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The liver X receptor gene team: Potential new players in atherosclerosis

Nature Medicine volume 8, pages 12431248 (2002) | Download Citation

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Liver X receptors (LXRs) are sterol-responsive transcription factors that regulate expression of genes involved in cholesterol metabolism and homeostasis. Maintenance of normal cholesterol levels has implicated the involvement of LXR-induced genes in the pathophysiology of atherosclerosis. The modulation of LXRs or their downstream targets may provide alternative therapeutic strategies for the management of this disease.

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References

  1. 1.

    , & Effect of statins on risk of coronary disease. J. Am. Med. Assoc. 282, 2340–2346 (1999).

  2. 2.

    & The myotoxicity of statins. Curr. Opin. Lipidol. 13, 415–420 (2002).

  3. 3.

    & High-density lipoprotein: Gene-based approaches to the prevention of atherosclerosis. Ann. Med. 32, 642–651 (2000).

  4. 4.

    , & Pivotal role of ABCA1 in reverse cholesterol transport influencing HDL levels and susceptibility to atherosclerosis. J. Lipid Res. 42, 1717–1726 (2001).

  5. 5.

    & LuXuRies of lipid homeostasis: The unity of nuclear hormone receptors, transcription regulation, and cholesterol sensing. Mol. Interven. 2, 78–87 (2002).

  6. 6.

    et al. Key regulatory oxysterols in liver: Analysis as Δ4-3-ketone derivatives by HPLC and response to physiological pertubations. J. Lipid Res. 42, 649–658 (2001).

  7. 7.

    , , , & An oxysterol signalling pathway mediated by the nuclear receptor LXRα. Nature 383, 728–731 (1996).

  8. 8.

    et al. 27-Hydroxycholesterol is an endogenous ligand for liver X receptor in cholesterol-loaded cells. J. Biol. Chem. 276, 38378–38387 (2001).

  9. 9.

    et al. Identification of a nonsteroidal liver X receptor agonist through parallel array synthesis of tertiary amines. J. Med. Chem. 45, 1963–1966 (2002).

  10. 10.

    et al. Regulation of absorption and ABC1-mediated efflux of cholesterol by RXR heterodimers. Science 289, 1524–1529 (2000).

  11. 11.

    et al. Role of LXRs in control of lipogenesis. Genes Dev. 14, 2831–2838 (2000).

  12. 12.

    et al. A potent synthetic LXR agonist is more effective than cholesterol loading at inducing ABCA1 mRNA and stimulating cholesterol efflux. J. Biol. Chem. 277, 10021–10027 (2002).

  13. 13.

    et al. Cholesterol and bile acid metabolism are impaired in mice lacking the nuclear oxysterol receptor LXRα. Cell 93, 693–704 (1998).

  14. 14.

    & Mouse models of atherosclerosis. Curr. Opin. Lipidol. 12, 167–173 (2001).

  15. 15.

    et al. Reduction of atherosclerosis in apolipoprotein E knockout mice by activation of the retinoid X receptor. Proc. Natl. Acad. Sci. USA 98, 2610–2615 (2001).

  16. 16.

    et al. Synthetic LXR ligand inhibits the development of atherosclerosis in mice. Proc. Natl. Acad. Sci. USA 99, 7610–7616 (2002).

  17. 17.

    et al. Human White/murine ABC8 mRNA levels are highly induced in lipid-loaded macrophages. J. Biol. Chem. 275, 14700–14707 (2000).

  18. 18.

    et al. Identification of liver X receptors as inhibitors of atherosclerosis. Proc. Natl. Acad. Sci. USA 99, 11896–11901 (2002).

  19. 19.

    et al. A PPARγ-LXR-ABCA1 pathway in macrophages is involved in cholesterol efflux and atherogenesis. Mol. Cell 7, 161–171 (2001).

  20. 20.

    et al. PPAR-α and PPAR-γ activators induce cholesterol removal from human macrophage foam cells through stimulation of the ABCA1 pathway. Nature Med. 7, 53–58 (2001).

  21. 21.

    et al. Autoregulation of the human liver X receptor α promoter. Mol. Cell. Biol. 21, 7558–7568 (2001).

  22. 22.

    et al. Liver X receptor (LXR) regulation of the LXRα gene in human macrophages. J. Biol. Chem. 276, 43509–43515 (2001).

  23. 23.

    et al. The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease. Nature Genet. 22, 347–351 (1999).

  24. 24.

    et al. Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency. Nature Genet. 22, 336–345 (1999).

  25. 25.

    et al. Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1. Nature Genet. 22, 352–355 (1999).

  26. 26.

    , & in The Metabolic and Molecular Bases of Inherited Disease (eds. Scriver, C.R., Beaudet, A.L., Sly, W.S. & Valle, D.) 2937–2960 (McGraw-Hill, New York, 2001).

  27. 27.

    et al. Homozygous Tangier disease and cardiovascular disease. Atherosclerosis 107, 85–98 (1994).

