Synthetic LXR agonist suppresses endogenous cholesterol biosynthesis and efficiently lowers plasma cholesterol

Current Pharmaceutical Biotechnology

Volumn 12, Issue 2, 2011, Pages 285-292

  Pfeifer, Thomas ^a   Buchebner, Marlene ^a   Chandak, Prakash G ^a   Patankar, Jay ^a   Kratzer, Adelheid ^a   Obrowsky, Sascha ^a   Rechberger, Gerald N ^b   Kadam, Rajendra S ^c   Kompella, Uday B ^c   Kostner, Gerhard M ^a   Kratky, Dagmar ^a   Levak Frank, Sanja ^a  

^a MEDICAL UNIVERSITY OF GRAZ   (Austria)

^b UNIVERSITY OF GRAZ   (Austria)

^c UNIVERSITY OF COLORADO   (United States)

Author keywords

Cholesterol absorption; Cholesterol biosynthesis; Desmosterol; DHCR24; DMHCA; Liver X receptor

Indexed keywords

3 BETA HYDROXYSTEROL DELTA 24 REDUCTASE; CHOLESTEROL; DESMOSTEROL; LIVER X RECEPTOR; LIVER X RECEPTOR AGONIST; N,N DIMETHYL 3 BETA HYDROXYCHOLENAMIDE; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; CHOLESTEROL BLOOD LEVEL; CHOLESTEROL SYNTHESIS; DUODENUM; FATTY LIVER; HEART; HYDROPHOBICITY; HYPERTRIGLYCERIDEMIA; INTESTINE CELL; JEJUNUM; KIDNEY; LUNG; MALE; MOUSE; NONHUMAN;

MUS;

EID: 79551644401     PISSN: 13892010     EISSN: 18734316     Source Type: Journal    
DOI: 10.2174/138920111794295774     Document Type: Article

References (38)

