FXR activation by obeticholic acid or nonsteroidal agonists induces a human-like lipoprotein cholesterol change in mice with humanized chimeric liver

Journal of Lipid Research

Volumn 59, Issue 6, 2018, Pages 982-993

  Papazyan, Romeo ^a   Liu, Xueqing ^a   Liu, Jingwen ^b   Dong, Bin ^b   Plummer, Emily M ^a   Lewis, Ronald D ^a   Roth, Jonathan D ^a   Young, Mark A ^a  

^a INTERCEPT PHARMACEUTICALS   (United States)

^b VA PALO ALTO HEALTH CARE SYSTEM   (United States)

Author keywords

Atorvastatin; Chimeric mice; Farnesoid X receptor agonist; LDL cholesterol; Nuclear receptor

Indexed keywords

ATORVASTATIN; BILE ACID; CHOLESTEROL; FARNESOID X RECEPTOR; HIGH DENSITY LIPOPROTEIN CHOLESTEROL; LIPID; LIPOPROTEIN; LOW DENSITY LIPOPROTEIN CHOLESTEROL; LOW DENSITY LIPOPROTEIN RECEPTOR; NONSTEROID ANTIINFLAMMATORY AGENT; OBETICHOLIC ACID; PHOSPHOLIPID TRANSFER PROTEIN; SCAVENGER RECEPTOR BI; STEROL REGULATORY ELEMENT BINDING PROTEIN 2; VERY LOW DENSITY LIPOPROTEIN RECEPTOR; CELL RECEPTOR; CHENODEOXYCHOLIC ACID; FARNESOID X-ACTIVATED RECEPTOR; LIPOPROTEIN CHOLESTEROL;

ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; BILE ACID METABOLISM; CHIMERA; CHOLESTEROL LIVER LEVEL; CHOLESTEROL TRANSPORT; CONTROLLED STUDY; ENZYME LINKED IMMUNOSORBENT ASSAY; GENE EXPRESSION; GENE TARGETING; LIPID METABOLISM; LIVER; LIVER CELL; MALE; MOUSE; NONHUMAN; PHENOTYPE; POLYMERASE CHAIN REACTION; PRIORITY JOURNAL; WESTERN BLOTTING; ANALOGS AND DERIVATIVES; ANIMAL; BLOOD; CYTOLOGY; DRUG EFFECT; HUMAN; METABOLISM;

ANIMALS; ATORVASTATIN; CHENODEOXYCHOLIC ACID; CHIMERA; CHOLESTEROL; HUMANS; LIPOPROTEINS; LIVER; MALE; MICE; RECEPTORS, CYTOPLASMIC AND NUCLEAR;

EID: 85048166835     PISSN: 00222275     EISSN: 15397262     Source Type: Journal    
DOI: 10.1194/jlr.M081935     Document Type: Article

References (70)

