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Molecular and Cellular Biology, March 2003, p. 2182-2191, Vol. 23, No. 6
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.6.2182-2191.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

The Phospholipid Transfer Protein Gene Is a Liver X Receptor Target Expressed by Macrophages in Atherosclerotic Lesions

Bryan A. Laffitte,1 Sean B. Joseph,2 Mingyi Chen,2 Antonio Castrillo,1 Joyce Repa,3 Damien Wilpitz,1 David Mangelsdorf,1,3 and Peter Tontonoz1,2*

Howard Hughes Medical Institute,1 Department of Pathology and Laboratory Medicine, University of California, Los Angeles, California 90095-1662,2 Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-90503

Received 14 August 2002/ Returned for modification 14 October 2002/ Accepted 9 December 2002

The liver X receptors (LXRs) are members of the nuclear receptor superfamily that are activated by oxysterols. In response to ligand binding, LXRs regulate a variety of genes involved in the catabolism, transport, and uptake of cholesterol and its metabolites. Here we demonstrate that LXRs also regulate plasma lipoprotein metabolism through control of the phospholipid transfer protein (PLTP) gene. LXR ligands induce the expression of PLTP in cultured HepG2 cells and mouse liver in vivo in a coordinate manner with known LXR target genes. Moreover, plasma phospholipid transfer activity is increased in mice treated with the synthetic LXR ligand GW3965. Unexpectedly, PLTP expression was also highly inducible by LXR in macrophages, a cell type not previously recognized to express this enzyme. The ability of synthetic and oxysterol ligands to regulate PLTP mRNA in macrophages and liver is lost in animals lacking both LXR{alpha} and LXRß, confirming the critical role of these receptors. We further demonstrate that the PLTP promoter contains a high-affinity LXR response element that is bound by LXR/RXR heterodimers in vitro and is activated by LXR/RXR in transient-transfection studies. Finally, immunohistochemistry studies reveal that PLTP is highly expressed by macrophages within human atherosclerotic lesions, suggesting a potential role for this enzyme in lipid-loaded macrophages. These studies outline a novel pathway whereby LXR and its ligands may modulate lipoprotein metabolism.

* 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, March 2003, p. 2182-2191, Vol. 23, No. 6
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.6.2182-2191.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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