  28. 28.

    et al. Association between increased arterial-wall thickness and impairment in ABCA1-driven cholesterol efflux: An observational study. Lancet 359, 37–41 (2002).

  29. 29.

    , , & ATP-binding cassette transporter A1 (ABCA1) functions as a cholesterol efflux regulatory protein. J. Biol. Chem. 276, 23742–23747 (2001).

  30. 30.

    , & Sterol-dependent transactivation of the ABC1 promoter by the liver X receptor/retinoid X receptor. J. Biol. Chem. 275, 28240–28245 (2000).

  31. 31.

    et al. Transport of lipids from Golgi to plasma membrane is defective in Tangier disease patients and Abc1-deficient mice. Nature Genet. 24, 192–196 (2000).

  32. 32.

    et al. Increased atherosclerosis in hyperlipidemic mice with inactivation of ABCA1 in macrophages. Arterioscler. Thromb. Vasc. Biol. 22, 630–637 (2002).

  33. 33.

    et al. Leukocyte ABCA1 controls susceptibility to atherosclerosis and macrophage recruitment into tissues. Proc. Natl. Acad. Sci. USA 99, 6298–6303 (2002).

  34. 34.

    et al. Increased ABCA1 activity protects against atherosclerosis. J. Clin. Invest. 110, 35–42 (2002).

  35. 35.

    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. USA 99, 407–412 (2002).

  36. 36.

    et al. ABCG1 (ABC8), the human homolog of the Drosophila white gene, is a regulator of macrophage cholesterol and phospholipid transport. Proc. Natl. Acad. Sci. USA 97, 817–822 (2000).

  37. 37.

    & Apolipoprotein E and atherosclerosis. Curr. Opin. Lipidol. 11, 243–251 (2000).

  38. 38.

    et al. LXRs control lipid-inducible expression of the apolipoprotein E gene in macrophages and adipocytes. Proc. Natl. Acad. Sci. USA 98, 507–512 (2001).

  39. 39.

    et al. Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells. Cell 71, 343–353 (1992).

  40. 40.

    , & Prevention of atherosclerosis in apolipoprotein E-deficient mice by bone marrow transplantation. Science 267, 1034–1037 (1995).

  41. 41.

    et al. Increased atherosclerosis in mice reconstituted with apolipoprotein E null macrophages. Proc. Natl. Acad. Sci. USA 94, 4647–4652 (1997).

  42. 42.

    et al. Regulated expression of the apoE/C-I/C-IV/C-II gene cluster in murine and human macrophages; a critical role for the nuclear receptors LXRα and LXRβ. J. Biol. Chem. 277, 31900–31908 (2002).

  43. 43.

    Lipoprotein lipase and lipolysis: Central roles in lipoprotein metabolism and atherogenesis. J. Lipid Res. 37, 693–707 (1996).

  44. 44.

    , , & Regulation of lipoprotein lipase by the oxysterol receptors, LXRα and LXRβ. J. Biol. Chem. 276, 43018–43024 (2001).

  45. 45.

    , , & Lipoprotein lipase in the arterial wall. Arterioscler. Thromb. Vasc. Biol. 22, 211–217 (2002).

  46. 46.

    et al. Overexpression of lipoprotein lipase in transgenic rabbits inhibits diet-induced hypercholesterolemia and atherosclerosis. J. Biol. Chem. 276, 40071–40079 (2001).

  47. 47.

    et al. Suppression of diet-induced atherosclerosis in low density lipoprotein receptor knockout mice overexpressing lipoprotein lipase. Proc. Natl. Acad. Sci. USA 93, 7242–7246 (1996).

  48. 48.

    et al. Overexpressed lipoprotein lipase protects against atherosclerosis in apolipoprotein E knockout mice. J. Lipid Res. 40, 1677–1685 (1999).

  49. 49.

    et al. Inactive lipoprotein lipase (LPL) alone increases selective cholesterol ester uptake in vivo, whereas in the presence of active LPL it also increases triglyceride hydrolysis and whole particle lipoprotein uptake. J. Biol. Chem. 277, 7405–7411 (2002).

  50. 50.

    et al. Lipoprotein lipase mediates an increase in the selective uptake of high density lipoprotein-associated cholesteryl esters by hepatic cells in culture. J. Lipid Res. 39, 1335–1348 (1998).

  51. 51.

    et al. Adenovirus-mediated gene transfer of human lipoprotein lipase ameliorates the hyperlipidemias associated with apolipoprotein E and LDL receptor deficiencies in mice. Hum. Gene Ther. 8, 1921–1933 (1997).

  52. 52.

    , , , & Macrophage lipoprotein lipase promotes foam cell formation and atherosclerosis in low density lipoprotein receptor-deficient mice. J. Biol. Chem. 275, 26293–26299 (2000).

  53. 53.

    , , , & Macrophage-specific expression of human lipoprotein lipase accelerates atherosclerosis in transgenic apolipoprotein E knockout mice but not in C57BL/6 mice. Arterioscler. Thromb. Vasc. Biol. 21, 1809–1815 (2001).

