Selective targeting of nuclear receptor FXR by avermectin analogues with therapeutic effects on nonalcoholic fatty liver disease

Scientific Reports

Volumn 5, Issue , 2015, Pages

  Jin, Lihua ^a   Wang, Rui ^a   Zhu, Yanlin ^a   Zheng, Weili ^a   Han, Yaping ^a   Guo, Fusheng ^a   Ye, Frank Bin ^a   Li, Yong ^a  

^a XIAMEN UNIVERSITY   (China)

Author keywords

[No Author keywords available]

Indexed keywords

AVERMECTIN; CELL RECEPTOR; FARNESOID X-ACTIVATED RECEPTOR; IVERMECTIN;

AGONISTS; ANALOGS AND DERIVATIVES; ANIMAL; DRUG DELIVERY SYSTEM; GENETICS; KNOCKOUT MOUSE; METABOLISM; MOUSE; NONALCOHOLIC FATTY LIVER; PRECLINICAL STUDY; PROCEDURES;

ANIMALS; DRUG DELIVERY SYSTEMS; DRUG EVALUATION, PRECLINICAL; IVERMECTIN; MICE; MICE, KNOCKOUT; NON-ALCOHOLIC FATTY LIVER DISEASE; RECEPTORS, CYTOPLASMIC AND NUCLEAR;

EID: 84949237519     PISSN: None     EISSN: 20452322     Source Type: Journal    
DOI: 10.1038/srep17288     Document Type: Article

References (52)

