Activation of Liver X Receptor Decreases Atherosclerosis in <i>Ldlr</i> <sup> <i>−/−</i> </sup> Mice in the Absence of ATP-Binding Cassette Transporters A1 and G1 in Myeloid Cells

DOI Web Site 被引用文献3件
  • Mojdeh S. Kappus
    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.).
  • Andrew J. Murphy
    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.).
  • Sandra Abramowicz
    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.).
  • Vusisizwe Ntonga
    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.).
  • Carrie L. Welch
    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.).
  • Alan R. Tall
    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.).
  • Marit Westerterp
    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.).

説明

<jats:sec> <jats:title>Objective—</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Approach and Results—</jats:title> <jats:p> LXR activator T0901317 substantially reduced inflammatory gene expression in macrophages lacking ABCA1/G1. <jats:italic>Ldlr</jats:italic> <jats:sup> <jats:italic>−/−</jats:italic> </jats:sup> mice were transplanted with <jats:italic>Abca1</jats:italic> <jats:sup> <jats:italic>−/−</jats:italic> </jats:sup> <jats:italic>Abcg1</jats:italic> <jats:sup> <jats:italic>−/−</jats:italic> </jats:sup> or wild-type bone marrow (BM) and fed a Western-type diet for 6 weeks with or without T0901317 supplementation. <jats:italic>Abca1/g1</jats:italic> 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 <jats:italic>Abca1</jats:italic> <jats:sup> <jats:italic>−/−</jats:italic> </jats:sup> <jats:italic>Abcg1</jats:italic> <jats:sup> <jats:italic>−/−</jats:italic> </jats:sup> BM–transplanted mice. To investigate whether this was because of macrophage <jats:italic>Abca1/g1</jats:italic> deficiency, <jats:italic>Ldlr</jats:italic> <jats:sup> <jats:italic>−/−</jats:italic> </jats:sup> mice were transplanted with <jats:italic>LysmCreAbca1</jats:italic> <jats:sup> <jats:italic>fl/fl</jats:italic> </jats:sup> <jats:italic>Abcg1</jats:italic> <jats:sup> <jats:italic>fl/fl</jats:italic> </jats:sup> or <jats:italic>Abca1</jats:italic> <jats:sup> <jats:italic>fl/fl</jats:italic> </jats:sup> <jats:italic>Abcg1</jats:italic> <jats:sup> <jats:italic>fl/fl</jats:italic> </jats:sup> 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 <jats:italic>LysmCreAbca1</jats:italic> <jats:sup> <jats:italic>fl/fl</jats:italic> </jats:sup> <jats:italic>Abcg1</jats:italic> <jats:sup> <jats:italic>fl/fl</jats:italic> </jats:sup> group. </jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions—</jats:title> <jats:p>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.</jats:p> </jats:sec>

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