A liver-selective LXR inverse agonist that suppresses hepatic steatosis

ACS Chemical Biology

Volumn 8, Issue 3, 2013, Pages 559-567

  Griffett, Kristine ^a   Solt, Laura A ^a   El Gendy, Bahaa El Dien M ^a   Kamenecka, Theodore M ^a   Burris, Thomas P ^a  

^a SCRIPPS RESEARCH INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

COREPRESSOR PROTEIN; LIVER X RECEPTOR AGONIST; 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; SR 10389; SR 9238; UNCLASSIFIED DRUG; CHOLESTEROL; FUSED HETEROCYCLIC RINGS; LIVER X RECEPTOR; ORPHAN NUCLEAR RECEPTOR; SR9238;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; CELL STRAIN HEK293; CHOLESTEROL TRANSPORT; DRUG MECHANISM; DRUG POTENCY; DRUG STRUCTURE; DRUG SYNTHESIS; GENE SILENCING; GENETIC TRANSFECTION; HUMAN; HUMAN CELL; HUMAN CELL CULTURE; IC 50; INFLAMMATION; LIPID LIVER LEVEL; LIPOGENESIS; MOUSE; NONALCOHOLIC FATTY LIVER; NONHUMAN; PRIORITY JOURNAL; TREATMENT DURATION; ANIMAL; ANTAGONISTS AND INHIBITORS; ANTIBODY SPECIFICITY; BLOOD; CHEMICAL STRUCTURE; CHEMISTRY; DISEASE MODEL; DOSE RESPONSE; FATTY LIVER; INVERSE AGONISM; LIVER; METABOLISM; MOUSE MUTANT; STRUCTURE ACTIVITY RELATION;

ANIMALS; CHOLESTEROL; DISEASE MODELS, ANIMAL; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG INVERSE AGONISM; FATTY LIVER; HETEROCYCLIC COMPOUNDS WITH 4 OR MORE RINGS; HUMANS; LIVER; MICE; MICE, OBESE; MOLECULAR STRUCTURE; ORGAN SPECIFICITY; ORPHAN NUCLEAR RECEPTORS; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 84875171894     PISSN: 15548929     EISSN: 15548937     Source Type: Journal    
DOI: 10.1021/cb300541g     Document Type: Article

References (30)

