Autoregulation of the Human Liver X Receptor α Promoter

Abstract

Previous work has implicated the nuclear receptors liver X receptor α (LXRα) and LXRβ in the regulation of macrophage gene expression in response to oxidized lipids. Macrophage lipid loading leads to ligand activation of LXRs and to induction of a pathway for cholesterol efflux involving the LXR target genes ABCA1 andapoE. We demonstrate here that autoregulation of the LXRα gene is an important component of this lipid-inducible efflux pathway in human macrophages. Oxidized low-density lipoprotein, oxysterols, and synthetic LXR ligands induce expression of LXRα mRNA in human monocyte-derived macrophages and human macrophage cell lines but not in murine peritoneal macrophages or cell lines. This is in contrast to peroxisome proliferator-activated receptor γ (PPARγ)-specific ligands, which stimulate LXRα expression in both human and murine macrophages. We further demonstrate that LXR and PPARγ ligands cooperate to induce LXRα expression in human but not murine macrophages. Analysis of the human LXRα promoter led to the identification of multiple LXR response elements. Interestingly, the previously identified PPAR response element (PPRE) in the murine LXRα gene is not conserved in humans; however, a different PPRE is present in the human LXR 5′-flanking region. These results have implications for cholesterol metabolism in human macrophages and its potential to be regulated by synthetic LXR and/or PPARγ ligands. The ability of LXRα to regulate its own promoter is likely to be an integral part of the macrophage physiologic response to lipid loading.

ACKNOWLEDGMENTS

We thank Tim Willson (GlaxoSmithKline) for GW3965, GW7845, and T0901317; Rich Heyman (Ligand Pharmaceuticals) for LG268; and Harleen Ahuja for help with real-time PCR assays. We also thank Peter Edwards, Matthew Kennedy, and Tim Willson for helpful discussions and Brenda Mueller for administrative support.

P.T. is an Assistant Investigator of the Howard Hughes Medical Institute at the University of California, Los Angeles.