1. Fuchs, C. D., S. A. Traussnigg, and M. Trauner. 2016. Nuclear Receptor Modulation for the Treatment of Nonalcoholic Fatty Liver Disease. Semin. Liver Dis. 36: 69–86.
2. Rizzo, G., D. Passeri, F. De Franco, G. Ciaccioli, L. Donadio, S. Orlandi, B. Sadeghpour, X. X.. Wang, T. Jiang, M. Levi, et al. 2010. Functional characterization of the semisynthetic bile acid derivative INT-767, a dual farnesoid X receptor and TGR5 agonist. Mol. Pharmacol. 78: 617–630.
3. Nevens, F., P. Andreone, G. Mazzella, S. I. Strasser, C. Bowlus, P. Invernizzi, J. P. Drenth, P. J. Pockros, J. Regula, U. Beuers, et al. 2016. A placebo-controlled trial of obeticholic acid in primary biliary cholangitis. N. Engl. J. Med. 375: 631–643.
4. B. A. Neuschwander-Tetri, R. Loomba, A. J. Sanyal, J. E. Lavine, M. L. Van Natta, M. F. Abdelmalek, N. Chalasani, S. Dasarathy, A. M. Diehl, B. Hameed, et al. 2015. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): A multicentre, randomised, placebo-controlled trial. The Lancet. 385: 956–965.
5. Pellicciari, R., S. Fiorucci, E. Camaioni, C. Clerici, G. Costantino, P. R. Maloney, A. Morelli, D. J. Parks, and T. M. Willson. 2002. 6alpha-ethyl-chenodeoxycholic acid (6-ECDCA), a potent and selective FXR agonist endowed with anticholestatic activity. J. Med. Chem. 45: 3569–3572.
6. Maneschi, E., L. Vignozzi, A. Morelli, T. Mello, S. Filippi, I. Cellai, P. Comeglio, E. Sarchielli, A. Calcagno, B. Mazzanti, et al. 2013. FXR activation normalizes insulin sensitivity in visceral preadipocytes of a rabbit model of MetS. J. Endocrinol. 218: 215–231.
7. Vignozzi, L., S. Filippi, P. Comeglio, I. Cellai, E. Sarchielli, A. Morelli, A. Morelli, A. Morelli, A. Morelli, A. Morelli, et al. 2014. Nonalcoholic steatohepatitis as a novel player in metabolic syndrome-induced erectile dysfunction: an experimental study in the rabbit. Mol. Cell. Endocrinol. 384: 143–154.
8. Dong, B., M. Young, X. Liu, A. B. Singh, and J. Liu. 2017. Regulation of lipid metabolism by obeticholic acid in hyperlipidemic hamsters. J. Lipid Res. 58: 350–363.
9. Xu, Y., F. Li, M. Zalzala, J. Xu, F. J. Gonzalez, L. Adorini, Y. K. Lee, L. Yin, and Y. Zhang. 2016. Farnesoid X receptor activation increases reverse cholesterol transport by modulating bile acid composition and cholesterol absorption in mice. Hepatology. 64: 1072–1085.
10. Pencek, R., T. Marmon, J. D. Roth, A. Liberman, R. Hooshmand-Rad, and M. A. Young. 2016. Effects of obeticholic acid on lipoprotein metabolism in healthy volunteers. Diabetes Obes. Metab. 18: 936–940.
11. Mudaliar, S., R. R. Henry, A. J. Sanyal, L. Morrow, H-U. Marschall, M. Kipnes, L. Adorini, C. I.. Sciacca, P. Clopton, E. Castelloe, et al. 2013. Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease. Gastroenterology. 145: 574-82.e1.
12. Schoenfield, L. J., and J. M. Lachin. 1981. Chenodiol (chenodeoxycholic acid) for dissolution of gallstones: the National Cooperative Gallstone Study. A controlled trial of efficacy and safety. Ann. Intern. Med. 95: 257–282.
13. Nilsson, L. M., A. Abrahamsson, S. Sahlin, U. Gustafsson, B. Angelin, P. Parini, and C. Einarsson. 2007. Bile acids and lipoprotein metabolism: effects of cholestyramine and chenodeoxycholic acid on human hepatic mRNA expression. Biochem. Biophys. Res. Commun. 357: 707–711.
14. Laskar, M. G., M. Eriksson, M. Rudling, and B. Angelin. 2017. Treatment with the natural FXR agonist chenodeoxycholic acid reduces clearance of plasma LDL whilst decreasing circulating PCSK9, lipoprotein(a) and apolipoprotein C–III. J. Intern. Med. 281: 575–585.
15. Mencarelli, A., B. Renga, E. Distrutti, and S. Fiorucci. 2009. Antiatherosclerotic effect of farnesoid X receptor. Am. J. Physiol. Heart Circ. Physiol. 296: H272–H281.
16. Gardés, C., E. Chaput, A. Staempfli, D. Blum, H. Richter, and G. M. Benson. 2013. Differential regulation of bile acid and cholesterol metabolism by the farnesoid X receptor in Ldlr/ mice versus hamsters. J. Lipid Res. 54: 1283–1299.
17. Hartman, H. B., S. J. Gardell, C. J. Petucci, S. Wang, J. A. Krueger, and M. J. Evans. 2009. Activation of farnesoid X receptor prevents atherosclerotic lesion formation in LDLR/ and apoE/ mice. J. Lipid Res. 50: 1090–1100.
18. Evans, M. J., P. E. Mahaney, L. Borges-Marcucci, K. Lai, S. Wang, J. A. Krueger, S. J. Gardell, C. Huard, R. Martinez, G. P. Vlasuk, et al. 2009. A synthetic farnesoid X receptor (FXR) agonist promotes cholesterol lowering in models of dyslipidemia. Am. J. Physiol. Gastrointest. Liver Physiol. 296: G543–G552.
19. Lefebvre, P., B. Cariou, F. Lien, F. Kuipers, and B. Staels. 2009. Role of bile acids and bile acid receptors in metabolic regulation. Physiol. Rev. 89: 147–191.
20. Adorini, L., M. Pruzanski, and D. Shapiro. 2012. Farnesoid X receptor targeting to treat nonalcoholic steatohepatitis. Drug Discov. Today. 17: 988–997.
21. Sinal, C. J., M. Tohkin, M. Miyata, J. M. Ward, G. Lambert, and F. J. Gonzalez. 2000. Targeted disruption of the nuclear receptor FXR/ BAR impairs bile acid and lipid homeostasis. Cell. 102: 731–744.
22. Lambert, G., M. J. Amar, G. Guo, H. B. Brewer, Jr., F. J. Gonzalez, and C. J. Sinal. 2003. The farnesoid X-receptor is an essential regulator of cholesterol homeostasis. J. Biol. Chem. 278: 2563–2570.
23. Hanniman, E. A., G. Lambert, T. C. McCarthy, and C. J. Sinal. 2005. Loss of functional farnesoid X receptor increases atherosclerotic lesions in apolipoprotein E-deficient mice. J. Lipid Res. 46: 2595–2604.
24. Watanabe, M., S. M. Houten, L. Wang, A. Moschetta, D. J. Mangelsdorf, R. A. Heyman, D. D. Moore, and J. Auwerx. 2004. Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c. J. Clin. Invest. 113: 1408–1418.
25. Kast, H. R., C. M. Nguyen, C. J. Sinal, S. A. Jones, B. A. Laffitte, K. Reue, F. J. Gonzalez, T. M. Willson, and P. A. Edwards. 2001. Farnesoid X-activated receptor induces apolipoprotein C–II transcription: a molecular mechanism linking plasma triglyceride levels to bile acids. Mol. Endocrinol. 15: 1720–1728.
26. Sirvent, A., T. Claudel, G. Martin, J. Brozek, V. Kosykh, R. Darteil, D. W. Hum, J. C. Fruchart, and B. Staels. 2004. The farnesoid X receptor induces very low density lipoprotein receptor gene expression. FEBS Lett. 566: 173–177.
27. Li, G., A. M. Thomas, J. A. Williams, B. Kong, J. Liu, Y. Inaba, W. Xie, and G. L. Guo. 2012. Farnesoid X receptor induces murine scavenger receptor class B type I via intron binding. PLoS One. 7: e35895.
28. J. F. de Boer, M. Schonewille, M. Boesjes, H. Wolters, V. W. Bloks, T. Bos, T. H. van Dijk, A. Jurdzinski, R. Boverhof, J. C. Wolters, et al. 2017. Intestinal farnesoid X receptor controls transintestinal cholesterol excretion in mice. Gastroenterology. 152: 1126–1138.
