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Liver X receptors as therapeutic targets in metabolism and atherosclerosis

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Abstract

The liver X receptors (LXRs) are ligand-activated transcription factors belonging to the nuclear hormone receptor superfamily. Since their initial identification more than a decade ago, LXRs have been characterized as key transcriptional regulators of lipid and carbohydrate homeostasis. LXRs are activated by the intracellular accumulation of cholesterol derivatives to stimulate cholesterol efflux and reverse cholesterol transport and excretion into the bile. Glucose functions as an LXR ligand in carbohydrate metabolism, and receptor agonism suppresses hepatic gluconeogenesis and improves insulin sensitivity. In addition to these beneficial metabolic effects, LXR ligands suppress inflammatory and proliferative responses of vascular cells and prevent the development of atherosclerosis and its complications. In this review, we summarize the important roles of LXRs in metabolism and vascular biology and discuss their implications as potential molecular drug targets for the treatment of cardiovascular diseases.

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References and Recommended Reading

  1. Zelcer N, Tontonoz P: Liver X receptors as integrators of metabolic and inflammatory signaling. J Clin Invest 2006, 116:607–614.

    Article  PubMed  CAS  Google Scholar 

  2. Lund EG, Menke JG, Sparrow CP: Liver X receptor agonists as potential therapeutic agents for dyslipidemia and atherosclerosis. Arterioscler Thromb Vasc Biol 2003, 23:1169–1177.

    Article  PubMed  CAS  Google Scholar 

  3. Mitro N, Mak PA, Vargas L, et al.: The nuclear receptor LXR is a glucose sensor. Nature 2007, 445:219–223.

    Article  PubMed  CAS  Google Scholar 

  4. Joseph SB, Castrillo A, Laffitte BA, et al.: Reciprocal regulation of inflammation and lipid metabolism by liver X receptors. Nat Med 2003, 9:213–219.

    Article  PubMed  CAS  Google Scholar 

  5. Blaschke F, Leppanen O, Takata Y, et al.: Liver X receptor agonists suppress vascular smooth muscle cell proliferation and inhibit neointima formation in balloon-injured rat carotid arteries. Circ Res 2004, 95:e110–e123.

    Article  PubMed  CAS  Google Scholar 

  6. Joseph SB, McKilligin E, Pei L, et al.: Synthetic LXR ligand inhibits the development of atherosclerosis in mice. Proc Natl Acad Sci U S A 2002, 99:7604–7609.

    Article  PubMed  CAS  Google Scholar 

  7. Willy PJ, Umesono K, Ong ES, et al.: LXR, a nuclear receptor that defines a distinct retinoid response pathway. Genes Dev 1995, 9:1033–1045.

    Article  PubMed  CAS  Google Scholar 

  8. Janowski BA, Willy PJ, Devi TR, et al.: An oxysterol signalling pathway mediated by the nuclear receptor LXR[alpha]. Nature 1996, 383:728–731.

    Article  PubMed  CAS  Google Scholar 

  9. Janowski BA, Grogan MJ, Jones SA, et al.: Structural requirements of ligands for the oxysterol liver X receptors LXRalpha and LXRbeta. Proc Natl Acad Sci U S A 1999, 96:266–271.

    Article  PubMed  CAS  Google Scholar 

  10. Alberti S, Steffensen KR, Gustafsson JA: Structural characterisation of the mouse nuclear oxysterol receptor genes LXRalpha and LXRbeta. Gene 2000, 243:93–103.

    Article  PubMed  CAS  Google Scholar 

  11. Schultz JR, Tu H, Luk A, et al.: Role of LXRs in control of lipogenesis. Genes Dev 2000, 14:2831–2838.

    Article  PubMed  CAS  Google Scholar 

  12. Collins JL, Fivush AM, Watson MA, et al.: Identification of a nonsteroidal liver X receptor agonist through parallel array synthesis of tertiary amines. J Med Chem 2002, 45:1963–1966.

    Article  PubMed  CAS  Google Scholar 

  13. Repa JJ, Turley SD, Lobaccaro JA, et al.: Regulation of absorption and ABC1-mediated efflux of cholesterol by RXR heterodimers. Science 2000, 289:1524–1529.

    Article  PubMed  CAS  Google Scholar 

  14. Dean M, Allikmets R: Evolution of ATP-binding cassette transporter genes. Curr Opin Genet Dev 1995, 5:779–785.

    Article  PubMed  CAS  Google Scholar 

  15. Repa JJ, Berge KE, Pomajzl C, et al.: Regulation of ATP-binding cassette sterol transporters ABCG5 and ABCG8 by the liver X receptors alpha and beta. J Biol Chem 2002, 277:18793–18800.

    Article  PubMed  CAS  Google Scholar 

  16. Yu L, Hammer RE, Li-Hawkins J, et al.: Disruption of Abcg5 and Abcg8 in mice reveals their crucial role in biliary cholesterol secretion. Proc Natl Acad Sci U S A 2002, 99:16237–16242.

    Article  PubMed  CAS  Google Scholar 

  17. Peet DJ, Turley SD, Ma W, et al.: Cholesterol and bile acid metabolism are impaired in mice lacking the nuclear oxysterol receptor LXR alpha. Cell 1998, 93:693–704.

    Article  PubMed  CAS  Google Scholar 

  18. von Eckardstein A, Nofer JR, Assmann G: High density lipoproteins and arteriosclerosis. Role of cholesterol efflux and reverse cholesterol transport. Arterioscler Thromb Vasc Biol 2001, 21:13–27.

    Google Scholar 

  19. Venkateswaran A, Repa JJ, Lobaccaro JM, et al.: Human white/murine ABC8 mRNA levels are highly induced in lipid-loaded macrophages. A transcriptional role for specific oxysterols. J Biol Chem 2000, 275:14700–14707.

    Article  PubMed  CAS  Google Scholar 

  20. Bodzioch M, Orso E, Klucken J, et al.: The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease. Nat Genet 1999, 22:347–351.

    Article  PubMed  CAS  Google Scholar 

  21. Brooks-Wilson A, Marcil M, Clee SM, et al.: Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency. Nat Genet 1999, 22:336–345.

    Article  PubMed  CAS  Google Scholar 

  22. Rust S, Rosier M, Funke H, et al.: Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1. Nat Genet 1999, 22:352–355.

    Article  PubMed  CAS  Google Scholar 

  23. Singaraja RR, Fievet C, Castro G, et al.: Increased ABCA1 activity protects against atherosclerosis. J Clin Invest 2002, 110:35–42.

    Article  PubMed  CAS  Google Scholar 

  24. Joyce CW, Amar MJ, Lambert G, et al.: the ATP binding cassette transporter A1 (ABCA1) modulates the development of aortic atherosclerosis in C57BL/6 and apoE-knockout mice. Proc Natl Acad Sci U S A 2002, 99:407–412.

    Article  PubMed  CAS  Google Scholar 

  25. Costet P, Luo Y, Wang N, Tall AR: Sterol-dependent transactivation of the ABC1 promoter by the liver X receptor/retinoid X receptor. J Biol Chem 2000, 275:28240–28245.

    PubMed  CAS  Google Scholar 

  26. Venkateswaran A, Laffitte BA, Joseph SB, et al.: Control of cellular cholesterol efflux by the nuclear oxysterol receptor LXR alpha. Proc Natl Acad Sci U S A 2000, 97:12097–12102.

    Article  PubMed  CAS  Google Scholar 

  27. Schwartz K, Lawn RM, Wade DP: ABC1 gene expression and ApoA-I-mediated cholesterol efflux are regulated by LXR. Biochem Biophys Res Commun 2000, 274:794–802.

    Article  PubMed  CAS  Google Scholar 

  28. Miao B, Zondlo S, Gibbs S, et al.: Raising HDL cholesterol without inducing hepatic steatosis and hypertriglyceridemia by a selective LXR modulator. J Lipid Res 2004, 45:1410–1417.

    Article  PubMed  CAS  Google Scholar 

  29. Naik SU, Wang X, Da Silva JS, et al.: Pharmacological activation of liver X receptors promotes reverse cholesterol transport in vivo. Circulation 2006, 113:90–97.

    Article  PubMed  CAS  Google Scholar 

  30. Lehmann JM, Kliewer SA, Moore LB, et al.: Activation of the nuclear receptor LXR by oxysterols defines a new hormone response pathway. J Biol Chem 1997, 272:3137–3140.

    Article  PubMed  CAS  Google Scholar 

  31. Chiang JY, Kimmel R, Stroup D: Regulation of cholesterol 7alpha-hydroxylase gene (CYP7A1) transcription by the liver orphan receptor (LXRalpha). Gene 2001, 262:257–265.

