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Activation of liver X receptor decreases atherosclerosis in Ldlr⁻/⁻ mice in the absence of ATP-binding cassette transporters A1 and G1 in myeloid cells

Kappus, M. S., Murphy, A. J., Abramowicz, S., Ntonga, V., Welch, C. L., Tall, A. R. & Westerterp, M., Feb-2014, In : Arteriosclerosis, thrombosis, and vascular biology. 34, 2, p. 279-284 6 p.

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

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DOI

  • Mojdeh S Kappus
  • Andrew J Murphy
  • Sandra Abramowicz
  • Vusisizwe Ntonga
  • Carrie L Welch
  • Alan R Tall
  • Marit Westerterp

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.

APPROACH AND 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.

Original languageEnglish
Pages (from-to)279-284
Number of pages6
JournalArteriosclerosis, thrombosis, and vascular biology
Volume34
Issue number2
Publication statusPublished - Feb-2014

    Keywords

  • ATP Binding Cassette Transporter 1/deficiency, ATP Binding Cassette Transporter, Subfamily G, Member 1, ATP-Binding Cassette Transporters/deficiency, Animals, Anti-Inflammatory Agents/pharmacology, Aorta/drug effects, Atherosclerosis/genetics, Benzoates/pharmacology, Benzylamines/pharmacology, Biological Transport, Bone Marrow Transplantation, Cholesterol/metabolism, Cytokines/genetics, Disease Models, Animal, Female, Gene Expression Regulation, Hydrocarbons, Fluorinated/pharmacology, Inflammation Mediators/metabolism, Lipopolysaccharides/pharmacology, Lipoproteins/deficiency, Liver X Receptors, Macrophages/drug effects, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Myocardium/metabolism, Orphan Nuclear Receptors/agonists, Receptors, LDL/deficiency, Sulfonamides/pharmacology

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