Raising HDL cholesterol without inducing hepatic steatosis and hypertriglyceridemia by a selective LXR modulator

Journal of Lipid Research

Volumn 45, Issue 8, 2004, Pages 1410-1417

  Miao, Bowman ^a   Zondlo, Susan ^a   Gibbs, Sandy ^a   Cromley, Debra ^a,b   Hosagrahara, Vinayak P ^a   Kirchgessner, Todd G ^a   Billeheimer, Jeffrey ^a,b   Mukherjee, Ranjan ^a  

^a BRISTOL MYERS SQUIBB   (United States)

^b UNIVERSITY OF PENNSYLVANIA   (United States)

Author keywords

Fatty acid synthetase; High density lipoprotein; Liver X receptor; Sterol response element binding protein 1 c; Triglyceride

Indexed keywords

ABC TRANSPORTER; FATTY ACID SYNTHASE; HIGH DENSITY LIPOPROTEIN CHOLESTEROL; LIVER X RECEPTOR; STEROL REGULATORY ELEMENT BINDING PROTEIN 1; TRANSCRIPTION FACTOR; TRIACYLGLYCEROL;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CHOLESTEROL BLOOD LEVEL; CHOLESTEROL TRANSPORT; CONTROLLED STUDY; ESTERIFICATION; FATTY LIVER; FLUORESCENCE RESONANCE ENERGY TRANSFER; GENE INDUCTION; GENETIC TRANSFECTION; HEPATOMA CELL; HYPERTRIGLYCERIDEMIA; INTESTINE ABSORPTION; LIPOGENESIS; MALE; MOUSE; NONHUMAN; NUCLEOTIDE SEQUENCE; PRIORITY JOURNAL; PROMOTER REGION; RECEPTOR AFFINITY;

ANIMALS; BENZOIC ACIDS; BENZYLAMINES; CHOLESTEROL, HDL; DNA-BINDING PROTEINS; FATTY LIVER; HYPERTRIGLYCERIDEMIA; LIGANDS; MALE; MICE; MICE, INBRED C57BL; ORGAN SPECIFICITY; RECEPTORS, CYTOPLASMIC AND NUCLEAR;

EID: 3442894108     PISSN: 00222275     EISSN: None     Source Type: Journal    
DOI: 10.1194/jlr.M300450-JLR200     Document Type: Article

References (27)

