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The effect of statins on ABCA1 and ABCG1 expression in human macrophages is influenced by cellular cholesterol levels and extent of differentiation

      Abstract

      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 PPARα and PPARγ agonists did not. The significance of these results in light of current and future combination therapies is discussed.

      Abbreviations:

      ABCA1 (ATP-binding cassette transporter A1), ABCG1 (ATP-binding cassette transporter G1), apoAI (apolipoprotein AI), HMG-CoA reductase (3-hydroxy-3-methylglutaryl-CoA), HMDMs (human monocyte-derived macrophages), HPβCD (2-hydroxypropyl-β-cyclodextrin), LXRα (liver X receptor alpha), LDL-R (low density lipoprotein receptor), LPDS (lipoprotein-deficient serum), MeβCD (methyl-β-cyclodextrin), PPAR (peroxisome proliferator-activated receptors), PDBu (phorbol 12, 13-dibutyrate), PMA (phorbol 12-myristate 13-acetate), QRT-PCR (quantitative (‘real-time’) reverse transcriptase-polymerase chain reaction), SREBP (sterol regulatory element-binding protein)

      Keywords

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      References

        • Li A.C.
        • Glass C.K.
        The macrophage foam cell as a target for therapeutic intervention.
        Nat Med. 2002; 8: 1235-1242
        • Lee J.Y.
        • Parks J.S.
        ATP-binding cassette transporter AI and its role in HDL formation.
        Curr Opin Lipidol. 2005; 16: 19-25
        • Soumian S.
        • Albrecht C.
        • Davies A.H.
        • Gibbs R.G.
        ABCA1 and atherosclerosis.
        Vasc Med. 2005; 10: 109-119
        • Wang N.
        • Lan D.
        • Chen W.
        • Matsuura F.
        • Tall A.R.
        ATP-binding cassette transporters G1 and G4 mediate cellular cholesterol efflux to high-density lipoproteins.
        Proc Natl Acad Sci USA. 2004; 101: 9774-9779
        • Kennedy M.A.
        • Barrera G.C.
        • Nakamura K.
        • et al.
        ABCG1 has a critical role in mediating cholesterol efflux to HDL and preventing cellular lipid accumulation.
        Cell Metab. 2005; 1: 121-131
        • Gelissen I.C.
        • Harris M.
        • Rye K.A.
        • et al.
        ABCA1 and ABCG1 synergize to mediate cholesterol export to apoA-I.
        Arterioscler Thromb Vasc Biol. 2006; 26: 534-540
        • Vaughan A.M.
        • Oram J.F.
        ABCA1 and ABCG1 or ABCG4 act sequentially to remove cellular cholesterol and generate cholesterol-rich HDL.
        J Lipid Res. 2006; 47: 2433-2443
        • Vaughan C.J.
        • Gotto Jr., A.M.
        Update on statins: 2003.
        Circulation. 2004; 110: 886-892
        • Pillarisetti S.
        • Alexander C.W.
        • Saxena U.
        Atherosclerosis—new targets and therapeutics.
        Curr Med Chem Cardiovasc Hematol Agents. 2004; 2: 327-334
        • Liao J.K.
        • Laufs U.
        Pleiotropic effects of statins.
        Annu Rev Pharmacol Toxicol. 2005; 45: 89-118
        • Sone H.
        • Shimano H.
        • Shu M.
        • et al.
        Statins downregulate ATP-binding-cassette transporter A1 gene expression in macrophages.
        Biochem Biophys Res Commun. 2004; 316: 790-794
        • Wong J.
        • Quinn C.M.
        • Brown A.J.
        Statins inhibit synthesis of an oxysterol ligand for the liver X receptor in human macrophages with consequences for cholesterol flux.
        Arterioscler Thromb Vasc Biol. 2004; 24: 2365-2371
        • Ando H.
        • Tsuruoka S.
        • Yamamoto H.
        • et al.
        Effects of pravastatin on the expression of ATP-binding cassette transporter A1.
        J Pharmacol Exp Ther. 2004; 311: 420-425
        • Llaverias G.
        • Rebollo A.
        • Pou J.
        • et al.
        Effects of rosiglitazone and atorvastatin on the expression of genes that control cholesterol homeostasis in differentiating monocytes.
        Biochem Pharmacol. 2006; 71: 605-614
        • Costet P.
        • Luo Y.
        • Wang N.
        • Tall A.R.