    Article  PubMed  CAS  Google Scholar 

  32. Yu L, Li-Hawkins J, Hammer RE, et al.: Overexpression of ABCG5 and ABCG8 promotes biliary cholesterol secretion and reduces fractional absorption of dietary cholesterol. J Clin Invest 2002, 110:671–680.

    Article  PubMed  CAS  Google Scholar 

  33. Berge KE, Tian H, Graf GA, et al.: Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters. Science 2000, 290:1771–1775.

    Article  PubMed  CAS  Google Scholar 

  34. Repa JJ, Liang G, Ou J, et al.: Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRalpha and LXRbeta. Genes Dev 2000, 14:2819–2830.

    Article  PubMed  CAS  Google Scholar 

  35. Yoshikawa T, Shimano H, Amemiya-Kudo M, et al.: Identification of liver X receptor-retinoid X receptor as an activator of the sterol regulatory element-binding protein 1c gene promoter. Mol Cell Biol 2001, 21:2991–3000.

    Article  PubMed  CAS  Google Scholar 

  36. Alberti S, Schuster G, Parini P, et al.: Hepatic cholesterol metabolism and resistance to dietary cholesterol in LXR-beta-deficient mice. J Clin Invest 2001, 107:565–573.

    Article  PubMed  CAS  Google Scholar 

  37. Tobin KA, Ulven SM, Schuster GU, et al.: Liver X receptors as insulin-mediating factors in fatty acid and cholesterol biosynthesis. J Biol Chem 2002, 277:10691–10697.

    Article  PubMed  CAS  Google Scholar 

  38. Stulnig TM, Steffensen KR, Gao H, et al.: Novel roles of liver X receptors exposed by gene expression profiling in liver and adipose tissue. Mol Pharmacol 2002, 62:1299–1305.

    Article  PubMed  CAS  Google Scholar 

  39. Cao G, Liang Y, Broderick CL, et al.: Antidiabetic action of a liver x receptor agonist mediated by inhibition of hepatic gluconeogenesis. J Biol Chem 2003, 278:1131–1136.

    Article  PubMed  CAS  Google Scholar 

  40. Laffitte BA, Chao LC, Li J, et al.: Activation of liver X receptor improves glucose tolerance through coordinate regulation of glucose metabolism in liver and adipose tissue. Proc Natl Acad Sci U S A 2003, 100:5419–5424.

    Article  PubMed  CAS  Google Scholar 

  41. Fernandez-Veledo S, Nieto-Vazquez I, Rondinone CM, Lorenzo M: Liver X receptor agonists ameliorate TNFalpha-induced insulin resistance in murine brown adipocytes by downregulating protein tyrosine phosphatase-1B gene expression. Diabetologia 2006, 49:3038–3048.

    Article  PubMed  CAS  Google Scholar 

  42. Grefhorst A, van Dijk TH, Hammer A, et al.: Differential effects of pharmacological liver X receptor activation on hepatic and peripheral insulin sensitivity in lean and ob/ob mice. Am J Physiol Endocrinol Metab 2005, 289:E829–E838.

    Article  PubMed  CAS  Google Scholar 

  43. Efanov AM, Sewing S, Bokvist K, Gromada J: Liver X receptor activation stimulates insulin secretion via modulation of glucose and lipid metabolism in pancreatic beta-cells. Diabetes 2004, 53(Suppl 3):S75–S78.

    Article  PubMed  CAS  Google Scholar 

  44. Gerin I, Dolinsky VW, Shackman JG, et al.: LXRbeta is required for adipocyte growth, glucose homeostasis, and beta cell function. J Biol Chem 2005, 280:2 3024–2 3031.

    Article  CAS  Google Scholar 

  45. Glass CK, Witztum JL: Atherosclerosis. The road ahead. Cell 2001, 104:503–516.

    Article  PubMed  CAS  Google Scholar 

  46. Castrillo A, Joseph SB, Marathe C, et al.: Liver X receptor-dependent repression of matrix metalloproteinase-9 expression in macrophages. J Biol Chem 2003, 278:10443–10449.

    Article  PubMed  CAS  Google Scholar 

  47. Terasaka N, Hiroshima A, Koieyama T, 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.

    Article  PubMed  CAS  Google Scholar 

  48. Ogawa D, Stone JF, Takata Y, et al.: Liver X receptor agonists inhibit cytokine-induced osteopontin expression in macrophages through interference with activator protein-1 signaling pathways. Circ Res 2005, 96:e59–e67.