1. Janowski, B. A.; Willy, P. J.; Devi, T. R.; Falck, J. R.; Mangelsdorf, D. J. An oxysterol signalling pathway mediated by the nuclear receptor LXR alpha. Nature, 1996, 383, 728-731.
2. Zelcer, N.; Tontonoz, P. Liver X receptors as integrators of metabolic and inflammatory signaling. J. Clin. Invest., 2006, 116, 607-614.
3. Molteni, V.; Li, X.; Nabakka, J.; Liang, F.; Wityak, J.; Koder, A.; Vargas, L.; Romeo, R.; Mitro, N.; Mak, P. A.; Seidel, H. M.; Haslam, J. A.; Chow, D.; Tuntland, T.; Spalding, T. A.; Brock, A.; Bradley, M.; Castrillo, A.; Tontonoz, P.; Saez, E. NAcylthiadiazolines, a new class of liver X receptor agonists with selectivity for LXRbeta. J.Med. Chem., 2007, 50, 4255-4259.
4. Fievet, C.; Staels, B. Liver X receptor modulators, effects on lipid metabolism and potential use in the treatment of atherosclerosis. Biochem. Pharmacol., 2009, 77, 1316-1327.
5. Baldan, A.; Bojanic, D.D.; Edwards, P.A. The ABCs of sterol transport. J. Lipid. Res., 2009, 50(Suppl.), S80-85.
6. Zanotti, I.; Poti, F.; Pedrelli, M.; Favari, E.; Moleri, E.; Franceschini, G.; Calabresi, L.; Bernini, F. The LXR agonist T0901317 promotes the reverse cholesterol transport from macrophages by increasing plasma efflux potential. J. Lipid Res., 2008, 49, 954-960.
7. Repa, J. J.; Turley, S. D.; Lobaccaro, J. A.; Medina, J.; Li, L.; Lustig, K.; Shan, B.; Heyman, R. A.; Dietschy, J. M.; Mangelsdorf, D. J. Regulation of absorption and ABC1-mediated efflux of cholesterol by RXR heterodimers. Science, 2000, 289, 1524-1529.
8. Kruit, J.K.; Plosch, T.; Havinga, R.; Boverhof, R.; Groot, P.H.; Groen, A.K.; Kuipers, F. Increased fecal neutral sterol loss upon liver X receptor activation is independent of biliary sterol secretion in mice. Gastroenterology, 2005, 128, 147-156.
9. Plosch, T.; Kok, T.; Bloks, V. W.; Smit, M. J.; Havinga, R.; Chimini, G.; Groen, A. K.; Kuipers, F. Increased hepatobiliary and fecal cholesterol excretion upon activation of the liver X receptor is independent of ABCA1. J. Biol. Chem., 2002, 277, 33870-33877.
10. Duval, C.; Touche, V.; Tailleux, A.; Fruchart, J. C.; Fievet, C.; Clavey, V.; Staels, B.; Lestavel, S. Niemann-Pick C1 like 1 gene expression is down-regulated by LXR activators in the intestine. Biochem. Biophys. Res. Commun., 2006, 340,1259-1263.
11. Tang, W.; Ma, Y.; Jia, L.; Ioannou, Y. A.; Davies, J.P.; Yu, L. Niemann-Pick C1-like 1 is required for an LXR agonist to raise plasma HDL cholesterol in mice. Arterioscler. Thromb. Vasc. Biol., 2008, 28, 448-454.
12. 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.; Tran, J.; Tippin, T. K.; Wang, X.; Lusis, A. J.; Hsueh, W. A.; Law, R. E.; Collins, J. L.; Willson, T. M.; Tontonoz, P. Synthetic LXR ligand inhibits the development of atherosclerosis in mice. Proc. Natl. Acad. Sci. USA, 2002, 99, 7604-7609.
13. Levin, N.; Bischoff, E. D.; Daige, C. L.; Thomas, D.; Vu, C. T.; Heyman, R. A.; Tangirala, R. K.; Schulman I. G. Macrophage liver X receptor is required for antiatherogenic activity of LXR agonists. Arterioscler. Thromb. Vasc. Biol., 2005, 25, 135-142.
14. Peng, D.; Hiipakka, R. A.; Reardon, C. A.; Getz, G. S.; Liao, S. Differential anti-atherosclerotic effects in the innominate artery and aortic sinus by the liver X receptor agonist T09013 Atherosclerosis 2009, 203, 59-66.
15. Kratzer, A.; Buchebner, M.; Pfeifer, T.; Becker, T.M; Uray, G.; Miyazaki, M.; Miyazaki-Anzai, S.; Ebner, B.; Chandak, P. G.; Kadam, R. S.; Calayir, E.; Rathke, N.; Ahammer, H.; Radovic, B.; Trauner, M.; Hoefler, G.; Kompella, U.B.; Fauler, G.; Levi, M.; Levak-Frank, S.; Kostner, G. M.; Kratky, D. Synthetic LXR agonist attenuates plaque formation in apoE-/- mice without inducing liver steatosis and hypertriglyceridemia. J. Lipid Res., 2009, 50, 312-326.
16. Chisholm, J. W.; Hong, J.; Mills, S. A.; Lawn, R. M. The LXR ligand T0901317 induces severe lipogenesis in the db/db diabetic mouse. J. Lipid Res., 2003, 44, 2039-2048.
17. Samyn, H.; Moerland, M.; van Gent, T.; van Haperen, R.; van Tol, A.; de Crom, R. Reduction of HDL levels lowers plasma PLTP and affects its distribution among lipoproteins in mice. Biochim. Biophys. Acta, 2009, 1791, 790-796.
18. 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.
19. Schultz, J. R.; Tu, H.; Luk, A.; Repa, J. J.; Medina, J. C.; Li, L.; Schwendner, S.; Wang, S.; Thoolen, M.; Mangelsdorf D. J.; Lustig, K. D.; Shan, B. Role of LXRs in control of lipogenesis. Genes Dev., 2000, 14, 2831-2838.
20. 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.
