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

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

Research output: Contribution to journalArticleAcademicpeer-review

69 Citations (Scopus)

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.

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
DOIs
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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