The effect of statins on ABCA1 and ABCG1 expression in human macrophages is influenced by cellular cholesterol levels and extent of differentiation.
The ATP-binding cassette transporters, ABCA1 and ABCG1, are LXR-target genes that participate in the removal of cholesterol from lipid-laden macrophages, a crucial anti-atherogenic mechanism. Statins are currently the most efficacious therapy for the treatment of hypercholesterolemia and cardiovascular disease. We and others have shown that statins decrease ABCA1 and ABCG1 expression as well as cholesterol efflux from human macrophages. However, other studies have reported that statins produce no change, or even a modest increase in these variables. In an attempt to reconcile these conflicting reports, we investigated how the effect of statins on transcription of ABCA1 and ABCG1 is modulated by cellular cholesterol status and the extent of macrophage differentiation. We showed that supplementing human macrophages with cholesterol reversed the statin-mediated down-regulation of ABC transporter expression whereas depletion of cellular cholesterol tended to accentuate the statin effect. Down-regulation of ABC transporter expression was more pronounced with increased macrophage differentiation status and already evident at statin concentrations equivalent to those present in plasma. Addition of LXR agonists, which are currently on trial as anti-atherogenic agents, reversed the effects on ABC transporter expression while PPAR alpha and PPAR gamma agonists did not. The significance of these results in light of current and future combination therapies is discussed.
Wong
Jenny
J
School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney 2052, Australia.
Quinn
Carmel M
CM
Centre for Vascular Research, The University of New South Wales and Department of Haematology, Prince of Wales Hospital, Sydney, Australia.
Gelissen
Ingrid C
IC
Centre for Vascular Research, The University of New South Wales and Department of Haematology, Prince of Wales Hospital, Sydney, Australia.
Jessup
Wendy
W
Centre for Vascular Research, The University of New South Wales and Department of Haematology, Prince of Wales Hospital, Sydney, Australia.
Brown
Andrew J
AJ
School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney 2052, Australia. Electronic address: aj.brown@unsw.edu.au.
D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000187:drug effects* / Q000378:metabolism; D001565:Benzoates / Q000494:pharmacology; D001596:Benzylamines / Q000494:pharmacology; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000819:agonists / Q000187:drug effects; D015536:Down-Regulation; D020869:Gene Expression Profiling; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000493:pharmacokinetics; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D000071518:Liver X Receptors; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000187:drug effects; D013449:Sulfonamides / Q000493:pharmacokinetics; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D001565:Benzoates; D001596:Benzylamines; D002784:Cholesterol; D004268:DNA-Binding Proteins; D006845:Hydrocarbons, Fluorinated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D013449:Sulfonamides; C577836:ABCA1 protein, human; C419353:ABCG1 protein, human; C473027:GW 3965; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides