Inflammation Research

, Volume 61, Issue 12, pp 1299–1307 | Cite as

Liver X receptor activation attenuates plaque formation and improves vasomotor function of the aortic artery in atherosclerotic ApoE−/− mice

  • Jianghong Chen
  • Li Zhao
  • Dongdong SunEmail author
  • Kazim Narsinh
  • Chunhong Li
  • Zheng Zhang
  • Shun Qi
  • Guangquan Wei
  • Weijie Li
  • Wenyi GuoEmail author
  • Feng CaoEmail author
Original Research Paper



The severity of atherosclerosis is primarily determined by overall lipid metabolism and the degree of inflammation present within the vessel wall. We evaluated the effects of T-0901317, a liver X receptor agonist, on the atherosclerosis process, and especially on the endothelial function in ApoE−/− mice.

Methods and results

ApoE−/− mice were treated with LXR agonist T-0901317 (1 μmol/L) for 6 weeks. ApoE−/− mice receiving T-0901317 were found to have markedly improved overall serum lipid profiles, albeit increased serum triglycerides. MRI imaging demonstrated that T-0901317 attenuated the atherosclerotic plaque burden in the aorta of ApoE−/− mice. Transmission electron microscopy and immunohistochemistry revealed attenuated ultrastructural changes as well as enhanced expression of the ATP-binding cassette transporter ABCA1. In addition, treatment with the LXR agonist improved the vasomotor function of atherosclerotic arteries, as assessed by KCl/norepinephrine-induced vasoconstrictive and acetylcholine-induced vasorelaxation functional assays. In vitro studies showed increased ABCG1, phospho-Akt and phospho-eNOS expression in ApoE−/− mice aorta endothelial cells (ECs) after T0901317 treatment.


The present study suggest that LXR agonists protect the endothelium against atherosclerotic insults by increasing ABCA1 and ABCG1 expression, and improve the endothelial-dependent vasomotor function probably by promoting Akt and eNOS phosphorylation.


Liver X receptors (LXRs) ATP-binding cassette transporter A1 (ABCA1) Apolipoprotein E gene knockout (ApoE−/−) mice Atherosclerosis Vasomotoricity Endothelium 



This work was supported by National Nature Science Foundation of China (No. 81090274, No. 81090270, No. 81100579), Innovation Team Start-up Grant by China Department of Education (2010CXTD01) and China's Ministry of Science and Technology 863 Program (2012AA02A603).

Conflict of interest

None declared.


  1. 1.
    Brooks-Wilson A, Marcil M, Clee SM, Zhang LH, Roomp K, van Dam M, et al. Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency. Nat Genet. 1999;22:336–45.PubMedCrossRefGoogle Scholar
  2. 2.
    Zhang LN, Zhang LF, Ma J. Simulated microgravity enhances vasoconstrictor responsiveness of rat basilar artery. J Appl Physiol. 2001;90:2296–305.PubMedCrossRefGoogle Scholar
  3. 3.
    Sangha DS, Vaziri ND, Ding Y, Purdy RE. Vascular hyporesponsiveness in simulated microgravity: role of nitric oxide-dependent mechanisms. J Appl Physiol. 2000;88:507–17.PubMedGoogle Scholar
  4. 4.
    Terasaka N, Hiroshima A, Koieyama T, Ubukata N, Morikawa Y, Nakai D, et al. T-0901317, a synthetic liver X receptor ligand, inhibits development of atherosclerosis in LDL receptor-deficient mice. FEBS Lett. 2003;536:6–11.PubMedCrossRefGoogle Scholar
  5. 5.
    Willy PJ, Umesono K, Ong ES, Evans RM, Heyman RA, Mangelsdorf DJ. LXR, a nuclear receptor that defines a distinct retinoid response pathway. Genes Dev. 1995;9:1033–45.PubMedCrossRefGoogle Scholar
  6. 6.
    Schultz JR, Tu H, Luk A, Repa JJ, Medina JC, Li L, et al. Role of LXRs in control of lipogenesis. Genes Dev. 2000;14:2831–8.PubMedCrossRefGoogle Scholar
  7. 7.
    Fukuchi J, Kokontis JM, Hiipakka RA, Chuu CP, Liao S. Antiproliferative effect of liver X receptor agonists on LNCaP human prostate cancer cells. Cancer Res. 2004;64:7686–9.PubMedCrossRefGoogle Scholar
  8. 8.
    Koldamova RP, Lefterov IM, Staufenbiel M, Wolfe D, Huang S, Glorioso JC, et al. The liver X receptor ligand T0901317 decreases amyloid beta production in vitro and in a mouse model of Alzheimer’s disease. J Biol Chem. 2005;280:4079–88.PubMedCrossRefGoogle Scholar
  9. 9.
    Basciano H, Miller A, Baker C, Naples M, Adeli K. LXRalpha activation perturbs hepatic insulin signaling and stimulates production of apolipoprotein B-containing lipoproteins. Am J Physiol Gastrointest Liver Physiol. 2009;297:G323–32.PubMedCrossRefGoogle Scholar
  10. 10.
    Joseph SB, Castrillo A, Laffitte BA, Mangelsdorf DJ, Tontonoz P. Reciprocal regulation of inflammation and lipid metabolism by liver X receptors. Nat Med. 2003;9:213–9.PubMedCrossRefGoogle Scholar
  11. 11.
    Chen J, Cui X, Zacharek A, Roberts C, Chopp M. eNOS mediates TO90317 treatment-induced angiogenesis and functional outcome after stroke in mice. Stroke: A Journal of Cerebral Circulation. 2009;40:2532–8.CrossRefGoogle Scholar
  12. 12.
    Jeong Y, Mangelsdorf DJ. Nuclear receptor regulation of stemness and stem cell differentiation. Exp Mol Med. 2009;41:525–37.PubMedCrossRefGoogle Scholar
  13. 13.
    Song C, Hiipakka RA, Liao S. Auto-oxidized cholesterol sulfates are antagonistic ligands of liver X receptors: implications for the development and treatment of atherosclerosis. Steroids. 2001;66:473–9.PubMedCrossRefGoogle Scholar
  14. 14.
    Bennett DJ, Cooke AJ, Edwards AS. Non-steroidal LXR agonists; an emerging therapeutic strategy for the treatment of atherosclerosis. Recent Pat Cardiovasc Drug Discov. 2006;1:21–46.PubMedCrossRefGoogle Scholar
  15. 15.
    Joseph SB, McKilligin E, Pei L, Watson MA, Collins AR, Laffitte BA, et al. Synthetic LXR ligand inhibits the development of atherosclerosis in mice. Proc Natl Acad Sci USA. 2002;99:7604–9.PubMedCrossRefGoogle Scholar
  16. 16.
    Verschuren L, de Vries-van der Weij J, Zadelaar S, Kleemann R, Kooistra T. LXR agonist suppresses atherosclerotic lesion growth and promotes lesion regression in apoE*3Leiden mice: time course and mechanisms. J Lipid Res. 2009;50:301–11.PubMedCrossRefGoogle Scholar
  17. 17.
    de la Llera-Moya M, Drazul-Schrader D, Asztalos BF, Cuchel M, Rader DJ, Rothblat GH. The ability to promote efflux via ABCA1 determines the capacity of serum specimens with similar high-density lipoprotein cholesterol to remove cholesterol from macrophages. Arterioscler Thromb Vasc Biol. 2010;30:796–801.CrossRefGoogle Scholar
  18. 18.
    Kratzer A, Buchebner M, Pfeifer T, Becker TM, Uray G, Miyazaki M, et al. Synthetic LXR agonist attenuates plaque formation in apoE-/- mice without inducing liver steatosis and hypertriglyceridemia. J Lipid Res. 2009;50:312–26.PubMedCrossRefGoogle Scholar
  19. 19.
    Johnstone MT, Creager SJ, Scales KM, Cusco JA, Lee BK, Creager MA. Impaired endothelium-dependent vasodilation in patients with insulin-dependent diabetes mellitus. Circulation. 1993;88:2510–6.PubMedCrossRefGoogle Scholar
  20. 20.
    Hamabe A, Takase B, Uehata A, Kurita A, Ohsuzu F, Tamai S. Impaired endothelium-dependent vasodilation in the brachial artery in variant angina pectoris and the effect of intravenous administration of vitamin C. Am J Cardiol. 2001;87:1154–9.PubMedCrossRefGoogle Scholar
  21. 21.
    Schmitz G, Kaminski WE, Porsch-Ozcurumez M, Klucken J, Orso E, Bodzioch M, et al. ATP-binding cassette transporter A1 (ABCA1) in macrophages: a dual function in inflammation and lipid metabolism? Pathobiology. 1999;67:236–40.PubMedCrossRefGoogle Scholar
  22. 22.
    Hassan HH, Denis M, Krimbou L, Marcil M, Genest J. Cellular cholesterol homeostasis in vascular endothelial cells. Can J Cardiol. 2006;22(Suppl B):35B–40B.PubMedCrossRefGoogle Scholar
  23. 23.
    Jaccard E, Widmann C. ABC transporters: hDL-regulated gatekeepers at the endothelial border. Curr Opin Lipidol. 2009;20:526–7.PubMedCrossRefGoogle Scholar
  24. 24.
    Curtiss LK, Valenta DT, Hime NJ, Rye KA. What is so special about apolipoprotein AI in reverse cholesterol transport? Arterioscler Thromb Vasc Biol. 2006;26:12–9.PubMedCrossRefGoogle Scholar
  25. 25.
    Rohrer L, Ohnsorg PM, Lehner M, Landolt F, Rinninger F, von Eckardstein A. High-density lipoprotein transport through aortic endothelial cells involves scavenger receptor BI and ATP-binding cassette transporter G1. Circ Res. 2009;104:1142–50.PubMedCrossRefGoogle Scholar
  26. 26.
    Cavelier C, Rohrer L, von Eckardstein A. ATP-Binding cassette transporter A1 modulates apolipoprotein A-I transcytosis through aortic endothelial cells. Circ Res. 2006;99:1060–6.PubMedCrossRefGoogle Scholar
  27. 27.
    Terasaka N, Yu S, Yvan-Charvet L, Wang N, Mzhavia N, Langlois R, et al. ABCG1 and HDL protect against endothelial dysfunction in mice fed a high-cholesterol diet. J Clin Invest. 2008;118:3701–13.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Basel AG 2012

Authors and Affiliations

  1. 1.Department of Cardiology, Xijing HospitalFourth Military Medical UniversityXi’anChina
  2. 2.Department of Radiology, Xijing HospitalFourth Military Medical UniversityXi’anChina
  3. 3.Department of Radiology, Stanford Medical CenterStanford UniversityStanfordUSA

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