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Molecular and Cellular Biology, November 2001, p. 7558-7568, Vol. 21, No. 22
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.22.7558-7568.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Autoregulation of the Human Liver X Receptor alpha  Promoter

Bryan A. Laffitte,1 Sean B. Joseph,2 Robert Walczak,1 Liming Pei,2 Damien C. Wilpitz,1 Jon L. Collins,3 and Peter Tontonoz1,2,*

Howard Hughes Medical Institute1 and Department of Pathology and Laboratory Medicine,2 University of California, Los Angeles, California 90095-1662, and Nuclear Receptor Discovery Research, GlaxoSmithKline, Research Triangle Park, North Carolina 27709-33983

Received 17 April 2001/Returned for modification 29 June 2001/Accepted 28 August 2001

Previous work has implicated the nuclear receptors liver X receptor alpha  (LXRalpha ) and LXRbeta 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 and apoE. We demonstrate here that autoregulation of the LXRalpha 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 LXRalpha 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 gamma  (PPARgamma )-specific ligands, which stimulate LXRalpha expression in both human and murine macrophages. We further demonstrate that LXR and PPARgamma ligands cooperate to induce LXRalpha expression in human but not murine macrophages. Analysis of the human LXRalpha promoter led to the identification of multiple LXR response elements. Interestingly, the previously identified PPAR response element (PPRE) in the murine LXRalpha 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 PPARgamma ligands. The ability of LXRalpha to regulate its own promoter is likely to be an integral part of the macrophage physiologic response to lipid loading.

* Corresponding author. Mailing address: Howard Hughes Medical Institute, UCLA School of Medicine, Box 951662, Los Angeles, CA 90095-1662. Phone: (310) 206-4546. Fax: (310) 267-0382. E-mail: ptontonoz{at}mednet.ucla.edu.

Molecular and Cellular Biology, November 2001, p. 7558-7568, Vol. 21, No. 22
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.22.7558-7568.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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