Functional and Structural Features of Cholangiocytes in Health and Disease

Cellular and Molecular Gastroenterology and Hepatology

Volumn 1, Issue 4, 2015, Pages 368-380

  Maroni, Luca ^a   Haibo, Bai ^b   Ray, Debolina ^c   Zhou, Tianhao ^c   Wan, Ying ^b   Meng, Fanyin ^b,c,d   Marzioni, Marco ^a   Alpini, Gianfranco ^b,c,d  

^a UNIVERSITÀ POLITECNICA DELLE MARCHE   (Italy)

^b SCOTT AND WHITE MEMORIAL HOSPITAL   (United States)

^c TEXAS A AND M HEALTH SCIENCE CENTER   (United States)

^d VETERANS AFFAIRS MEDICAL CENTER   (United States)

Author keywords

Biliary epithelium; Primary biliary cirrhosis; Primary sclerosing cholangitis

Indexed keywords

HIPPO PROTEIN; MONOCLONAL ANTIBODY; NORURSODEOXYCHOLIC ACID; NOTCH RECEPTOR; OBETICHOLIC ACID; PROTEIN; SONIC HEDGEHOG PROTEIN; UNCLASSIFIED DRUG; URSODEOXYCHOLIC ACID;

BILE DUCT; BILE DUCT DISEASE; BILE DUCT INJURY; CELL FUNCTION; CELL STRUCTURE; CHOLANGIOCYTE; CLINICAL RESEARCH; EPITHELIUM CELL; HUMAN; LIVER CIRCULATION; MORPHOGENESIS; NEUROENDOCRINOLOGY; NONHUMAN; PATHOPHYSIOLOGY; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PRIMARY SCLEROSING CHOLANGITIS; PRIORITY JOURNAL; REVIEW; SIGNAL TRANSDUCTION;

EID: 84937735169     PISSN: None     EISSN: 2352345X     Source Type: Journal    
DOI: 10.1016/j.jcmgh.2015.05.005     Document Type: Review

References (141)

