Molecular biology and functional genomics of liver X receptors (LXR) in relationship to metabolic diseases

Current Opinion in Pharmacology

Volumn 10, Issue 6, 2010, Pages 692-697

  Faulds, Malin Hedengran ^a   Zhao, Chunyan ^a   Dahlman Wright, Karin ^a  

^a KAROLINSKA INSTITUTE   (Sweden)

Author keywords

[No Author keywords available]

Indexed keywords

ABC TRANSPORTER; ACYL COENZYME A DESATURASE; ANGIOPOIETIN; ANGIOPOIETIN LIKE PROTEIN 3; CHOLESTEROL ESTER TRANSFER PROTEIN; GLUCOSE TRANSPORTER 3; LIPOPROTEIN LIPASE; LIVER X RECEPTOR; LIVER X RECEPTOR ALPHA; LIVER X RECEPTOR BETA; N (2,2,2 TRIFLUOROETHYL) N [4 [2,2,2 TRIFLUORO 1 HYDROXY 1 (TRIFLUOROMETHOXY)ETHYL]PHENYL]BENZENESULFONAMIDE; STEROID 21 MONOOXYGENASE; UNCLASSIFIED DRUG; VERY LOW DENSITY LIPOPROTEIN CHOLESTEROL;

ANTIINFLAMMATORY ACTIVITY; ATHEROGENESIS; BILE ACID SYNTHESIS; BINDING AFFINITY; CARBOHYDRATE METABOLISM; CHOLESTEROL TRANSPORT; DIMERIZATION; FATTY ACID SYNTHESIS; FUNCTIONAL GENOMICS; GENE EXPRESSION PROFILING; GENE EXPRESSION REGULATION; GENE OVEREXPRESSION; GLUCOSE HOMEOSTASIS; HUMAN; INSULIN RELEASE; LIPOGENESIS; METABOLIC DISORDER; MOLECULAR BIOLOGY; NONHUMAN; PRIORITY JOURNAL; PROMOTER REGION; PROTEIN BINDING; PROTEIN FUNCTION; PROTEIN PHOSPHORYLATION; PROTEIN PROTEIN INTERACTION; REVIEW; SIGNAL TRANSDUCTION; UBIQUITINATION; UPREGULATION;

ANIMALS; CARDIOVASCULAR DISEASES; CHOLESTEROL; DNA-BINDING PROTEINS; GLUCOSE METABOLISM DISORDERS; HUMANS; INFLAMMATION; LIPOGENESIS; METABOLIC DISEASES; METABOLIC SYNDROME X; MICE; MICE, MUTANT STRAINS; MOLECULAR TARGETED THERAPY; ORPHAN NUCLEAR RECEPTORS; PROTEIN ISOFORMS;

EID: 78149496368     PISSN: 14714892     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.coph.2010.07.003     Document Type: Review

References (41)

