title: Activation of liver X receptor decreases atherosclerosis in Ldlr⁻/⁻ mice in the absence of ATP-binding cassette transporters A1 and G1 in myeloid cells.
abstract: OBJECTIVE
  Liver X receptor (LXR) activators decrease atherosclerosis in mice. LXR activators (1) directly upregulate genes involved in reverse cholesterol transport and (2) exert anti-inflammatory effects mediated by transrepression of nuclear factor-κB target genes. We investigated whether myeloid cell deficiency of ATP-binding cassette transporters A1 and G1 (ABCA1/G1), principal targets of LXR that promote macrophage cholesterol efflux and initiate reverse cholesterol transport, would abolish the beneficial effects of LXR activation on atherosclerosis.
  
  
  RESULTS
  LXR activator T0901317 substantially reduced inflammatory gene expression in macrophages lacking ABCA1/G1. Ldlr(-/-) mice were transplanted with Abca1(-/-)Abcg1(-/-) or wild-type bone marrow (BM) and fed a Western-type diet for 6 weeks with or without T0901317 supplementation. Abca1/g1 BM deficiency increased atherosclerotic lesion complexity and inflammatory cell infiltration into the adventitia and myocardium. T0901317 markedly decreased lesion area, complexity, and inflammatory cell infiltration in the Abca1(-/-)Abcg1(-/-) BM-transplanted mice. To investigate whether this was because of macrophage Abca1/g1 deficiency, Ldlr(-/-) mice were transplanted with LysmCreAbca1(fl/fl)Abcg1(fl/fl) or Abca1(fl/fl)Abcg1(fl/fl) BM and fed Western-type diet with or without the more specific LXR agonist GW3965 for 12 weeks. GW3965 decreased lesion size in both groups, and the decrease was more prominent in the LysmCreAbca1(fl/fl)Abcg1(fl/fl) group.
  
  
  CONCLUSIONS
  The results suggest that anti-inflammatory effects of LXR activators are of key importance to their antiatherosclerotic effects in vivo independent of cholesterol efflux pathways mediated by macrophage ABCA1/G1. This has implications for the development of LXR activators that lack adverse effects on lipogenic genes while maintaining the ability to transrepress inflammatory genes.
authors: From the Division of Molecular Medicine, Department of Medicine, Columbia University, New York, NY (M.S.K., A.J.M., S.A., V.N., C.L.W., A.R.T., M.W.); Department of Surgery, Montefiore Medical Center, Albert Einstein College of Medicine, New York, NY (M.S.K.); and Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, The Netherlands (M.W.).
authors: Mojdeh S
authors: MS
authors: Kappus
authors: Andrew J
authors: AJ
authors: Murphy
authors: Sandra
authors: S
authors: Abramowicz
authors: Vusisizwe
authors: V
authors: Ntonga
authors: Carrie L
authors: CL
authors: Welch
authors: Alan R
authors: AR
authors: Tall
authors: Marit
authors: M
authors: Westerterp
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000172:deficiency* / Q000235:genetics; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D050197:Atherosclerosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D001565:Benzoates / Q000494:pharmacology*; D001596:Benzylamines / Q000494:pharmacology*; D001692:Biological Transport; D016026:Bone Marrow Transplantation; D002784:Cholesterol / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008074:Lipoproteins / Q000172:deficiency* / Q000235:genetics; D000071518:Liver X Receptors; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D057093:Orphan Nuclear Receptors / Q000819:agonists* / Q000378:metabolism; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics; D013449:Sulfonamides / Q000494:pharmacology*; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D000893:Anti-Inflammatory Agents; D001565:Benzoates; D001596:Benzylamines; D002784:Cholesterol; D016207:Cytokines; D006845:Hydrocarbons, Fluorinated; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D008074:Lipoproteins; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D011973:Receptors, LDL; D013449:Sulfonamides; C577833:Abca1 protein, mouse; C487540:ABCG1 protein, mouse; C473027:GW 3965; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
keywords: ATP-binding cassette transporters; atherosclerosis; inflammation; liver X receptor; macrophages