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

Abstract

The nuclear oxysterol receptors LXR (NR1H3) and LXR (NR1H2) coordinately regulate the expression of genes involved in the transport and catabolism of cholesterol. In macrophages, LXR stimulates the transcription of genes encoding transporters involved in cholesterol efflux, which may limit the transformation of these cells into foam cells in response to lipid loading. Here, we report that natural and synthetic LXR ligands induce the expression of the LXR gene in primary human macrophages and differentiated THP-1 macrophages. This regulation was not observed in primary human adipocytes or hepatocytes, a human intestinal cell line, or in any mouse tissue or cell line examined. The human LXR gene was isolated, and the transcription initiation site delineated. Analysis of the LXR promoter revealed a functional LXR/RXR binding site ~2.9 kb upstream of the transcription initiation site. We conclude that LXR 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 the importance of LXR as a potential therapeutic target for the treatment of atherosclerosis.