A 15-ketosterol is a liver X receptor ligand that suppresses sterol-responsive element binding protein-2 activity

Journal of Lipid Research

Volumn 47, Issue 5, 2006, Pages 1037-1044

  Schmidt, Robert J ^a   Ficorilli, James V ^a   Zhang, Youyan ^a   Bramlett, Kelli S ^a   Beyer, Thomas P ^a   Borchert, Kristen ^a   Dowless, Michele S ^a   Houck, Keith A ^a   Burris, Thomas P ^a   Eacho, Patrick I ^a   Liang, Guosheng ^a   Guo, Li Wei ^b   Wilson, William K ^b   Michael, Laura F ^a   Cao, Guoqing ^a  

^a ELI LILLY AND COMPANY   (United States)

^b RICE UNIVERSITY   (United States)

Author keywords

Hypercholesterolemia; Scintillation proximity assay; Statin

Indexed keywords

ATP-BINDING CASSETTE TRANSPORTERS; CELLS, CULTURED; CHOLESTENONES; DNA-BINDING PROTEINS; GENE EXPRESSION REGULATION; HUMANS; HYDROXYMETHYLGLUTARYL COA REDUCTASES; RECEPTORS, CYTOPLASMIC AND NUCLEAR; SERINE ENDOPEPTIDASES; STEROL REGULATORY ELEMENT BINDING PROTEIN 2;

EID: 33646815299     PISSN: 00222275     EISSN: 15397262     Source Type: Journal    
DOI: 10.1194/jlr.M500526-JLR200     Document Type: Article

References (35)

1. Brown, M. S., and J. L. Goldstein. 1996. Heart attacks: gone with the century? Science. 272: 629.
2. Kandutsch, A. A., and H. W. Chen. 1973. Inhibition of sterol synthesis in cultured mouse cells by 7alpha-hydroxycholesterol, 7beta-hydroxycholesterol, and 7-ketocholesterol. J. Biol. Chem. 248: 8408-8417.
3. Brown, M. S., and J. L. Goldstein. 1974. Suppression of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and inhibition of growth of human fibroblasts by 7-ketocholesterol. J. Biol. Chem. 249: 7306-7314.
4. Brown, M. S., and J. L. Goldstein. 1999. A proteolytic pathway that controls the cholesterol content of membranes, cells, and blood. Proc. Natl. Acad. Sci. USA. 96: 11041-11048.
5. Janowski, B. A., P. J. Willy, T. R. Devi, J. R. Falck, and D. J. Mangelsdorf. 1996. An oxysterol signalling pathway mediated by the nuclear receptor LXR alpha. Nature. 383: 728-731.
6. Janowski, B. A., M. J. Grogan, S. A. Jones, G. B. Wisely, S. A. Kliewer, E. J. Corey, and D. J. Mangelsdorf. 1999. Structural requirements of ligands for the oxysterol liver X receptors LXRalpha and LXRbeta. Proc. Natl. Acad. Sci. USA. 96: 266-271.
7. Tontonoz, P., and D. J. Mangelsdorf. 2003. Liver X receptor signaling pathways in cardiovascular disease. Mol. Endocrinol. 17: 985-993.
8. Costet, P., Y. Luo, N. Wang, and A. R. Tall. 2000. Sterol-dependent transactivation of the ABC1 promoter by the liver X receptor/retinoid X receptor. J. Biol. Chem. 275: 28240-28245.
9. Repa, J. J., K. E. Berge, C. Pomajzl, J. A. Richardson, H. H. Hobbs, and D. J. Mangelsdorf. 2002. Regulation of ATP-binding cassette sterol transporters ABCG5 and ABCG8 by the liver X receptors α and β. J. Biol. Chem. 277: 18793-18800.
10. Kennedy, M. A., A. Venkateswaran, P. T. Tarr, I. Xenarios, J. Kudoh, N. Shimizu, and P. A. Edwards. 2001. Characterization of the human ABCG1 gene: liver X receptor activates an internal promoter that produces a novel transcript encoding an alternative form of the protein. J. Biol. Chem. 276: 39438-39447.
11. Luo, Y., and A. R. Tall. 2000. Sterol upregulation of human CETP expression in vitro and in transgenic mice by an LXR element. J. Clin. Invest. 105: 513-520.
12. Cao, G., T. P. Beyer, X. P. Yang, R. J. Schmidt, Y. Zhang, W. R. Bensch, R. F. Kauffman, H. Gao, T. P. Ryan, Y. Liang, et al. 2002. Phospholipid transfer protein is regulated by liver X receptors in vivo. J. Biol. Chem. 277: 39561-39565.
13. Laffitte, B. A., J. J. Repa, S. B. Joseph, D. C. Wilpitz, H. R. Kast, D. J. Mangelsdorf, and P. Tontonoz. 2001. LXRs control lipid-inducible expression of the apolipoprotein E gene in macrophages and adipocytes. Proc. Natl. Acad. Sci. USA. 98: 507-512.
14. Mak, P. A., B. A. Laffitte, C. Desrumaux, S. B. Joseph, L. K. Curtiss, D. J. Mangelsdorf, P. Tontonoz, and P. A. Edwards. 2002. Regulated expression of the apolipoprotein E/C-I/C-IV/C-II gene cluster in murine and human macrophages. A critical role for nuclear liver X receptors α and β. J. Biol. Chem. 277: 31900-31908.
15. Liang, Y., X. C. Jiang, R. Liu, G. Liang, T. P. Beyer, H. Gao, T. P. Ryan, S. Dan Li, P. I. Eacho, and G. Cao. 2004. Liver X receptors (LXRs) regulate apolipoprotein AIV-implications of the antiatherosclerotic effect of LXR agonists. Mol. Endocrinol. 18: 2000-2010.
16. Schultz, J. R., H. Tu, A. Luk, J. J. Repa, J. C. Medina, L. Li, S. Schwendner, S. Wang, M. Thoolen, D. J. Mangelsdorf, et al. 2000. Role of LXRs in control of lipogenesis. Genes Dev. 14: 2831-2838.
17. Joseph, S. B., E. McKilligin, L. Pei, M. A. Watson, A. R. Collins, B. A. Laffitte, M. Chen, G. Noh, J. Goodman, G. N. Hagger, et al. 2002. Synthetic LXR ligand inhibits the development of atherosclerosis in mice. Proc. Natl. Acad. Sci. USA. 99: 7604-7609.
18. Terasaka, N., A. Hiroshima, T. Koieyama, N. Ubukata, Y. Morikawa, D. Nakai, and T. Inaba. 2003. T-0901317, a synthetic liver X receptor ligand, inhibits development of atherosclerosis in LDL receptor-deficient mice. FEBS Lett. 536: 6-11.
19. Gibbons, G. F. 2002. From gallstones to genes: two hundred years of sterol research. A tribute to George J. Schroepfer Jr. Lipids. 37: 1153-1162.
20. Schroepfer, G. J., Jr. 1996. Design of new oxysterols for regulation of cholesterol metabolism. Curr. Pharm. Des. 2: 103-120.
21. Schroepfer, G. J., Jr., D. Monger, A. S. Taylor, J. S. Chamberlain, E. J. Parish, A. Kisic, and A. A. Kandutsch. 1977. Inhibitors of sterol synthesis. Hypocholesterolemic action of dietary 5alpha-cholest-8(14)-en-3beta-ol-15-one in rats and mice. Biochem. Biophys. Res. Commun. 78: 1227-1233.
22. Brabson, J. S., and G. J. Schroepfer, Jr. 1988. Inhibitors of sterol synthesis. The effects of dietary 5 alpha-cholest-8(14)-en-3 beta-ol-15-one on the fate of [4-14C]cholesterol and [2,4-3H]5 alphacholest-8(14)-en-3 beta-ol-15-one after intragastric administration to rats. Chem. Phys. Lipids. 47: 1-20.
23. Schroepfer, G. J., Jr., E. J. Parish, A. Kisic, E. M. Jackson, C. M. Farley, and G. E. Mott. 1982. 5 Alpha-cholest-8(14)-en-3 beta-ol-15-one, a potent inhibitor of sterol biosynthesis, lowers serum cholesterol and alters distributions of cholesterol in lipoproteins in baboons. Proc. Natl. Acad. Sci. USA. 79: 3042-3046.
24. Schroepfer, G. J., Jr., B. C. Sherrill, K. S. Wang, W. K. Wilson, A. Kisic, and T. B. Clarkson. 1984. 5 Alpha-cholest-8(14)-en-3 beta-ol-15-one lowers serum cholesterol and induces profound changes in the levels of lipoprotein cholesterol and apoproteins in monkeys fed a diet of moderate cholesterol content. Proc. Natl. Acad. Sci. USA. 81: 6861-6865.
25. Wilson, D. K., W. K. Wilson, F. A. Quiocho, and G. J. Schroepfer, Jr. 1988. Concerning the structure of 3 beta-benzoyloxy-5 beta-cholesta-8,14-diene, a major byproduct in the chemical synthesis of 5 alphacholest-8(14)-en-3 beta-ol-15-one. Chem. Phys. Lipids. 47: 273-282.
26. Bramlett, K. S., K. A. Houck, K. M. Borchert, M. S. Dowless, P. Kulanthaivel, Y. Zhang, T. P. Beyer, R. Schmidt, J. S. Thomas, L. F. Michael, et al. 2003. A natural product ligand of the oxysterol receptor, liver X receptor. J. Pharmacol. Exp. Ther. 307: 291-296.
27. Zhang, Y., T. Beyer, K. Bramlett, S. Yao, T. Burris, R. Schmidt, P. Eacho, and G. Cao. 2002. Liver X receptor and retinoic X receptor mediated ABCA1 regulation and cholesterol efflux in macrophage cells-messenger RNA measured by branched DNA technology. Mol. Genet. Metab. 77: 150-158.
28. Cao, G., J. L. Goldstein, and M. S. Brown. 1996. Complementation of mutation in acyl-CoA:cholesterol acyltransferase (ACAT) fails to restore sterol regulation in ACAT-defective sterol-resistant hamster cells. J. Biol. Chem. 271: 14642-14648.
29. Horton, J. D., N. A. Shah, J. A. Warrington, N. N. Anderson, S. W. Park, M. S. Brown, and J. L. Goldstein. 2003. Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes. Proc. Natl. Acad. Sci. USA. 100: 12027-12032.
30. Rashid, S., D. E. Curtis, R. Garuti, N. N. Anderson, Y. Bashmakov, Y. K. Ho, R. E. Hammer, Y. A. Moon, and J. D. Horton. 2005. Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9. Proc. Natl. Acad. Sci. USA. 102: 5374-5379.
31. Dubuc, G., A. Chamberland, H. Wassef, J. Davignon, N. G. Seidah, L. Bernier, and A. Prat. 2004. Statins upregulate PCSK9, the gene encoding the proprotein convertase neural apoptosis-regulated convertase-1 implicated in familial hypercholesterolemia. Arterioscler. Thromb. Vasc. Biol. 24: 1454-1459.
32. Hannah, V. C., J. Ou, A. Luong, J. L. Goldstein, and M. S. Brown. 2001. Unsaturated fatty acids down-regulate SREBP isoforms 1a and 1c by two mechanisms in HEK-293 cells. J. Biol. Chem. 276: 4365-4372.
33. Brown, M. S., and J. L. Goldstein. 1986. A receptor-mediated pathway for cholesterol homeostasis. Science. 232: 34-47.
34. Yang, J., J. L. Goldstein, R. E. Hammer, Y-A. Moon, M. S. Brown, and J. D. Horton. 2001. Decreased lipid synthesis in livers of mice with disrupted Site-1 protease gene. Proc. Natl. Acad. Sci. USA. 98: 13607-13612.
35. Matsuda, M., B. S. Korn, R. E. Hammer, Y-A. Moon, R. Komuro, J. D. Horton, J. L. Goldstein, M. S. Brown, and I. Shimomura. 2001. SREBP cleavage-activating protein (SCAP) is required for increased lipid synthesis in liver induced by cholesterol deprivation and insulin elevation. Genes Dev. 15: 1206-1216.