29. Hambruch, E., S. Miyazaki-Anzai, U. Hahn, S. Matysik, A. Boettcher, S. Perovic-Ottstadt, T. Schlüter, O. Kinzel, H. D. Krol, U. Deuschle, et al. 2012. Synthetic farnesoid X receptor agonists induce high-density lipoprotein-mediated transhepatic cholesterol efflux in mice and monkeys and prevent atherosclerosis in cholesteryl ester transfer protein transgenic low-density lipoprotein receptor (/) mice. J. Pharmacol. Exp. Ther. 343: 556–567.
30. de Aguiar Vallim, T. Q., E. J. Tarling, and P. A. Edwards. 2013. Pleiotropic roles of bile acids in metabolism. Cell Metab. 17: 657–669.
31. Miyazaki-Anzai, S., M. Levi, A. Kratzer, T. C. Ting, L. B. Lewis, and M. Miyazaki. 2010. Farnesoid X receptor activation prevents the development of vascular calcification in ApoE/ mice with chronic kidney disease. Circ. Res. 106: 1807–1817.
32. Bilz, S., V. Samuel, K. Morino, D. Savage, C. S. Choi, and G. I. Shulman. 2006. Activation of the farnesoid X receptor improves lipid metabolism in combined hyperlipidemic hamsters. Am. J. Physiol. Endocrinol. Metab. 290: E716–E722.
33. Langhi, C., C. Le May, S. Kourimate, S. Caron, B. Staels, M. Krempf, P. Costet, and B. Cariou. 2008. Activation of the farnesoid X receptor represses PCSK9 expression in human hepatocytes. FEBS Lett. 582: 949–955.
34. Nakahara, M., H. Fujii, P. R. Maloney, M. Shimizu, and R. Sato. 2002. Bile acids enhance low density lipoprotein receptor gene expression via a MAPK cascade-mediated stabilization of mRNA. J. Biol. Chem. 277: 37229–37234.
35. Kawabe, Y., T. Shimokawa, A. Matsumoto, M. Honda, Y. Wada, Y. Yazaki, A. Endo, H. Itakura, and T. Kodama. 1995. The molecular mechanism of the induction of the low density lipoprotein receptor by chenodeoxycholic acid in cultured human cells. Biochem. Biophys. Res. Commun. 208: 405–411.
36. Ellis, E. C., W. E. Naugler, P. Parini, L. M. Mork, C. Jorns, H. Zemack, A. L. Sandblom, I. Björkhem, B. G. Ericzon, E. M. Wilson, et al. 2013. Mice with chimeric livers are an improved model for human lipoprotein metabolism. PLoS One. 8: e78550.
37. National Cholesterol Education Program (NCEP) Expert Panel on Detection E, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). 2002. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 106: 3143–3421.
38. Wiest, R., A. Albillos, M. Trauner, J. Bajaj, and R. Jalan. 2017. Targeting the gut-liver axis in liver disease. J. Hepatol.
39. Verbeke, L., F. Nevens, and W. Laleman. 2017. Steroidal or nonsteroidal FXR agonists—Is that the question? J. Hepatol. 66: 680–681.
40. Djedjos, C. S., B. Kirby, A. Billin, J. Gosink, Q. Song, R. Srihari, K. Grycz, J. Weston, G. Mani Subramanian, W. J. Watkins, et al. 2016. Pharmacodynamic effects of the oral, non-steroidal farnesoid X receptor agonist GS-9674 in healthy volunteers (Abstract). Hepatology . 64: 543a-a.
41. Badman, M. K., S. Desai, B. Laffitte, M. Decristofaro, T. Lin, J. Chen, J. F. Reilly, and L. Klickstein. 2016. First-in-human experience with LJN452, an orally available non-bile acid FXR agonist, demonstrates potent activation of FXR in healthy subjects. Hepatology. 64: 16a–17a.
42. Kinzel, O., C. Steeneck, and C. Kremoser, inventors; Gilead Sciences, Inc., assignee. 2014. Novel fxr (nr1h4) binding and activity modulating compounds. US Patent no. US20140221659A1.
43. Tully, D. C., P. V. Rucker, P. B. Alper, D. Mutnick, and D. Chianelli, inventors; Novartis AG, assignee. 2015. Compositions and methods for modulating FXR. Patent no. US009150568B2.
44. Tully, D. C., P. V. Rucker, D. Chianelli, J. Williams, A. Vidal, P. B. Alper, D. Mutnick, B. Bursulaya, J. Schmeits, X. Wu, et al. 2017. Discovery of tropifexor (LJN452), a highly potent non-bile acid FXR agonist for the treatment of cholestatic liver diseases and nonalcoholic steatohepatitis (NASH). J. Med. Chem. 60: 9960–9973.
45. Tateno, C., Y. Yoshizane, N. Saito, M. Kataoka, R. Utoh, C. Yamasaki, A. Tachibana, Y. Soeno, K. Asahina, H. Hino, et al. 2004. Near completely humanized liver in mice shows human-type metabolic responses to drugs. Am. J. Pathol. 165: 901–912.
46. Tateno, C., Y. Kawase, Y. Tobita, S. Hamamura, H. Ohshita, H. Yokomichi, H. Sanada, M. Kakuni, A. Shiota, Y. Kojima, et al. 2015. Generation of novel chimeric mice with humanized livers by using hemizygous cDNA-uPA/SCID mice. PLoS One. 10: e0142145.
47. Toshima, G., Y. Iwama, F. Kimura, Y. Matsumoto, M. Miura, J. Takahashi, H. Yasuda, N. Arai, H. Mizutani, K. Hata, et al. 2013. LipoSEARCH; analytical GP-HPLC method for lipoprotein profiling and its applications. J Biol Macromol. 13: 21–32.
48. Folch, J., M. Lees, and G. H. Sloane Stanley. 1957. A simple method for the isolation and purification of total lipides from animal tissues. J. Biol. Chem. 226: 497–509.
49. Grompe, M., and S. Strom. 2013. Mice with human livers. Gastroenterology. 145: 1209–1214.
50. Naugler, W. E., B. D. Tarlow, L. M., Fedorov, M. Taylor, C. Pelz, B. Li, J. Darnell, and M. Grompe. 2015. Fibroblast growth factor signaling controls liver size in mice with humanized livers. Gastroenterology. 149: 728–740.
51. Schaap, F. G., N. A. van der Gaag, D. J. Gouma, and P. L. Jansen. 2009. High expression of the bile salt-homeostatic hormone fibroblast growth factor 19 in the liver of patients with extrahepatic cho-lestasis. Hepatology. 49: 1228–1235.
52. Holt, J. A., G. Luo, A. N. Billin, J. Bisi, Y. Y. McNeill, K. F. Kozarsky, M. Donahee, D. Y. Wang, T. A. Mansfield, S. A. Kliewer, et al. 2003. Definition of a novel growth factor-dependent signal cascade for the suppression of bile acid biosynthesis. Genes Dev. 17: 1581–1591.
53. Neuschwander-Tetri B., A. Sanyal, R. Loomba, N. Chalasani, K. Kowdley, M. Abdelmalek, E. Brunt, and D. Shapiro. 2015. Obeticholic acid for NASH: benefits in a high risk subgroup and the effects of concomitant statin use. J. Hepatol. 62(Suppl.): S272.
54. Intercept Pharmaceuticals. 2017. I. CONTROL Trial Shows Statin Therapy Reversed LDL Increases to Below Baseline Levels in NASH Patients Treated with OCA (Press release).
55. Horton, J. D., J. L. Goldstein, and M. S. Brown. 2002. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J. Clin. Invest. 109: 1125–1131.
56. Laffitte, B., K. Young, S. Joseph, B. Lui, D. Bao, Z. Jocelyn, J. Wu, A. Chu, J. Schmeits, R. Valdez, et al. 2016. A novel, highly potent, non-bile acid FXR agonist for the treatment of NASH and cholesta-sis. Hepatol. Int. 10(Suppl 1): S97.
57. Inagaki, T., M. Choi, A. Moschetta, L. Peng, C. L. Cummins, J. G. McDonald, G. Luo, S. A. Jones, B. Goodwin, J. A. Richardson, et al. 2005. Fibroblast growth factor 15 functions as an enterohe-patic signal to regulate bile acid homeostasis. Cell Metab. 2: 217–225.