        Sterol-dependent transactivation of the ABC1 promoter by the liver X receptor/retinoid X receptor.
        J Biol Chem. 2000; 275: 28240-28245
        • Venkateswaran A.
        • Laffitte B.A.
        • Joseph S.B.
        • et al.
        Control of cellular cholesterol efflux by the nuclear oxysterol receptor LXR alpha.
        Proc Natl Acad Sci USA. 2000; 97: 12097-12102
        • Lund E.G.
        • Menke J.G.
        • Sparrow C.P.
        Liver X receptor agonists as potential therapeutic agents for dyslipidemia and atherosclerosis.
        Arterioscler Thromb Vasc Biol. 2003; 23: 1169-1177
        • Schmitz G.
        • Langmann T.
        Transcriptional regulatory networks in lipid metabolism control ABCA1 expression.
        Biochim Biophys Acta. 2005; 1735: 1-19
        • Argmann C.A.
        • Edwards J.Y.
        • Sawyez C.G.
        • et al.
        Regulation of macrophage cholesterol efflux through hydroxymethylglutaryl-CoA reductase inhibition: a role for RhoA in ABCA1-mediated cholesterol efflux.
        J Biol Chem. 2005; 280: 22212-22221
        • Sparrow C.P.
        • Baffic J.
        • Lam M.H.
        • et al.
        A potent synthetic LXR agonist is more effective than cholesterol loading at inducing ABCA1 mRNA and stimulating cholesterol efflux.
        J Biol Chem. 2002; 277: 10021-10027
        • Terasaka N.
        • Hiroshima A.
        • Koieyama T.
        • et al.
        T-0901317, a synthetic liver X receptor ligand, inhibits development of atherosclerosis in LDL receptor-deficient mice.
        FEBS Lett. 2003; 536: 6-11
        • Jaye M.
        LXR agonists for the treatment of atherosclerosis.
        Curr Opin Investig Drugs. 2003; 4: 1053-1058
        • Joseph S.B.
        • McKilligin E.
        • Pei L.
        • et al.
        Synthetic LXR ligand inhibits the development of atherosclerosis in mice.
        Proc Natl Acad Sci USA. 2002; 99: 7604-7609
        • Collins J.L.
        • Fivush A.M.
        • Watson M.A.
        • et al.
        Identification of a nonsteroidal liver X receptor agonist through parallel array synthesis of tertiary amines.
        J Med Chem. 2002; 45: 1963-1966
        • Li A.C.
        • Glass C.K.
        PPAR- and LXR-dependent pathways controlling lipid metabolism and the development of atherosclerosis.
        J Lipid Res. 2004; 45: 2161-2173
        • Bruemmer D.
        • Law R.E.
        Liver X receptors: potential novel targets in cardiovascular diseases.
        Curr Drug Targets Cardiovasc Haematol Disord. 2005; 5: 533-540
        • Chawla A.
        • Boisvert W.A.
        • Lee C.H.
        • et al.
        A PPAR gamma-LXR-ABCA1 pathway in macrophages is involved in cholesterol efflux and atherogenesis.
        Mol Cell. 2001; 7: 161-171
        • Kepez A.
        • Oto A.
        • Dagdelen S.
        Peroxisome proliferator-activated receptor-gamma: novel therapeutic target linking adiposity, insulin resistance, and atherosclerosis.
        BioDrugs. 2006; 20: 121-135
        • Gouni-Berthold I.
        • Krone W.
        Peroxisome proliferator-activated receptor alpha (PPARalpha) and atherosclerosis.
        Curr Drug Targets Cardiovasc Haematol Disord. 2005; 5: 513-523
        • Goldstein J.L.
        • Basu S.K.
        • Brown M.S.
        Receptor-mediated endocytosis of low-density lipoprotein in cultured cells.
        Methods Enzymol. 1983; 98: 241-260
        • Brown A.J.
        • Sun L.
        • Feramisco J.D.
        • Brown M.S.
        • Goldstein J.L.
        Cholesterol addition to ER membranes alters conformation of SCAP, the SREBP escort protein that regulates cholesterol metabolism.
        Mol Cell. 2002; 10: 237-245
        • Peiser L.
        • Gough PJ
        • Kodama T.
        • Gordon S.
        Macrophage class A scavenger receptor-mediated phagocytosis of Escherichia coli: role of cell heterogeneity, microbial strain, and culture conditions in vitro.
        Infect Immun. 2000; 68: 1953-1963
        • Phillips R.J.
        • Lutz M.
        • Premack B.
        Differential signaling mechanisms regulate expression of CC chemokine receptor-2 during monocyte maturation.
