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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.
Arterioscler Thromb Vasc Biol. 2014 Feb; 34(2):279-84.AT

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.

Authors+Show Affiliations

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.).No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

24311381

Citation

Kappus, Mojdeh S., et al. "Activation of Liver X Receptor Decreases Atherosclerosis in Ldlr⁻/⁻ Mice in the Absence of ATP-binding Cassette Transporters A1 and G1 in Myeloid Cells." Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 34, no. 2, 2014, pp. 279-84.
Kappus MS, Murphy AJ, Abramowicz S, et al. Activation of liver X receptor decreases atherosclerosis in Ldlr⁻/⁻ mice in the absence of ATP-binding cassette transporters A1 and G1 in myeloid cells. Arterioscler Thromb Vasc Biol. 2014;34(2):279-84.
Kappus, M. S., Murphy, A. J., Abramowicz, S., Ntonga, V., Welch, C. L., Tall, A. R., & Westerterp, M. (2014). Activation of liver X receptor decreases atherosclerosis in Ldlr⁻/⁻ mice in the absence of ATP-binding cassette transporters A1 and G1 in myeloid cells. Arteriosclerosis, Thrombosis, and Vascular Biology, 34(2), 279-84. https://doi.org/10.1161/ATVBAHA.113.302781
Kappus MS, et al. Activation of Liver X Receptor Decreases Atherosclerosis in Ldlr⁻/⁻ Mice in the Absence of ATP-binding Cassette Transporters A1 and G1 in Myeloid Cells. Arterioscler Thromb Vasc Biol. 2014;34(2):279-84. PubMed PMID: 24311381.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Activation of liver X receptor decreases atherosclerosis in Ldlr⁻/⁻ mice in the absence of ATP-binding cassette transporters A1 and G1 in myeloid cells. AU - Kappus,Mojdeh S, AU - Murphy,Andrew J, AU - Abramowicz,Sandra, AU - Ntonga,Vusisizwe, AU - Welch,Carrie L, AU - Tall,Alan R, AU - Westerterp,Marit, Y1 - 2013/12/05/ PY - 2013/12/7/entrez PY - 2013/12/7/pubmed PY - 2014/3/22/medline KW - ATP-binding cassette transporters KW - atherosclerosis KW - inflammation KW - liver X receptor KW - macrophages SP - 279 EP - 84 JF - Arteriosclerosis, thrombosis, and vascular biology JO - Arterioscler Thromb Vasc Biol VL - 34 IS - 2 N2 - 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. SN - 1524-4636 UR - https://www.unboundmedicine.com/medline/citation/24311381/Activation_of_liver_X_receptor_decreases_atherosclerosis_in_Ldlr⁻/⁻_mice_in_the_absence_of_ATP_binding_cassette_transporters_A1_and_G1_in_myeloid_cells_ L2 - https://www.ahajournals.org/doi/10.1161/ATVBAHA.113.302781?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -