Inflammation, HDL and class B Scavenger Rectors

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，在很大程度上通过它的能力发挥其保护作用 动员外周细胞中的胆固醇，刺激胆固醇反向转运到肝脏。 动脉粥样硬化和炎症有许多共同的特征，动脉粥样硬化的过程表现为 慢性炎症的特点。炎症显著改变高密度脂蛋白的结构、组成和 但是，这种修改的基本机制和后果尚不清楚。在……里面 因此，研究高密度脂蛋白对动脉粥样硬化的影响是至关重要的。 修饰，这可能会在系统内和动脉粥样硬化病变的微环境中导致， 影响高密度脂蛋白代谢及其在胆固醇运输中的作用。高密度脂蛋白中的炎性修饰也可能 改变高密度脂蛋白中和细菌脂多糖炎症反应的保护作用。 炎症和急性时相反应导致急性时相蛋白的显著诱导，包括 血清淀粉样蛋白A(SAA)，它成为主要的高密度脂蛋白载脂蛋白。最近，我们确定了两个B类 清道夫受体SR-BI和CD36作为SAA的高亲和力受体，也表明SAA 促进细胞胆固醇外流。此外，SR-BI和CD36被证明有效地将SAA吸收到 细胞，这一过程可能在SAA的功能和新陈代谢中起重要作用。在本提案中，我们将 检验通过B类清道夫受体转运高密度脂蛋白的总体假设 在炎症过程中，通过急性时相蛋白的影响和高密度脂蛋白结构的改变而改变。 目标1将检验B类清道夫受体介导细胞摄取和 SAA的分解代谢。研究将探讨SR-BI和CD36在细胞摄取、循环和 SAA在肝细胞和巨噬细胞中的降解目标2将确定SAA和高密度脂蛋白如何重塑 在炎症影响期间，高密度脂蛋白通过B类清道夫受体运输。研究将会 研究SAA和高密度脂蛋白急性时相改变对SR-BI依赖的胆固醇流出的影响 从肝细胞和巨噬细胞和SR-BI介导的选择性脂质摄取到肝细胞。目标3将 验证B类清道夫受体和SAA对内毒素诱导的炎症反应的调节作用 回应。研究将探讨SR-BI和CD36在内毒素和LTA诱导的炎症中的作用以及 SAA的调节作用。这些研究有望提供更多关于如何 炎症影响高密度脂蛋白的保护作用。

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.