  54. 54.

    et al. Phospholipid transfer protein is regulated by liver X receptors in vivo. J. Biol. Chem.; published online August 9, 2002, doi:10.1074/jbc.M207187200.

  55. 55.

    & Sterol upregulation of human CETP expression in vitro and in transgenic mice by an LXR element. J. Clin. Invest. 105, 513–520 (2000).

  56. 56.

    Phospholipid transfer protein. Curr. Opin. Lipidol. 13, 135–139 (2002).

  57. 57.

    et al. Plasma phospholipid transfer protein. Adenovirus-mediated overexpression in mice leads to decreased plasma high density lipoprotein (HDL) and enhanced hepatic uptake of phospholipids and cholesteryl esters from HDL. J. Biol. Chem. 272, 27393–27400 (1997).

  58. 58.

    et al. Dynamic changes in mouse lipoproteins induced by transiently expressed human phospholipid transfer protein (PLTP): importance of PLTP in preβ-HDL generation. Comp. Biochem. Physiol. Part B 128, 781–792 (2001).

  59. 59.

    et al. Human plasma phospholipid transfer protein increases the antiatherogenic potential of high density lipoproteins in transgenic mice. Arterioscler. Thromb. Vasc. Biol. 20, 1082–1088 (2000).

  60. 60.

    et al. Targeted mutation of plasma phospholipid transfer protein gene markedly reduces high-density lipoprotein levels. J. Clin. Invest. 103, 907–914 (1999).

  61. 61.

    et al. Apolipoprotein B secretion and atherosclerosis are decreased in mice with phospholipid-transfer protein deficiency. Nature Med. 7, 847–852 (2001).

  62. 62.

    et al. Increased atherosclerosis in apoE and LDL receptor gene knockout-out mice as a result of human cholesteryl ester transfer protein transgene expression. Arterioscler. Thromb. Vasc. Biol. 19, 1105–1110 (1999).

  63. 63.

    & Control of cholesterol turnover in the mouse. J. Biol. Chem. 277, 3801–3804 (2002).

  64. 64.

    , , , & Dietary cholesterol fails to stimulate the human cholesterol 7α-hydroxylase gene (CYP7A1) in transgenic mice. J. Biol. Chem. 277, 20131–20134 (2002).

  65. 65.

    et al. Coexpression of ATP-binding cassette proteins ABCG5 and ABCG8 permits their transport to the apical surface. J. Clin. Invest. 110, 659–669 (2002).

  66. 66.

    , & Genetic basis of sitosterolemia. Curr. Opin. Lipidol. 12, 141–149 (2001).

  67. 67.

    et al. Regulation of ATP-binding cassette sterol transporters ABCG5 and ABCG8 by the liver X receptors α and β. J. Biol. Chem. 277, 18793–18800 (2002).

  68. 68.

    et al. Increased hepatobiliary and fecal cholesterol excretion upon activation of the liver X-receptor (LXR) is independent of ABCA1. J. Biol. Chem. 277, 33870–33877 (2002).

  69. 69.

    et al. Overexpression of ABCG5 and ABCG8 promotes biliary cholesterol secretion and reduces fractional absorption of dietary cholesterol. J. Clin. Invest. 110, 671–680 (2002).

  70. 70.

    et al. High density lipoprotein deficiency and foam cell accumulation in mice with targeted disruption of ATP-binding cassette transporter-1. Proc. Natl. Acad. Sci. USA 97, 4245–4250 (2000).

  71. 71.

    et al. Hepatobiliary cholesterol transport is not impaired in Abca1-null mice lacking HDL. J. Clin. Invest. 108, 843–850 (2001).

  72. 72.

    et al. ATP-binding cassette transporter A1 (ABCA1) affects total body sterol metabolism. Gastroenterology 120, 1203–1211 (2001).

  73. 73.

    , , & LXR/RXR activation enhances basolateral efflux of cholesterol in CaCo-2 cells. J. Lipid Res. 43, 1054–1064 (2002).

  74. 74.

    et al. ABCA1 mRNA and protein distribution patterns predict multiple different roles and levels of regulation. Lab. Invest. 82, 273–283 (2002).

  75. 75.

    et al. Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRα and LXRβ. Genes Dev. 14, 2819–2830 (2000).

  76. 76.

    The molecular pharmacology of SERMs. Trends Endocrinol. Metab. 10, 301–311 (1999).

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Acknowledgements

Many primary references could not be included because of space limitations. D.J.M. is an investigator of the Howard Hughes Medical Institute. This work was supported by the Howard Hughes Medical Institute and the Robert A. Welch Foundation.

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Affiliations

  1. Departments of Physiology and Internal Medicine, Touchstone Center for Diabetes Research, University of Texas Southwestern Medical Center, Dallas, Texas, USA

    • Joyce J. Repa
  2. Howard Hughes Medical Institute and the Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA

    • David J. Mangelsdorf

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Correspondence to David J. Mangelsdorf.

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https://doi.org/10.1038/nm1102-1243

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