1. Willy, P. J., K. Umesono, E. S. Ong, R. M. Evans, R. A. Heyman, and D. J. Mangelsdorf. 1995. LXR, a nuclear receptor that defines a distinct retinoid response pathway. Genes Dev. 9: 1033-1045.
2. Teboul, M., E. Enmark, Q. Li, A. C. Wikstrom, M. Pelto-Huikko, and J. A. Gustafsson. 1995. OR-1, a member of the nuclear receptor superfamily that interacts with the 9-cis-retinoic acid receptor. Proc. Natl. Acad. Sci. USA. 92: 2096-2100.
3. Repa, J. J., G. S. Liang, J. F. Ou, Y. Bashmakov, J. M. A. Lobaccaro, I. Shimomura, B. Shan, M. S. Brown, J. L. Goldstein, and D. J. Mangelsdorf. 2000. Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXR alpha and LXR beta. Genes Dev. 14: 2819-2830.
4. Collins, J. L., A. M. Fivush, M. A. Watson, C. M. Galardi, M. C. Lewis, L. B. Moore, D. J. Parks, J. G. Wilson, T. K. Tippin, J. G. Binz, K. D. Plunket, D. G. Morgan, E.J. Beaudet, K. D. Whitney, S. A. Kliewer, and T. M. Willson. 2002. Identification of a nonsteroidal liver X receptor agonist through parallel array synthesis of tertiary amines. J. Med. Chem. 45: 1963-1966.
5. 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, P. I. Eacho, and X. C. Jiang. 2002. Phospholipid transfer protein is regulated by liver X receptors in vivo. J. Biol. Chem. 277: 39561-39565.
6. 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.
7. Repa, J. J., S. D. Turley, J. A. Lobaccaro, J. Medina, L. Li, K. Lustig, B. Shan, R. A. Heyman, J. M. Dietschy, and D. J. Mangelsdorf. 2000. Regulation of absorption and ABC1-mediated efflux of cholesterol by RXR heterodimers. Science. 289: 1524-1529.
8. Repa, J. J., K. E. Berge, C. Pomajzl, J. A. Richardson, H. Hobbs, D. J. Mangelsdorf, S. D. Turley, J. A. Lobaccaro, J. Medina, L. Li, K. Lustig, B. Shan, R. A. Heyman, and J. M. Dietschy. 2002. Regulation of ATP-binding cassette sterol transporters ABCG5 and ABCG8 by the liver X receptors alpha and beta regulation of absorption and ABC1-mediated efflux of cholesterol by RXR heterodimers. J. Biol. Chem. 277: 18793-18800.
9. 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.
10. Laffitte, B. A., S. B. Joseph, M. Chen, A. Castrillo, J. Repa, D. Wilpitz, D. Mangelsdorf, and P. Tontonoz. 2003. The phospholipid transfer protein gene is a liver X receptor target expressed by macrophages in atherosclerotic lesions. Mol. Cell. Biol. 23: 2182-2191.
11. Joseph, S. B., E. McKiiligin, L. Pei, M. A. Watson, A. R. Collins, B. A. Laffitte, M. Chen, G. Noh, J. Goodman, G. N. Hagger, J. Tran, T. K. Tippin, X. Wang, A. J. Lusis, W. A. Hsueh, R. E. Law, J. L. Collins, T. M. Willson, and P. Tontonoz. 2002. Synthetic LXR ligand inhibits the development of atherosclerosis in mice. Proc. Natl. Acad. Sci. USA. 99: 7604-7609.
12. 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.
13. Joseph, S. B., A. Castrillo, B. A. Laffitte, D. J. Mangelsdorf, and P. Tontonoz. 2003. Reciprocal regulation of inflammation and lipid metabolism by liver X receptors. Nat. Med. 9: 213-219.
14. Schultz, J. R., H. Tu, A. Luk, J. J. Repa, J. C. Medina, L. Li, S. Schwendner, S. Wang, M. Thoolen, D. J. Mangelsdorf, K. D. Lustig, and B. Shan. 2000. Role of LXRs in control of lipogenesis. Genes Dev. 14: 2831-2838.
15. Grefhorst, A., B. M. Elzinga, P. J. Voshol, T. Plosch, T. Kok, V. W. Bloks, F. H. van der Sluijs, L. M. Havekes, J. A. Romijn, H. J. Verkade, and F. Kuipers. 2002. 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. 277: 34182-34190.
16. Assmann, G., H. Schulte, and A. von Eckardstein. 1996. Hypertriglyceridemia and elevated lipoprotein (a) are risk factors for major coronary events in middle-aged men. Am. J. Cardiol. 77: 1179-1184.
17. Cullen, P. 2000. Evidence that triglycerides are an independent coronary heart disease risk factor. Am. J Cardiol. 86: 943-949.
18. Jeppesen, J., H. O. Hein, P. Suadicani, and F. Gyntelberg. 1998. Triglyceride concentration and ischemic heart disease: an eight-year follow-up in the Copenhagen Male Study. Circulation. 97: 1029-1036.
19. Joseph, S. B., B. A. Laffitte, P. H. Patel, M. A. Watson, K. E. Matsukuma, R. Walczak, J. L. Collins, T. F. Osborne, and P. Tontonoz. 2002. Direct and indirect mechanisms for regulation of fatty acid synthase gene expression by liver X receptors. J. Biol. Chem. 277: 11019-11025.
20. Zhou, G., R. Cummings, Y. Li, S. Mitra, H. A. Wilkinson, A. Elbrecht, J. D. Hermes, J. M. Schaeffer, R. G. Smith, and D. E. Moller. 1998. Nuclear receptors have distinct affinities for coactivators: characterization by fluorescence resonance energy transfer. Mol. Endocrinol. 12: 1594-1604.
21. Onate, S. A., S. Y. Tsai, M. J. Tsai, and B. W. O'Malley. 1995. Sequence and characterization of a coactivator for the steroid hormone receptor superfamily. Science. 270: 1354-1357.
22. Kamei, Y., L. Xu, T. Heinzel, J. Torchia, R. Kurokawa, B. Gloss, S. C. Lin, R. A. Heyman, D. W. Rose, C. K. Glass, and M. G. Rosenfeld. 1996. A CBP integrator complex mediates transcriptional activation and AP-1 inhibition by nuclear receptors. Cell. 85: 403-414.
23. Rachez, C., M. Gamble, C. P. Chang, G. B. Atkins, M. A. Lazar, and L. P. Freedman. 2000. The DRIP complex and SRC-1/p160 coactivators share similar nuclear receptor binding determinants but constitute functionally distinct complexes. Mol. Cell. Biol. 20: 2718-2726.
24. Mukherjee, R., S. Sun, L. Santomenna, B. Miao, H. Walton, B. Liao, K. Locke, J. Zhang, S. Nguyen, L. Zhang, K. Murphy, H. Ross, M. Xia, C. Teleha, S. Chen, B. Selling, R. Wynn, T. Burn, and P. Young. 2002. Ligand and coactivator recruitment preferences of peroxisome proliferator activated receptor alpha. J. Steroid Biochem. Mol. Biol. 81: 217-225.
25. Peet, D. J., S. D. Turley, W. Ma, B. A. Janowski, J. M. Lobaccaro, R. E. Hammer, and D. J. Mangelsdorf. 1998. Cholesterol and bile acid metabolism are impaired in mice lacking the nuclear oxysterol receptor LXR alpha. Cell. 93: 693-704.
26. Alberti, S., G. Schuster, P. Parini, D. Feltkamp, U. Diczfalusy, M. Rudling, B. Angelin, I. Bjorkhem, S. Pettersson, and J. A. Gustafsson. 2001. Hepatic cholesterol metabolism and resistance to dietary cholesterol in LXR beta-deficient mice. J. Clin. Invest. 107: 565-573.
27. Shang, Y., and M. Brown. 2002. Molecular determinants for the tissue specificity of SERMs. Science. 295: 2465-2468.