The phospholipid transfer protein gene is a liver X receptor target expressed by macrophages in atherosclerotic lesions

Bryan A. Laffitte, Sean B. Joseph, Mingyi Chen, Antonio Castrillo, Joyce Repa, Damien Wilpitz, David Mangelsdorf, Peter Tontonoz

Research output: Contribution to journalArticle

127 Scopus citations

Abstract

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 LXRα and LXRβ, 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.

Original languageEnglish (US)
Pages (from-to)2182-2191
Number of pages10
JournalMolecular and Cellular Biology
Volume23
Issue number6
DOIs
StatePublished - Mar 2003

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

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    Laffitte, B. A., Joseph, S. B., Chen, M., Castrillo, A., Repa, J., Wilpitz, D., Mangelsdorf, D., & Tontonoz, P. (2003). The phospholipid transfer protein gene is a liver X receptor target expressed by macrophages in atherosclerotic lesions. Molecular and Cellular Biology, 23(6), 2182-2191. https://doi.org/10.1128/MCB.23.6.2182-2191.2003