    Article  PubMed  CAS  Google Scholar 

  49. Fontaine C, Rigamonti E, Nohara A, et al.: Liver X receptor activation potentiates the lipopolysaccharide response in human macrophages. Circ Res 2007, 101:40–49.

    Article  PubMed  CAS  Google Scholar 

  50. Joseph SB, Bradley MN, Castrillo A, et al.: LXR-dependent gene expression is important for macrophage survival and the innate immune response. Cell 2004, 119:299–309.

    Article  PubMed  CAS  Google Scholar 

  51. Valledor AF, Hsu LC, Ogawa S, et al.: Activation of liver X receptors and retinoid X receptors prevents bacterialinduced macrophage apoptosis. Proc Natl Acad Sci U S A 2004, 101:17813–17818.

    Article  PubMed  CAS  Google Scholar 

  52. Antonio V, Janvier B, Brouillet A, et al.: Oxysterol and 9-cis-retinoic acid stimulate the group IIA secretory phospholipase A2 gene in rat smooth-muscle cells. Biochem J 2003, 376(Pt 2):351–360.

    Article  PubMed  CAS  Google Scholar 

  53. Pagano M: Control of DNA synthesis and mitosis by the Skp2-p27-Cdk1/2 axis. Molecular Cell 2004, 14:414–416.

    Article  PubMed  CAS  Google Scholar 

  54. Davies JD, Carpenter KL, Challis IR, et al.: Adipocytic differentiation and liver x receptor pathways regulate the accumulation of triacylglycerols in human vascular smooth muscle cells. J Biol Chem 2005, 280:3911–3919.

    Article  PubMed  CAS  Google Scholar 

  55. Delvecchio CJ, Bilan P, Radford K, et al.: Liver X receptor stimulates cholesterol efflux and inhibits expression of proinflammatory mediators in human airway smooth muscle cells. Mol Endocrinol 2007, 21:1324–1334.

    Article  PubMed  CAS  Google Scholar 

  56. Tangirala RK, Bischoff ED, Joseph SB, et al.: Identification of macrophage liver X receptors as inhibitors of atherosclerosis. Proc Natl Acad Sci U S A 2002, 99:11896–11901.

    Article  PubMed  CAS  Google Scholar 

  57. Levin N, Bischoff ED, Daige CL, et al.: Macrophage liver X receptor is required for antiatherogenic activity of LXR agonists. Arterioscler Thromb Vasc Biol 2005, 25:135–142.

    Article  PubMed  CAS  Google Scholar 

  58. Lund EG, Peterson LB, Adams AD, et al.: Different roles of liver X receptor alpha and beta in lipid metabolism: effects of an alpha-selective and a dual agonist in mice deficient in each subtype. Biochem Pharmacol 2006, 71:453–463.

    Article  PubMed  CAS  Google Scholar 

  59. Quinet EM, Savio DA, Halpern AR, et al.: Liver X receptor (LXR)-beta regulation in LXRalpha-deficient mice: implications for therapeutic targeting. Mol Pharmacol 2006, 70:1340–1349.

    Article  PubMed  CAS  Google Scholar 

  60. Bradley MN, Hong C, Chen M, et al.: Ligand activation of LXR beta reverses atherosclerosis and cellular cholesterol overload in mice lacking LXR alpha and apoE. J Clin Invest 2007, 117:2337–2346.

    Article  PubMed  CAS  Google Scholar 

  61. Chawla A, Repa JJ, Evans RM, Mangelsdorf DJ: Nuclear receptors and lipid physiology: opening the X-files. Science 2001, 294:1866–1870.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Division of Endocrinology and Molecular Medicine, Department of Internal Medicine, University of Kentucky College of Medicine, Wethington Health Sciences Building, Room 575, 900 South Limestone Street, Lexington, KY, 40536, USA

    Dennis Bruemmer

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  1. Takashi Nomiyama
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  2. Dennis Bruemmer
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Correspondence to Dennis Bruemmer.

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Nomiyama, T., Bruemmer, D. Liver X receptors as therapeutic targets in metabolism and atherosclerosis. Curr Atheroscler Rep 10, 88–95 (2008). https://doi.org/10.1007/s11883-008-0013-3

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