1. Browning, J. D., Szczepaniak, L. S., Dobbins, R., Nuremberg, P., Horton, J. D., Cohen, J. C., Grundy, S. M., and Hobbs, H. H. (2004) Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity Hepatology 40, 1387-1395
2. Szczepaniak, L. S., Nurenberg, P., Leonard, D., Browning, J. D., Reingold, J. S., Grundy, S., Hobbs, H. H., and Dobbins, R. L. (2005) Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population Am. J. Physiol. Endocrinol. Metab. 288, E462-468
3. Adams, L. A. and Angulo, P. (2006) Treatment of non-alcoholic fatty liver disease Postgrad. Med. J. 82, 315-322
4. Browning, J. D. and Horton, J. D. (2004) Molecular mediators of hepatic steatosis and liver injury J. Clin. Invest. 114, 147-152
5. Cohen, J. C., Horton, J. D., and Hobbs, H. H. (2011) Human fatty liver disease: old questions and new insights Science 332, 1519-1523
6. Calkin, A. C. and Tontonoz, P. (2012) Transcriptional integration of metabolism by the nuclear sterol-activated receptors LXR and FXR Nat. Rev. Mol. Cell. Biol. 13, 213-224
7. Uyeda, K. and Repa, J. J. (2006) Carbohydrate response element binding protein, ChREBP, a transcription factor coupling hepatic glucose utilization and lipid synthesis Cell Metab. 4, 107-110
8. Yoshikawa, T., Shimano, H., Amemiya-Kudo, M., Yahagi, N., Hasty, A. H., Matsuzaka, T., Okazaki, H., Tamura, Y., Iizuka, Y., Ohashi, K., Osuga, J., Harada, K., Gotoda, T., Kimura, S., Ishibashi, S., and Yamada, N. (2001) Identification of liver X receptor-retinoid X receptor as an activator of the sterol regulatory element-binding protein 1c gene promoter Mol. Cell. Biol. 21, 2991-3000
9. Joseph, S. B., Laffitte, B. A., Patel, P. H., Watson, M. A., Matsukuma, K. E., Walczak, R., Collins, J. L., Osborne, T. F., and Tontonoz, P. (2002) Direct and indirect mechanisms for regulation of fatty acid synthase gene expression by liver X receptors J. Biol. Chem. 277, 11019-11025
10. Repa, J. J., Liang, G., Ou, J., Bashmakov, Y., Lobaccaro, J. M., Shimomura, I., Shan, B., Brown, M. S., Goldstein, J. L., and Mangelsdorf, D. J. (2000) Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRalpha and LXRbeta Genes Dev. 14, 2819-2830
11. Lima-Cabello, E., Garcia-Mediavilla, M. V., Miquilena-Colina, M. E., Vargas-Castrillon, J., Lozano-Rodriguez, T., Fernandez-Bermejo, M., Olcoz, J. L., Gonzalez-Gallego, J., Garcia-Monzon, C., and Sanchez-Campos, S. (2011) Enhanced expression of pro-inflammatory mediators and liver X-receptor-regulated lipogenic genes in non-alcoholic fatty liver disease and hepatitis C Clin. Sci. 120, 239-250
12. Michael, L. F., Schkeryantz, J. M., and Burris, T. P. (2005) The pharmacology of LXR Mini Rev. Med. Chem. 5, 729-740
13. Zuercher, W. J., Buckholz, R. G., Campobasso, N., Collins, J. L., Galardi, C. M., Gampe, R. T., Hyatt, S. M., Merrihew, S. L., Moore, J. T., Oplinger, J. A., Reid, P. R., Spearing, P. K., Stanley, T. B., Stewart, E. L., and Willson, T. M. (2010) Discovery of tertiary sulfonamides as potent liver X receptor antagonists J. Med. Chem. 53, 3412-3416
14. Naik, S. U., Wang, X., Da Silva, J. S., Jaye, M., Macphee, C. H., Reilly, M. P., Billheimer, J. T., Rothblat, G. H., and Rader, D. J. (2006) Pharmacological activation of liver X receptors promotes reverse cholesterol transport in vivo Circulation 113, 90-97
15. Zanotti, I., Poti, F., Pedrelli, M., Bellosta, S., Favari, E., and Bernini, F. (2006) The liver-X-receptor agonist T0901317 stimulates in vivo reverse cholesterol transport in mice Arterioscler., Thromb., Vasc., Biol. 26, E54-E54
16. Zhang, Y., Breevoort, S. R., Angdisen, J., Fu, M., Schmidt, D. R., Holmstrom, S. R., Kliewer, S. A., Mangelsdorf, D. J., and Schulman, I. G. (2012) Liver LXRalpha expression is crucial for whole body cholesterol homeostasis and reverse cholesterol transport in mice J. Clin. Invest. 122, 1688-1699
17. Gramlich, T., Kleiner, D. E., McCullough, A. J., Matteoni, C. A., Boparai, N., and Younossi, Z. M. (2004) Pathologic features associated with fibrosis in nonalcoholic fatty liver disease Hum. Pathol. 35, 196-199
18. McCullough, A. J. (2004) The clinical features, diagnosis and natural history of nonalcoholic fatty liver disease Clin. Liver Dis. 8, 521-533
19. Tosello-Trampont, A.-C., Landes, S. G., Nguyen, V., Novobrantseva, T. I., and Hahn, Y. S. (2012) Kupffer cells trigger nonalcholic steatohepatitis development in diet-indiced model through TNF-α production J. Biol. Chem. 287, 40161-40172
20. Fernandez-Veledo, S., Nieto-Vazquez, I., Rondinone, C. M., and Lorenzo, M. (2006) Liver X receptor agonists ameliorate TNF alpha-induced insulin resistance in murine brown adipocytes by downregulating protein tyrosine phosphatase-1B gene expression Diabetologia 49, 3038-3048
21. Wang, H., Zhang, Y., Yehuda-Shnaidman, E., Medvedev, A. V., Kumar, N., Daniel, K. W., Robidoux, J., Czech, M. P., Mangelsdorf, D. J., and Collins, S. (2008) Liver X receptor alpha is a transcriptional repressor of the uncoupling protein 1 gene and the brown fat phenotype Mol. Cell. Biol. 28, 2187-2200
22. Korach-Andre, M., Archer, A., Barros, R. P., Parini, P., and Gustafsson, J. A. (2011) Both liver-X receptor (LXR) isoforms control energy expenditure by regulating brown adipose tissue activity Proc. Natl. Acad. Sci. U.S.A. 108, 403-408
23. Joseph, S. B., Castrillo, A., Laffitte, B. A., Mangelsdorf, D. J., and Tontonoz, P. (2003) Reciprocal regulation of inflammation and lipid metabolism by liver X receptors Nat. Med. 9, 213-219
24. Zelcer, N. and Tontonoz, P. (2006) Liver X receptors as integrators of metabolic and inflammatory signaling J. Clin. Invest. 116, 607-614
25. Lehmann, J. M., Kliewer, S. A., Moore, L. B., SmithOliver, T. A., Oliver, B. B., Su, J. L., Sundseth, S. S., Winegar, D. A., Blanchard, D. E., Spencer, T. A., and Willson, T. M. (1997) Activation of the nuclear receptor LXR by oxysterols defines a new hormone response pathway J. Biol. Chem. 272, 3137-3140
26. Peet, D. J., Turley, S. D., Ma, W., Janowski, B. A., Lobaccaro, J. M., Hammer, R. E., and Mangelsdorf, D. J. (1998) Cholesterol and bile acid metabolism are impaired in mice lacking the nuclear oxysterol receptor LXR alpha Cell 93, 693-704
27. Alberti, S., Schuster, G., Parini, P., Feltkamp, D., Diczfalusy, U., Rudling, M., Angelin, B., Bjorkhem, I., Pettersson, S., and Gustafsson, J. A. (2001) Hepatic cholesterol metabolism and resistance to dietary cholesterol in LXRbeta-deficient mice J. Clin. Invest. 107, 565-573
28. Schultz, J. R., Tu, H., Luk, A., Repa, J. J., Medina, J. C., Li, L. P., Schwendner, S., Wang, S., Thoolen, M., Mangelsdorf, D. J., Lustig, K. D., and Shan, B. (2000) Role of LXRs in control of lipogenesis Genes Dev. 14, 2831-2838
29. Brown, M. S. and Goldstein, J. L. (1997) The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor Cell 89, 331-340
30. Jeon, T. I. and Osborne, T. F. (2012) SREBPs: metabolic integrators in physiology and metabolism Trends Endocrinol Metab 23, 65-72