58. Fu, Z. D., J. Y. Cui, and C. D. Klaassen. 2014. Atorvastatin induces bile acid-synthetic enzyme Cyp7a1 by suppressing FXR signaling in both liver and intestine in mice. J. Lipid Res. 55: 2576–2586.
59. Parker, R. A., R. Garcia, C. S. Ryan, X. Liu, P. Shipkova, V. Livanov, P. Patel, and S. P. Ho. 2013. Bile acid and sterol metabolism with combined HMG-CoA reductase and PCSK9 suppression. J. Lipid Res. 54: 2400–2409.
60. Claudel, T., E. Sturm, H. Duez, I. P. Torra, A. Sirvent, V. Kosykh, J. C. Fruchart, J. Dallongeville, D. W. Hum, F. Kulpers, et al. 2002. Bile acid-activated nuclear receptor FXR suppresses apolipoprotein A-I transcription via a negative FXR response element. J. Clin. Invest. 109: 961–971.
61. Gautier, T., W. de Haan, J. Grober, D. Ye, M. J. Bahr, T. Claudel, N. Nijstad, T. J. Van Berkel, L. M. Havekes, M. P. Manns, et al. 2013. Farnesoid X receptor activation increases cholesteryl ester transfer protein expression in humans and transgenic mice. J. Lipid Res. 54: 2195–2205.
62. Hubbert, M. L., Y. Zhang, F. Y. Lee, and P. A. Edwards. 2007. Regulation of hepatic Insig-2 by the farnesoid X receptor. Mol. Endocrinol. 21: 1359–1369.
63. Briand, F., E. Brousseau, M. Quinsat, R. Burcelin, and T. Sulpice. 2018. Obeticholic acid raises LDL-cholesterol and reduces HDL-cholesterol in the diet-induced NASH (DIN) hamster model. Eur. J. Pharmacol. 818: 449–456.
64. Spady, D. K., E. F. Stange, L. E. Bilhartz, and J. M. Dietschy. 1986. Bile acids regulate hepatic low density lipoprotein receptor activity in the hamster by altering cholesterol flux across the liver. Proc. Natl. Acad. Sci. USA. 83: 1916–1920.
65. Angelin, B., C. A. Raviola, T. L. Innerarity, and R. W. Mahley. 1983. Regulation of hepatic lipoprotein receptors in the dog. Rapid regulation of apolipoprotein B,E receptors, but not of apolipoprotein E receptors, by intestinal lipoproteins and bile acids. J. Clin. Invest. 71: 816–831.
66. Chow, E. C., H. P. Quach, Y. Zhang, J. Z. Wang, D. C. Evans, A. P. Li, J. Silva, R. G. Tirona, Y. Lai, and X. S. Pang. 2017. Disrupted murine gut-to-human liver signaling alters bile acid homeostasis in humanized mouse liver models. J. Pharmacol. Exp. Ther. 360: 174–191.
67. Lorbek, G., M. Lewinska, and D. Rozman. 2012. Cytochrome P450s in the synthesis of cholesterol and bile acids–from mouse models to human diseases. FEBS J. 279: 1516–1533.
68. Liles, J. T., S. Karnik, E. Hambruch, C. Kremoser, M. Birkel, W. J. Watkins, D. Tumas, D. Breckenridge, and D. French. 2016. FXR ag-onism by Gs-9674 decreases steatosis and fibrosis in a murine model of NASH. J. Hepatol. 64(Suppl.): S169.
69. Luo, J., B. Ko, X. Ding, S. Rossi, A. DePaoli A, and H. Tian. 2017. Serum cholesterol changes associated with NGM282 treatment in obese insulin resistant cynomolgus monkeys are reversed with either a statin or a PCSK9 inhibitor. J. Hepatol. 66(Suppl.): S430.
70. Rinella, M. E., J. F. Trotter, G. Neff, G. Ortiz-La-santa, M. F. Abdelmalek, M. Kugelmas, A. H. Paredes, M. A. Connelly, L. Ling, S. J. Rossi, et al. 2017. NGM282 induces low density lipoprotein cholesterol (LDLc) changes, consistent with potent FGFR4 signaling, which are rapidly mitigated with statin therapy in patients with biopsy-confirmed nonalcoholic steatohepatitis (NASH) (Abstract). Hepatology. 66(Suppl.): 1132A.