Statins inhibit synthesis of an oxysterol ligand for the liver x receptor in human macrophages with consequences for cholesterol flux.
OBJECTIVE
Cholesterol efflux from macrophages in the artery wall, a key cardioprotective mechanism, is largely coordinated by the nuclear oxysterol-activated liver X receptor, LXRalpha. We investigated the effect of statins on LXR target gene expression and cholesterol efflux from human macrophages.


RESULTS
In human macrophages (THP-1 cell line and primary cells), the archetypal statin, compactin, greatly reduced mRNA levels of 2 LXR target genes, ABCA1 and ABCG1 mRNA, as well as decreased cholesterol efflux. Commonly prescribed statins also downregulated LXR target gene expression in THP-1 cells. We provide several lines of evidence indicating that statins decrease expression of LXR target genes by inhibiting the synthesis of an oxysterol ligand for LXR, 24(S),25-epoxycholesterol. When THP-1 cells were cholesterol-loaded via incubation with acetylated low-density lipoprotein, synthesis of 24(S),25-epoxycholesterol was greatly reduced and the downregulatory effect of compactin on ABCA1 mRNA levels and cholesterol efflux was lost.


CONCLUSIONS
Our results suggest that statins may downregulate cholesterol efflux from nonloaded human macrophages by inhibiting synthesis of an oxysterol ligand for LXR. Further work is needed to determine how relevant our observations are to arterial foam cells in vivo.
Wong
Jenny
J
School of Biotechnology and Biomolecular Sciences, The University of New South Wales and Centre for Vascular Research, Sydney, Australia.
Quinn
Carmel M
CM
Brown
Andrew J
AJ
D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D002784:Cholesterol / Q000031:analogs & derivatives* / Q000096:biosynthesis* / Q000378:metabolism* / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000378:metabolism*; D008024:Ligands; D000071518:Liver X Receptors; D008148:Lovastatin / Q000031:analogs & derivatives* / Q000494:pharmacology; D008264:Macrophages / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D009000:Monocytes / Q000502:physiology; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000031:analogs & derivatives* / Q000276:immunology
C577836:ABCA1 protein, human; C419353:ABCG1 protein, human; D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D004268:DNA-Binding Proteins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008024:Ligands; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; C012258:mevastatin; C020922:4-O-methyl-12-O-tetradecanoylphorbol 13-acetate; C028358:24,25-epoxycholesterol; D002784:Cholesterol; D008148:Lovastatin; D013755:Tetradecanoylphorbol Acetate