1. Nathanson M.H., Boyer J.L. Mechanisms and regulation of bile secretion. Hepatology 1991, 14:551-566.
2. Cardinale V., Wang Y., Carpino G., et al. The biliary tree-a reservoir of multipotent stem cells. Nat Rev Gastroenterol Hepatol 2012, 9:231-240.
3. Alpini G., Lenzi R., Sarkozi L., et al. Biliary physiology in rats with bile ductular cell hyperplasia. Evidence for a secretory function of proliferated bile ductules. J Clin Invest 1988, 81:569-578.
4. Franchitto A., Onori P., Renzi A., et al. Recent advances on the mechanisms regulating cholangiocyte proliferation and the significance of the neuroendocrine regulation of cholangiocyte pathophysiology. Ann Transl Med 2013, 1:27.
5. Afroze S., Meng F., Jensen K., et al. The physiological roles of secretin and its receptor. Ann Transl Med 2013, 1:29.
6. Trauner M., Boyer J.L. Bile salt transporters: molecular characterization, function, and regulation. Physiol Rev 2003, 83:633-671.
7. Lazaridis K.N., Strazzabosco M., Larusso N.F. The cholangiopathies: disorders of biliary epithelia. Gastroenterology 2004, 127:1565-1577.
8. Alpini G., Prall R.T., LaRusso N.F. The pathobiology of biliary epithelia. The liver: biology and pathobiology 2001, 421-435. Lippincott Williams & Wilkins, Philadelphia. 4th ed. I.M. Arias, J.L. Boyer, F.V. Chisari (Eds.).
9. Schaffner F., Popper H. Electron microscopic studies of normal and proliferated bile ductules. Am J Pathol 1961, 38:393-410.
10. Ludwig J. New concepts in biliary cirrhosis. Semin Liver Dis 1987, 7:293-301.
11. Sasaki H., Schaffner F., Popper H. Bile ductules in cholestasis: morphologic evidence for secretion and absorption in man. Lab Invest 1967, 16:84-95.
12. Alpini G., Roberts S., Kuntz S.M., et al. Morphological, molecular, and functional heterogeneity of cholangiocytes from normal rat liver. Gastroenterology 1996, 110:1636-1643.
13. Glaser S., Gaudio E., Rao A., et al. Morphological and functional heterogeneity of the mouse intrahepatic biliary epithelium. Lab Invest 2009, 89:456-469.
14. Alpini G., Glaser S., Robertson W., et al. Large but not small intrahepatic bile ducts are involved in secretin-regulated ductal bile secretion. Am J Physiol Gastrointest Liver Physiol 1997, 272:G1064-G1074.
15. LeSage G., Glaser S., Marucci L., et al. Acute carbon tetrachloride feeding induces damage of large but not small cholangiocytes from BDL rat liver. Am J Physiol 1999, 276:G1289-G1301.
16. Benedetti A., Bassotti C., Rapino K., et al. A morphometric study of the epithelium lining the rat intrahepatic biliary tree. J Hepatol 1996, 24:335-342.
17. Masyuk A.I., Masyuk T.V., LaRusso N.F. Cholangiocyte primary cilia in liver health and disease. Dev Dyn 2008, 237:2007-2012.
18. Woo K., Sathe M., Kresge C., et al. Adenosine triphosphate release and purinergic (P2) receptor-mediated secretion in small and large mouse cholangiocytes. Hepatology 2010, 52:1819-1828.
19. - channel activated by extracellular nucleotides, in biliary epithelium. J Biol Chem 2011, 286:766-776.
20. Mancinelli R., Franchitto A., Gaudio E., et al. After damage of large bile ducts by gamma-aminobutyric acid, small ducts replenish the biliary tree by amplification of calcium-dependent signaling and de novo acquisition of large cholangiocyte phenotypes. Am J Pathol 2010, 176:1790-1800.
21. 2+/CaMK I-dependent adenylyl cyclase 8. Hepatology 2013, 58:251-263.
22. Francis H., Glaser S., DeMorrow S., et al. Small mouse cholangiocytes proliferate in response to H1 histamine receptor stimulation by activation of the IP3/CaMK I/CREB pathway. Am J Physiol Cell Physiol 2008, 295:C499-C513.
23. Alvaro D., Mancino M.G., Glaser S., et al. Proliferating cholangiocytes: a neuroendocrine compartment in the diseased liver. Gastroenterology 2007, 132:415-431.
24. Renzi A., Glaser S., DeMorrow S., et al. Melatonin inhibits cholangiocyte hyperplasia in cholestatic rats by interaction with MT1 but not MT2 melatonin receptors. Am J Physiol Gastrointest Liver Physiol 2011, 301:G634-G643.
25. - umbrella: a unifying hypothesis on pathogenetic and therapeutic aspects of fibrosing cholangiopathies. Hepatology 2010, 52:1489-1496.
26. Yamaguti D.C., Patricio F.R. Morphometrical and immunohistochemical study of intrahepatic bile ducts in biliary atresia. Eur J Gastroenterol Hepatol 2011, 23:759-765.
27. Kumagi T., Guindi M., Fischer S.E., et al. Baseline ductopenia and treatment response predict long-term histological progression in primary biliary cirrhosis. Am J Gastroenterol 2010, 105:2186-2194.
28. Gaudio E., Barbaro B., Alvaro D., et al. Administration of r-VEGF-A prevents hepatic artery ligation-induced bile duct damage in bile duct ligated rats. Am J Physiol Gastrointest Liver Physiol 2006, 291:G307-G317.
29. Gaudio E., Barbaro B., Alvaro D., et al. Vascular endothelial growth factor stimulates rat cholangiocyte proliferation via an autocrine mechanism. Gastroenterology 2006, 130:1270-1282.