1. Lin J., Yang R., Tarr P.T., Wu P.H., Handschin C., Li S., Yang W., Pei L., Uldry M., Tontonoz P., et al. Hyperlipidemic effects of dietary saturated fats mediated through PGC-1beta coactivation of SREBP. Cell 2005, 120:261-273.
2. Jakobsson T., Venteclef N., Toresson G., Damdimopoulos A.E., Ehrlund A., Lou X., Sanyal S., Steffensen K.R., Gustafsson J.A., Treuter E. GPS2 is required for cholesterol efflux by triggering histone demethylation, LXR recruitment, and coregulator assembly at the ABCG1 locus. Mol Cell 2009, 34:510-518.
3. Kim G.H., Park K., Yeom S.Y., Lee K.J., Kim G., Ko J., Rhee D.K., Kim Y.H., Lee H.K., Kim H.W., et al. Characterization of ASC-2 as an antiatherogenic transcriptional coactivator of liver X receptors in macrophages. Mol Endocrinol 2009, 23:966-974.
4. Chen M., Bradley M.N., Beaven S.W., Tontonoz P. Phosphorylation of the liver X receptors. FEBS Lett 2006, 580:4835-4841.
5. Delvecchio C.J., Capone J.P. Protein kinase C alpha modulates liver X receptor alpha transactivation. J Endocrinol 2008, 197:121-130.
6. Ghisletti S., Huang W., Ogawa S., Pascual G., Lin M.E., Willson T.M., Rosenfeld M.G., Glass C.K. Parallel SUMOylation-dependent pathways mediate gene- and signal-specific transrepression by LXRs and PPARgamma. Mol Cell 2007, 25:57-70.
7. Liang G., Yang J., Horton J.D., Hammer R.E., Goldstein J.L., Brown M.S. Diminished hepatic response to fasting/refeeding and liver X receptor agonists in mice with selective deficiency of sterol regulatory element-binding protein-1c. J Biol Chem 2002, 277:9520-9528.
8. Chu K., Miyazaki M., Man W.C., Ntambi J.M. Stearoyl-coenzyme A desaturase 1 deficiency protects against hypertriglyceridemia and increases plasma high-density lipoprotein cholesterol induced by liver X receptor activation. Mol Cell Biol 2006, 26:6786-6798.
9. Joseph S.B., Laffitte B.A., Patel P.H., Watson M.A., Matsukuma K.E., Walczak R., Collins J.L., Osborne T.F., Tontonoz P. Direct and indirect mechanisms for regulation of fatty acid synthase gene expression by liver X receptors. J Biol Chem 2002, 277:11019-11025.
10. Talukdar S., Hillgartner F.B. The mechanism mediating the activation of acetyl-coenzyme A carboxylase-alpha gene transcription by the liver X receptor agonist T0-901317. J Lipid Res 2006, 47:2451-2461.
11. Repa J.J., Liang G., Ou J., Bashmakov Y., Lobaccaro J.M., Shimomura I., Shan B., Brown M.S., Goldstein J.L., Mangelsdorf D.J. Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRalpha and LXRbeta. Genes Dev 2000, 14:2819-2830.
12. Zhou J., Febbraio M., Wada T., Zhai Y., Kuruba R., He J., Lee J.H., Khadem S., Ren S., Li S., et al. Hepatic fatty acid transporter Cd36 is a common target of LXR, PXR, and PPARgamma in promoting steatosis. Gastroenterology 2008, 134:556-567.
13. Lund E.G., Peterson L.B., Adams A.D., Lam M.H., Burton C.A., Chin J., Guo Q., Huang S., Latham M., Lopez J.C., 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.
14. Cha J.Y., Repa J.J. The liver X receptor (LXR) and hepatic lipogenesis. The carbohydrate-response element-binding protein is a target gene of LXR. J Biol Chem 2007, 282:743-751.
15. Iizuka K., Bruick R.K., Liang G., Horton J.D., Uyeda K. Deficiency of carbohydrate response element-binding protein (ChREBP) reduces lipogenesis as well as glycolysis. Proc Natl Acad Sci USA 2004, 101:7281-7286.
16. Denechaud P.D., Bossard P., Lobaccaro J.M., Millatt L., Staels B., Girard J., Postic C. ChREBP, but not LXRs, is required for the induction of glucose-regulated genes in mouse liver. J Clin Invest 2008, 118:956-964.
17. Grefhorst A., Elzinga B.M., Voshol P.J., Plosch T., Kok T., Bloks V.W., van der Sluijs F.H., Havekes L.M., Romijn J.A., Verkade H.J., et al. Stimulation of lipogenesis by pharmacological activation of the liver X receptor leads to production of large, triglyceride-rich very low density lipoprotein particles. J Biol Chem 2002, 277:34182-34190.
18. Cao G., Beyer T.P., Yang X.P., Schmidt R.J., Zhang Y., Bensch W.R., Kauffman R.F., Gao H., Ryan T.P., Liang Y., et al. Phospholipid transfer protein is regulated by liver X receptors in vivo. J Biol Chem 2002, 277:39561-39565.
19. Shimizugawa T., Ono M., Shimamura M., Yoshida K., Ando Y., Koishi R., Ueda K., Inaba T., Minekura H., Kohama T., et al. ANGPTL3 decreases very low density lipoprotein triglyceride clearance by inhibition of lipoprotein lipase. J Biol Chem 2002, 277:33742-33748.
20. Stulnig T.M., Steffensen K.R., Gao H., Reimers M., Dahlman-Wright K., Schuster G.U., Gustafsson J.A. Novel roles of liver X receptors exposed by gene expression profiling in liver and adipose tissue. Mol Pharmacol 2002, 62:1299-1305.