        J Inflamm (Lond). 2005; 2: 14
        • Llaverias G.
        • Vazquez-Carrera M.
        • Sanchez R.M.
        • et al.
        Rosiglitazone upregulates caveolin-1 expression in THP-1 cells through a PPAR-dependent mechanism.
        J Lipid Res. 2004; 45: 2015-2024
        • Hua X.
        • Yokoyama C.
        • Wu J.
        • et al.
        SREBP-2, a second basic-helix-loop-helix-leucine zipper protein that stimulates transcription by binding to a sterol regulatory element.
        Proc Natl Acad Sci USA. 1993; 90: 11603-11607
        • Wong J.
        • Quinn C.M.
        • Brown A.J.
        SREBP-2 positively regulates transcription of the cholesterol efflux gene, ABCA1 by generating oxysterol ligands for LXR.
        Biochem J. 2006; 400: 485-491
        • Langmann T.
        • Klucken J.
        • Reil M.
        • et al.
        Molecular cloning of the human ATP-binding cassette transporter 1 (hABC1): evidence for sterol-dependent regulation in macrophages.
        Biochem Biophys Res Commun. 1999; 257: 29-33
        • Fu X.
        • Menke J.G.
        • Chen Y.
        • et al.
        27-hydroxycholesterol is an endogenous ligand for liver X receptor in cholesterol-loaded cells.
        J Biol Chem. 2001; 276: 38378-38387
        • Siljander P.
        • Hurme M.
        Continuous presence of phorbol ester is required for its IL-1 beta mRNA stabilizing effect.
        FEBS Lett. 1993; 315: 81-84
        • Kielar D.
        • Dietmaier W.
        • Langmann T.
        • et al.
        Rapid quantification of human ABCA1 mRNA in various cell types and tissues by real-time reverse transcription-PCR.
        Clin Chem. 2001; 47: 2089-2097
        • Langmann T.
        • Liebisch G.
        • Moehle C.
        • et al.
        Gene expression profiling identifies retinoids as potent inducers of macrophage lipid efflux.
        Biochim Biophys Acta. 2005; 1740: 155-161
        • Garcia M.J.
        • Reinoso R.F.
        • Sanchez Navarro A.
        • Prous J.R.
        Clinical pharmacokinetics of statins.
        Methods Find Exp Clin Pharmacol. 2003; 25: 457-481
        • Schroepfer Jr., G.J.
        Oxysterols: modulators of cholesterol metabolism and other processes.
        Physiol Rev. 2000; 80: 361-554
        • Llaverias G.
        • Lacasa D.
        • Vinals M.
        • et al.
        Reduction of intracellular cholesterol accumulation in THP-1 macrophages by a combination of rosiglitazone and atorvastatin.
        Biochem Pharmacol. 2004; 68: 155-163
        • van Reyk D.M.
        • Brown A.J.
        • Hult’en L.M.
        • Dean R.T.
        • Jessup W.
        Oxysterols in biological systems: sources, metabolism and pathophysiological relevance.
        RedoxRep. 2006; 11: 255-262
        • Tuomisto T.T.
        • Korkeela A.
        • Rutanen J.
        • et al.
        Gene expression in macrophage-rich inflammatory cell infiltrates in human atherosclerotic lesions as studied by laser microdissection and DNA array: overexpression of HMG-CoA reductase, colony stimulating factor receptors, CD11A/CD 18 integrins, and interleukin receptors.
        Arterioscler Thromb Vasc Biol. 2003; 23: 2235-2240
        • Ito M.K.
        • Talbert R.L.
        • Tsimikas S.
        Statin-associated pleiotropy: possible beneficial effects beyond cholesterol reduction.
        Pharmacotherapy. 2006; 26 (discussion 98S–101S; quiz 106S–108S): 85S-97S
        • Vosper H.
        • Khoudoli G.A.
        • Graham T.L.
        • Palmer C.N.
        Peroxisome proliferator-activated receptor agonists, hyperlipidaemia, and atherosclerosis.
        Pharmacol Ther. 2002; 95: 47-62
        • Quinet E.M.
        • Savio D.A.
        • Halpern A.R.
        • et al.
        Gene-selective modulation by a synthetic oxysterol ligand of the liver X receptor.
        J Lipid Res. 2004; 45: 1929-1942
        • Schultz J.R.
        • Tu H.
        • Luk A.
        • et al.
        Role of LXRs in control of lipogenesis.
        Genes Dev. 2000; 14: 2831-2838