Liver X receptor (LXR) regulation of the LMR alpha gene in human macrophages

The nuclear oxysterol receptors LXR alpha (NR1H3) and LXR beta (NR1H2) coor dinately regulate the expression of genes involved in the transport and cat abolism of cholesterol. In macrophages, LXR stimulates the transcription of genes encoding transporters involved in cholesterol efflux, which may limi t the transformation of these cells into foam cells in response to lipid lo ading. Here, we report that natural and synthetic LXR ligands induce the ex pression of the LXRa gene in primary human macrophages and differentiated T HP-1 macrophages. This regulation was not observed in primary human adipocy tes or hepatocytes, a human intestinal cell line, or in any mouse tissue or cell line examined. The human LXRa gene was isolated, and the transcriptio n initiation site delineated. Analysis of the LXR alpha promoter revealed a functional LXR/RXR binding site similar to2.9 kb upstream of the transcrip tion initiation site. We conclude that LXRa regulates its own expression in human macrophages and that this response is likely to amplify the effects of oxysterols on reverse cholesterol transport. These findings underscore t he importance of LXR as a potential therapeutic target for the treatment of atherosclerosis.