1. Adams, L. A., Ratziu, V. Non-alcoholic fatty liver-Perhaps not so benign. J. Hepatol. 62, 1002-4 (2015).
2. Ratziu, V. Starting the battle to control non-alcoholic steatohepatitis. Lancet 385, 922-4 (2015).
3. Cohen, J. C., Horton, J. D., Hobbs, H. H. Human fatty liver disease: old questions and new insights. Science 332, 1519-23 (2011).
4. Stine, J. G. et al. Increased risk of Portal Vein Thrombosis in Patients with Cirrhosis due to Non-Alcoholic Steatohepatitis (NASH). Liver Transpl, 21, 1016-21 (2015).
5. Targher, G., Byrne, C. D. Clinical Review: Nonalcoholic fatty liver disease: a novel cardiometabolic risk factor for type 2 diabetes and its complications. J. Clin. Endocrinol. Metab. 98, 483-495 (2013).
6. Byrne, C. D., Targher, G. NAFLD: A multisystem disease. J. Hepatol. 62, S47-S64 (2015).
7. Lefebvre, P., Cariou, B., Lien, F., Kuipers, F., Staels, B. Role of bile acids and bile acid receptors in metabolic regulation. Physiol. Rev. 89, 147-91 (2009).
8. Wang, Y. D., Chen, W. D., Moore, D. D., Huang, W. FXR: a metabolic regulator and cell protector. Cell Res. 18, 1087-95 (2008).
9. Beuers, U., Trauner, M., Jansen, P., Poupon, R. New paradigms in the treatment of hepatic cholestasis: From UDCA to FXR, PXR and beyond. J. Hepatol. 62, S25-S37 (2015).
10. Lefebvre, P., Staels, B. Failing FXR expression in the liver links aging to hepatic steatosis. J. Hepatol. 60, 689-90 (2014).
11. Lu, Y. et al. Yin Yang 1 promotes hepatic steatosis through repression of farnesoid X receptor in obese mice. Gut 63, 170-8 (2014).
12. Yang, Z. X., Shen, W., Sun, H. Effects of nuclear receptor FXR on the regulation of liver lipid metabolism in patients with non-alcoholic fatty liver disease. Hepatol. Int. 4, 741-8 (2010).
13. Xiong, X. et al. Hepatic steatosis exacerbated by endoplasmic reticulum stress-mediated downregulation of FXR in aging mice. J. Hepatol. 60, 847-54 (2014).
14. Sinal, C. J. et al. Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis. Cell 102, 731-44 (2000).
15. Zhang, Y. et al. Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice. Proc. Natl. Acad. Sci. USA 103, 1006-11 (2006).
16. Cipriani, S., Mencarelli, A., Palladino, G., Fiorucci, S. FXR activation reverses insulin resistance and lipid abnormalities and protects against liver steatosis in Zucker (fa/fa) obese rats. J. Lipid. Res. 51, 771-84 (2010).
17. Ma, Y., Huang, Y., Yan, L., Gao, M., Liu, D. Synthetic FXR agonist GW4064 prevents diet-induced hepatic steatosis and insulin resistance. Pharm. Res. 30, 1447-57 (2013).
18. Ge, X. et al. Aldo-keto reductase 1B7 is a target gene of FXR and regulates lipid and glucose homeostasis. J. Lipid Res. 52, 1561-8 (2011).
19. Watanabe, M. et al. Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c. J. Clin. Invest. 113, 1408-18 (2004).
20. Cariou, B. et al. The farnesoid X receptor modulates adiposity and peripheral insulin sensitivity in mice. J. Biol. Chem. 281, 11039-49 (2006).
21. Xing, X. et al. Hematopoietically expressed homeobox is a target gene of farnesoid X receptor in chenodeoxycholic acid-induced liver hypertrophy. Hepatology 49, 979-88 (2009).
22. Watanabe, M. et al. Lowering bile acid pool size with a synthetic farnesoid X receptor (FXR) agonist induces obesity and diabetes through reduced energy expenditure. J. Biol. Chem. 286, 26913-20 (2011).
23. Howarth, D. L. et al. Exposure to the synthetic FXR agonist GW4064 causes alterations in gene expression and sublethal hepatotoxicity in eleutheroembryo medaka (Oryziaslatipes). Toxicol. Appl. Pharmacol. 243, 111-21 (2010).
24. Campbell, W. C., Fisher, M. H., Stapley, E. O., Albers-Schönberg, G., Jacob, T. A. Ivermectin: a potent new antiparasitic agent. Science 221, 823-8 (1983).
25. Pitterna, T. et al. New ventures in the chemistry of avermectins. Bioorg. Med. Chem. 17, 4085-95 (2009).
26. Lynagh, T., Lynch, J. W. Ivermectin binding sites in human and invertebrate Cys-loop receptors. Trends Pharmacol. Sci. 33, 432-41 (2012).
27. Prichard, R., Ménez, C., Lespine, A. Moxidectin and the avermectins: Consanguinity but not identity. Int. J. Parasitol. Drugs Drug Resist. 2, 134-53 (2012).
28. Jin, L. et al. The antiparasitic drug ivermectin is a novel FXR ligand that regulates metabolism. Nat. Commun. 4, 1937 (2013).
29. Koo, S. H. Nonalcoholic fatty liver disease: molecular mechanisms for the hepatic steatosis. Clin. Mol. Hepatol. 19, 210-5 (2013).
30. Arner, P., Langin, D. Lipolysis in lipid turnover, cancer cachexia, and obesity-induced insulin resistance. Trends Endocrinol. Metab. 25, 255-62 (2014).
31. Asrih, M., Jornayvaz, F. R. Metabolic syndrome and nonalcoholic fatty liver disease: Is insulin resistance the link Mol. Cell Endocrinol, doi: 10.1016/j.mce.2015.02.018 (2015).
32. Horton, J. D., Goldstein, J. L., Brown, M. S. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J. Clin. Invest. 109, 1125-1131 (2002).
33. Shimomura, I., Bashmakov, Y., Horton, J. D. Increased levels of nuclear SREBP-1c associated with fatty livers in two mouse models of diabetes mellitus. J. Biol. Chem. 274, 30028-30032 (1999).
34. Yang, J. et al. Decreased lipid synthesis in livers of mice with disrupted Site-1 protease gene. Proc. Natl. Acad. Sci. USA 98, 13607-13612 (2001).
35. Chen, W. D. et al. Farnesoid X receptor alleviates age-related proliferation defects in regenerating mouse livers by activating forkhead box m1b transcription. Hepatology 51, 953-62 (2010).
36. Fang, S. et al. Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance. Nat. Med. 21, 159-65 (2015).
37. Li, Y., Lambert, M. H., Xu, H. E. Activation of nuclear receptors: a perspective from structural genomics. Structure 11, 741-6 (2003).
38. Sim, W. C. et al. LXR-antagonist meso-dihydroguaiaretic acid attenuates high-fat diet-induced nonalcoholic fatty liver. Biochem Pharmacol. 90, 414-24 (2014).
39. Jin, L., Li, Y. Structural and functional insights into nuclear receptor signaling. Adv. Drug Deliv. Rev. 62, 1218-26 (2010).
40. Chang, C. et al. Dissection of the LXXLL nuclear receptor-coactivator interaction motif using combinatorial peptide libraries: discovery of peptide antagonists of estrogen receptors alpha and beta. Mol. Cell Biol. 19, 8226-39 (1999).
41. Iannone, M. A. et al. Correlation between in vitro peptide binding profiles and cellular activities for estrogen receptor-modulating compounds. Mol. Endocrinol. 18, 1064-81 (2004).
42. Cully, D. F. et al. Cloning of an avermectin-sensitive glutamate-gated chloride channel from Caenorhabditis elegans. Nature 371, 707-11 (1994).
43. Kane, N. S. et al. Drug-resistant Drosophila indicate glutamate-gated chloride channels are targets for the antiparasitics nodulisporic acid and ivermectin. Proc. Natl. Acad. Sci. USA 97, 13949-54 (2000).
44. Han, S., Li, T., Ellis, E., Strom, S., Chiang, J. Y. A novel bile acid-activated vitamin D receptor signaling in human hepatocytes. Mol. Endocrinol. 24, 1151-64 (2010).
45. Wang, Q. et al. Equilibrium interactions of corepressors and coactivators with agonist and antagonist complexes of glucocorticoid receptors. Mol. Endocrinol. 18, 1376-95 (2004).
46. Gronemeyer, H., Gustafsson, J. A., Laudet, V. Principles for modulation of the nuclear receptor superfamily. Nat. Rev. Drug Discov. 3, 950-64 (2004)
47. Maloney, P. R. et al. Identification of a chemical tool for the orphan nuclear receptor FXR. J. Med. Chem. 43, 2971-4 (2000).
48. Gege, C., Kinzel, O., Steeneck, C., Schulz, A., Kremoser, C. Knocking on FXR's door: the "hammerhead"-structure series of FXR agonists-amphiphilic isoxazoles with potent in vitro and in vivo activities. Curr. Top Med. Chem. 14, 2143-58 (2014).
49. Akwabi-Ameyaw, A. et al. FXR agonist activity of conformationally constrained analogs of GW 4064. Bioorg. Med. Chem. Lett. 19, 4733-9 (2009).
50. Lloberas, M. et al. Comparative pharmacokinetic and pharmacodynamic response of single and double intraruminal doses of ivermectin and moxidectin in nematode-infected lambs. N. Z. Vet. J. 63, 227-34 (2015)
51. Long, Q., Ren, B., Li, S., Zeng G. Human pharmacokinetics of orally taking ivermectin. Chin. J. Clin. Pharmacol. 17, 203-6 (2001).
52. Trott, O., Olson, A. J. AutoDockVina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem. 31, 455-61 (2010).