21. Grefhorst, A.; Hoekstra, J.; Derks, T. G.; Ouwens, D. M.; Baller, J. F.; Havinga, R.; Havekes, L. M.; Romijn, J. A.; Kuipers, F. Acute hepatic steatosis in mice by blocking beta-oxidation does not reduce insulin sensitivity of very-low-density lipoprotein production. Am. J. Physiol. Gastrointest. Liver Physiol., 2005, 289, G592-598.
22. Groot, P. H.; Pearce, N. J.; Yates, J. W.; Stocker, C.; Sauermelch, C.; Doe, C. P.; Willette, R. N.; Olzinski, A.; Peters, T.; d'Epagnier, D.; Morasco, K.O.; Krawiec, J. A.; Webb, C. L.; Aravindhan, K.; Jucker, B.; Burgert, M.; Ma, C.; Marino, J. P.; Collins, J. L.; Macphee, C. H.; Thompson, S.K.; Jaye, M. Synthetic LXR agonists increase LDL in CETP species. J. Lipid Res., 2005, 46, 2182-2191.
23. Peng, D.; Hiipakka, R. A.; Dai, Q.; Guo, J.; Reardon, C. A.; Getz, G. S.; Liao, S. Antiatherosclerotic effects of a novel synthetic tissue- selective steroidal liver X receptor agonist in low-density lipoprotein receptor-deficient mice. J. Pharmacol. Exp. Ther., 2008, 327, 332-342.
24. Quinet, E. M.; Savio, D. A.; Halpern, A. R.; Chen, L.; Miller, C. P.; Nambi, P. Gene-selective modulation by a synthetic oxysterol ligand of the liver X receptor. J. Lipid Res., 2004, 45,1929-1942.
25. Song, C.; Liao, S. Hypolipidemic effects of selective liver X receptor alpha agonists. Steroids, 2001, 66, 673-681.
26. Temel, R. E.; Lee, R. G.; Kelley, K. L.; Davis, M. A.; Shah, R.; Sawyer, J. K.; Wilson, M. D.; Rudel, L. L. Intestinal cholesterol absorption is substantially reduced in mice deficient in both ABCA1 and ACAT2. J. Lipid Res., 2005, 46, 2423-2431.
27. Wang, D.Q.; Carey, M. C. Measurement of intestinal cholesterol absorption by plasma and fecal dual-isotope ratio, mass balance, and lymph fistula methods in the mouse, an analysis of direct versus indirect methodologies. J. Lipid Res., 2003, 44,1042-1059.
28. Wolfman, L.; Sachs, B. A. Separation of Cholesterol and demosterol by thin-layer chromatography. J. Lipid Res., 1964, 15,127-128.
29. Waterham, H.R.; Koster, J.; Romeijn, G. J.; Hennekam, R. C.; Vreken, P.; Andersson, H. C.; FitzPatrick, D. R.; Kelley, R. I.; Wanders, R. J. Mutations in the 3beta-hydroxysterol Delta24- reductase gene cause desmosterolosis, an autosomal recessive disorder of cholesterol biosynthesis. Am. J. Hum. Genet., 2001, 69, 685-694.
30. Nguyen, D. V.; Drover, V. A.; Knopfel, M.; Dhanasekaran, P.; Hauser, H.; Phillips, M. C. Influence of class B scavenger receptors on cholesterol flux across the brush border membrane and intestinal absorption. J. Lipid Res., 2009, 50, 2235-2244.
31. Bae, S. H.; Paik, Y. K. Cholesterol biosynthesis from lanosterol, development of a novel assay method and characterization of rat liver microsomal lanosterol delta 24-reductase. Biochem. J., 1997, 326(Pt 2), 609-616.
32. Yang, C.; McDonald, J. G.; Patel, A.; Zhang, Y.; Umetani, M.; Xu, F.; Westover, E. J.; Covey, D.F.; Mangelsdorf, D. J.; Cohen, J. C.; Hobbs, H.H. Sterol intermediates from cholesterol biosynthetic pathway as liver X receptor ligands. J. Biol. Chem., 2006, 281, 27816-27826.
33. Heverin, M.; Meaney, S.; Brafman, A.; Shafir, M.; Olin, M.; Shafaati, M.; von Bahr, S.; Larsson, L.; Lovgren-Sandblom, A.; Diczfalusy, U.; Parini, P.; Feinstein, E.; Björkhem, I. Studies on the cholesterol-free mouse, strong activation of LXR-regulated hepatic genes when replacing cholesterol with desmosterol. Arterioscler. Thromb. Vasc. Biol., 2007, 27, 2191-2197.
34. Janowski, B. A.; Grogan, M. J.; Jones, S. A.; Wisely, G. B.; Kliewer, S. A.; Corey, E. J.; Mangelsdorf, D. J. Structural requirements of ligands for the oxysterol liver X receptors LXRalpha and LXRbeta. Proc. Natl. Acad. Sci. USA, 1999, 96, 266-271.
35. Wechsler, A.; Brafman, A.; Shafir, M.; Heverin, M.; Gottlieb, H.; Damari, G.; Gozlan-Kelner, S.; Spivak, I.; Moshkin, O.; Fridman, E.; Becker, Y.; Skaliter, R.; Einat, P.; Faerman, A.; Björkhem, I.; Feinstein, E. Generation of viable cholesterol-free mice. Science, 2003, 302, 2087.
36. FitzPatrick, D. R.; Keeling, J. W.; Evans, M. J.; Kan, A. E.; Bell, J. E.; Porteous, M. E.; Mills, K.; Winter, R. M.; Clayton, P. T. Clinical phenotype of desmosterolosis. Am. J. Med. Genet., 1998, 75,145-152.
37. Koh, C. H.; Cheung, N. S. Cellular mechanism of U18666Amediated apoptosis in cultured murine cortical neurons, bridging Niemann-Pick disease type C and Alzheimer's disease. Cell Signal., 2006, 18,1844-1853.
38. Cenedella, R. J. Cholesterol and cataracts. Surv. Ophthalmol., 1996, 40, 320-337.