21. Cao G., Liang Y., Broderick C.L., Oldham B.A., Beyer T.P., Schmidt R.J., Zhang Y., Stayrook K.R., Suen C., Otto K.A., et al. Antidiabetic action of a liver x receptor agonist mediated by inhibition of hepatic gluconeogenesis. J Biol Chem 2003, 278:1131-1136.
22. Grefhorst A., van Dijk T.H., Hammer A., van der Sluijs F.H., Havinga R., Havekes L.M., Romijn J.A., Groot P.H., Reijngoud D.J., Kuipers F. 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.
23. Dalen K.T., Ulven S.M., Bamberg K., Gustafsson J.A., Nebb H.I. Expression of the insulin-responsive glucose transporter GLUT4 in adipocytes is dependent on liver X receptor alpha. J Biol Chem 2003, 278:48283-48291.
24. Zitzer H., Wente W., Brenner M.B., Sewing S., Buschard K., Gromada J., Efanov A.M. Sterol regulatory element-binding protein 1 mediates liver X receptor-beta-induced increases in insulin secretion and insulin messenger ribonucleic acid levels. Endocrinology 2006, 147:3898-3905.
25. Ogihara T., Chuang J.C., Vestermark G.L., Garmey J.C., Ketchum R.J., Huang X., Brayman K.L., Thorner M.O., Repa J.J., Mirmira R.G., et al. Liver X receptor agonists augment human islet function through activation of anaplerotic pathways and glycerolipid/free fatty acid cycling. J Biol Chem 2010, 285:5392-5404.
26. Choe S.S., Choi A.H., Lee J.W., Kim K.H., Chung J.J., Park J., Lee K.M., Park K.G., Lee I.K., Kim J.B. Chronic activation of liver X receptor induces beta-cell apoptosis through hyperactivation of lipogenesis: liver X receptor-mediated lipotoxicity in pancreatic beta-cells. Diabetes 2007, 56:1534-1543.
27. Zhao C., Dahlman-Wright K. Liver X receptor in cholesterol metabolism. J Endocrinol 2010, 204:233-240.
28. Russell D.W., Setchell K.D. Bile acid biosynthesis. Biochemistry 1992, 31:4737-4749.
29. Peet D.J., Turley S.D., Ma W., Janowski B.A., Lobaccaro J.M., Hammer R.E., Mangelsdorf D.J. Cholesterol and bile acid metabolism are impaired in mice lacking the nuclear oxysterol receptor LXR alpha. Cell 1998, 93:693-704.
30. Alberti S., Schuster G., Parini P., Feltkamp D., Diczfalusy U., Rudling M., Angelin B., Bjorkhem I., Pettersson S., Gustafsson J.A. Hepatic cholesterol metabolism and resistance to dietary cholesterol in LXRbeta-deficient mice. J Clin Invest 2001, 107:565-573.
31. Goodwin B., Jones S.A., Price R.R., Watson M.A., McKee D.D., Moore L.B., Galardi C., Wilson J.G., Lewis M.C., Roth M.E., et al. A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis. Mol Cell 2000, 6:517-526.
32. Zhang Y., Repa J.J., Gauthier K., Mangelsdorf D.J. Regulation of lipoprotein lipase by the oxysterol receptorsm LXRalpha and LXRbeta. J Biol Chem 2001, 276:43018-43024.
33. Luo Y., Tall A.R. Sterol upregulation of human CETP expression in vitro and in transgenic mice by an LXR element. J Clin Invest 2000, 105:513-520.
34. Joseph S.B., McKilligin E., Pei L., Watson M.A., Collins A.R., Laffitte B.A., Chen M., Noh G., Goodman J., Hagger G.N., et al. Synthetic LXR ligand inhibits the development of atherosclerosis in mice. Proc Natl Acad Sci USA 2002, 99:7604-7609.
35. Fowler A.J., Sheu M.Y., Schmuth M., Kao J., Fluhr J.W., Rhein L., Collins J.L., Willson T.M., Mangelsdorf D.J., Elias P.M., et al. Liver X receptor activators display anti-inflammatory activity in irritant and allergic contact dermatitis models: liver-X-receptor-specific inhibition of inflammation and primary cytokine production. J Invest Dermatol 2003, 120:246-255.
36. Joseph S.B., Castrillo A., Laffitte B.A., Mangelsdorf D.J., Tontonoz P. Reciprocal regulation of inflammation and lipid metabolism by liver X receptors. Nat Med 2003, 9:213-219.
37. Bradley M.N., Hong C., Chen M., Joseph S.B., Wilpitz D.C., Wang X., Lusis A.J., Collins A., Hseuh W.A., Collins J.L., 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.
38. Li X., Yeh V., Molteni V Liver X receptor modulators: a review of recently patented compounds (2007-2009). Expert Opin Ther Pat 2010, 20:535-562.
39. Yasuda T., Grillot D., Billheimer J.T., Briand F., Delerive P., Huet S., Rader D.J. Tissue-specific liver X receptor activation promotes macrophage reverse cholesterol transport in vivo. Arterioscler Thromb Vasc Biol 2010, 30:781-786.
40. Zelcer N., Hong C., Boyadjian R., Tontonoz P. LXR regulates cholesterol uptake through Idol-dependent ubiquitination of the LDL receptor. Science 2009, 325:100-104.
41. Herzog B., Hallberg M., Seth A., Woods A., White R., Parker M.G. The nuclear receptor cofactor, receptor-interacting protein 140, is required for the regulation of hepatic lipid and glucose metabolism by liver X receptor. Mol Endocrinol 2007, 21:2687-2697.