The phospholipid transfer protein gene is a liver X receptor target expressed by macrophages in atherosclerotic lesions.
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 LXRalpha and LXRbeta, 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.
Laffitte
Bryan A
BA
Howard Hughes Medical Institute, School of Medicine, University of California-Los Angeles, Los Angeles, CA 90095-1662, USA.
Joseph
Sean B
SB
Chen
Mingyi
M
Castrillo
Antonio
A
Repa
Joyce
J
Wilpitz
Damien
D
Mangelsdorf
David
D
Tontonoz
Peter
P
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D001161:Arteriosclerosis / Q000378:metabolism*; D001565:Benzoates / Q000494:pharmacology; D001596:Benzylamines / Q000494:pharmacology; D002352:Carrier Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured / Q000378:metabolism; D003324:Coronary Artery Disease / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins; D019281:Dimerization; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D008024:Ligands; D008075:Lipoproteins, HDL / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D000071518:Liver X Receptors; D008264:Macrophages / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D009930:Organic Chemicals; D057093:Orphan Nuclear Receptors; D049294:Phospholipid Transfer Proteins; D011401:Promoter Regions, Genetic; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000737:chemistry / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000502:physiology; D047488:Retinoid X Receptors; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism; D014162:Transfection
D000924:Anticholesteremic Agents; D001057:Apolipoproteins E; D001565:Benzoates; D001596:Benzylamines; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C473027:GW 3965; C423914:LG 268; D008024:Ligands; D008075:Lipoproteins, HDL; D000071518:Liver X Receptors; D008565:Membrane Proteins; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; D009930:Organic Chemicals; D057093:Orphan Nuclear Receptors; D049294:Phospholipid Transfer Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D011993:Recombinant Fusion Proteins; D047488:Retinoid X Receptors; D014157:Transcription Factors