Atherosclerosis is the leading cause of mortality in the western world. HDL, the levels of which are inverselycorrelated with the risk of atherosclerosis, exerts its protective effect in large part through its ability tomobilize cholesterol from peripheral cells and to stimulate reverse cholesterol transport to the liver.Atherosclerosis and inflammation share many common features and the atherosclerotic process exhibitscharacteristics of chronic inflammation. Inflammation significantly alters HDL structure, composition andlevels, but the underlying mechanisms and the consequences of such modifications are not understood. Instudying the impact of HDL on atherosclerosis it is therefore critical to understand how such HDLmodifications, 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 alsoalter 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 includingserum amyloid A (SAA), which becomes a major HDL apolipoprotein. Recently, we identified two Class Bscavenger receptors, SR-BI and CD36, as high-affinity receptors for SAA and also showed that SAApromotes cellular cholesterol efflux. Further, SR-BI and CD36 were shown to efficiently take up SAA intocells, a process that may be important in the function and metabolism of SAA. In this proposal we willexamine the overall hypothesis that HDL cholesterol transport by Class B scavenger receptors is significantlyaltered 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 andcatabolism of SAA. Studies will investigate the roles of SR-BI and CD36 in the cellular uptake, recycling anddegradation of SAA in hepatocytes and macrophages.
Aim 2 will determine how SAA and HDL remodelingduring inflammation impacts HDL cholesterol transport by Class B scavenger receptors. Studies willinvestigate how SAA and acute phase modifications of HDL influence SR-BI-dependent cholesterol effluxfrom hepatocytes and macrophages and SR-BI-mediated selective lipid uptake into hepatocytes.
Aim 3 willtest the hypothesis that Class B scavenger receptors and SAA regulate the LPS-induced inflammatoryresponse. Studies will examine the roles of SR-BI and CD36 in LPS- and LTA-induced inflammation and themodulating effects of SAA. These studies are expected to provide greater understanding of howinflammation influences the protective function of HDL.
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