显示出有效地将SAA摄取到细胞中。 细胞，这一过程可能是重要的SAA的功能和代谢。在本提案中，我们将 检查由B类清道夫受体转运HDL胆固醇的总体假设， 在炎症过程中通过急性期蛋白的作用和HDL结构的改变而改变。 目的1将检验B类清道夫受体介导细胞摄取的假设， SAA的分类研究将调查SR-BI和CD 36在细胞摄取、再循环和细胞凋亡中的作用。 SAA在肝细胞和巨噬细胞中的降解。目标2将确定SAA和HDL重塑 在炎症过程中通过B类清道夫受体影响HDL胆固醇转运。研究将 研究SAA和HDL急性期修饰如何影响SR-BI依赖性胆固醇流出 来自肝细胞和巨噬细胞以及SR-BI介导的肝细胞选择性脂质摄入。目标3将 验证B类清道夫受体和SAA调节LPS诱导的炎症反应的假设。 反应研究将检查SR-BI和CD 36在LPS和LTA诱导的炎症中的作用，以及SR-BI和CD 36在LPS和LTA诱导的炎症中的作用。 SAA的调节作用。预计这些研究将提供更多的了解如何 炎症影响HDL的保护功能。