Studies on scavenger receptor class B type I and genes implicated in foam cell formation

Abstract: The risk of atherosclerosis correlates with plasma levels of low-density lipoprotein (LDL) cholesterol and is inversely correlated to plasma levels of high-density lipoprotein (HDL) cholesterol. Accumulation of oxidized LDL (oxLDL) by arterial macrophages is a key event in the development of atherosclerosis. The atheroprotective effect of HDL is believed to be related to the HDL-mediated reverse cholesterol transport from peripheral tissues to the liver. The aim of this thesis was to examine the changes in gene expression during foam cell formation and to study the HDL-receptor scavenger receptor class B type I (SR-BI), which may be of importance for reverse cholesterol transport.To search for genes that may be of importance for foam cell formation, expression profiling of human macrophages exposed to oxLDL was performed. OxLDL increased expression of genes involved in uptake of oxLDL, storage of lipids and cholesterol efflux whereas expression of genes involved in cholesterol synthesis and LDL-uptake was decreased. OxLDL also induced a cellular stress response, with increased expression of genes encoding heat shock proteins, metallothioneins and enzymes in the glutathione and the thioredoxin system. An increased secretion of heat shock protein 70 (HSP70) by the macrophages after oxLDL exposure was also detected. Extracellular HSP70 may provide a link between macrophage lipid accumulation and release of pro-inflammatory cytokines.To investigate the function of SR-BI, the SR-BI cDNA was cloned in rat. The rat and human SR-BI genes were mapped to rat and human chromosomes 12. High levels of SR-BI mRNA were detected in the adrenal gland, ovary and liver. In the ovary, SR-BI was expressed in steroidogenically active theca cells in healthy follicles and in corpus luteum, where it may enhance cholesterol uptake as a substrate for steroid hormone production. SR-BI was also expressed in follicles undergoing atresia. Binding studies showed that SR-BI mediated the recognition of apoptotic granulosa cells. These results suggest that SR-BI may have both scavenger receptor and HDL-receptor function in the ovary. SR-BI, SR-BII and a novel SR-BI isoform (SR-BIII) were expressed in human atherosclerotic plaques and in human macrophages. SR-BI expression in macrophages was upregulated by oxLDL, suggesting that SR-BI may function as a mediator of cholesterol efflux. In conclusion, expression profiling of macrophages revealed changes in the expression of several genes and may provide clues to the mechanisms behind foam cell formation. Tissue distribution and regulation of SR-BI indicate that it may function both as a scavenger receptor and as a receptor for HDL-cholesterol.