30. Glaser S., Gaudio E., Alpini G. Vascular factors, angiogenesis and biliary tract disease. Curr Opin Gastroenterol 2010, 26:246-250.
31. Gaudio E., Onori P., Pannarale L., et al. Hepatic microcirculation and peribiliary plexus in experimental biliary cirrhosis: a morphological study. Gastroenterology 1996, 111:1118-1124.
32. Poupon R. Liver alkaline phosphatase: a missing link between choleresis and biliary inflammation. Hepatology 2015, 61:2080-2090.
33. Padda M.S., Sanchez M., Akhtar A.J., et al. Drug-induced cholestasis. Hepatology 2011, 53:1377-1387.
34. Azmaiparashvili E., Berishvili E., Kakabadze Z., et al. Ductular reaction at the early terms of common bile duct ligation in the rats. Acta Biol Hung 2012, 63:321-332.
35. Cardinale V., Wang Y., Carpino G., et al. Multipotent stem/progenitor cells in human biliary tree give rise to hepatocytes, cholangiocytes, and pancreatic islets. Hepatology 2011, 54:2159-2172.
36. Lesage G., Glaser S.S., Gubba S., et al. Regrowth of the rat biliary tree after 70% partial hepatectomy is coupled to increased secretin-induced ductal secretion. Gastroenterology 1996, 111:1633-1644.
37. Glaser S., Meng F., Han Y., et al. Secretin stimulates biliary cell proliferation by regulating expression of microRNA 125b and microRNA let7a in mice. Gastroenterology 2014, 146:1795-1808.e12.
38. Glaser S., Lam I.P., Franchitto A., et al. Knockout of secretin receptor reduces large cholangiocyte hyperplasia in mice with extrahepatic cholestasis induced by bile duct ligation. Hepatology 2010, 52:204-214.
39. Meng F., Onori P., Hargrove L., et al. Regulation of the histamine/VEGF axis by miR-125b during cholestatic liver injury in mice. Am J Pathol 2014, 184:662-673.
40. Ren X.S., Sato Y., Harada K., et al. Biliary infection may exacerbate biliary cystogenesis through the induction of VEGF in cholangiocytes of the polycystic kidney (PCK) rat. Am J Pathol 2011, 179:2845-2854.
41. Glaser S., Onori P., Gaudio E., et al. Taurocholic acid prevents biliary damage induced by hepatic artery ligation in cholestatic rats. Dig Liver Dis 2010, 42:709-717.
42. Mancinelli R., Onori P., Gaudio E., et al. Taurocholate feeding to bile duct ligated rats prevents caffeic acid-induced bile duct damage by changes in cholangiocyte VEGF expression. Exp Biol Med (Maywood) 2009, 234:462-474.
43. Marzioni M., Saccomanno S., Candelaresi C., et al. Pancreatic Duodenal Homeobox-1 de novo expression drives cholangiocyte neuroendocrine-like transdifferentiation. J Hepatol 2010, 53:663-670.
44. Fabris L., Cadamuro M., Libbrecht L., et al. Epithelial expression of angiogenic growth factors modulate arterial vasculogenesis in human liver development. Hepatology 2008, 47:719-728.
45. Mancinelli R., Onori P., Gaudio E., et al. Follicle-stimulating hormone increases cholangiocyte proliferation by an autocrine mechanism via cAMP-dependent phosphorylation of ERK1/2 and Elk-1. Am J Physiol Gastrointest Liver Physiol 2009, 297:G11-G26.
46. Jensen K., Marzioni M., Munshi K., et al. Autocrine regulation of biliary pathology by activated cholangiocytes. Am J Physiol Gastrointest Liver Physiol 2012, 302:G473-G483.
47. 2+ and cAMP-dependent signaling mechanisms. Lab Invest 2012, 92:282-294.
48. Gigliozzi A., Alpini G., Baroni G.S., et al. Nerve growth factor modulates the proliferative capacity of the intrahepatic biliary epithelium in experimental cholestasis. Gastroenterology 2004, 127:1198-1209.
49. Alvaro D., Alpini G., Onori P., et al. Effect of ovariectomy on the proliferative capacity of intrahepatic rat cholangiocytes. Gastroenterology 2002, 123:336-344.
50. Svegliati-Baroni G., Ghiselli R., Marzioni M., et al. Estrogens maintain bile duct mass and reduce apoptosis after biliodigestive anastomosis in bile duct ligated rats. J Hepatol 2006, 44:1158-1166.
51. Ray D., Han Y., Franchitto A., et al. Gonadotropin-releasing hormone stimulates biliary proliferation by paracrine/autocrine mechanisms. Am J Pathol 2015, 185:1061-1072.
52. Marzioni M., Glaser S., Francis H., et al. Autocrine/paracrine regulation of the growth of the biliary tree by the neuroendocrine hormone serotonin. Gastroenterology 2005, 128:121-137.
53. Omenetti A., Yang L., Gainetdinov R.R., et al. Paracrine modulation of cholangiocyte serotonin synthesis orchestrates biliary remodeling in adults. Am J Physiol Gastrointest Liver Physiol 2011, 300:G303-G315.
54. Han Y., Onori P., Meng F., et al. Prolonged exposure of cholestatic rats to complete dark inhibits biliary hyperplasia and liver fibrosis. Am J Physiol Gastrointest Liver Physiol 2014, 307:G894-G904.
55. Renzi A., DeMorrow S., Onori P., et al. Modulation of the biliary expression of arylalkylamine N-acetyltransferase alters the autocrine proliferative responses of cholangiocytes in rats. Hepatology 2013, 57:1130-1141.
56. Renzi A., Mancinelli R., Onori P., et al. Inhibition of the liver expression of arylalkylamine N-acetyltransferase increases the expression of angiogenic factors in cholangiocytes. Hepatobiliary Surg Nutr 2014, 3:4-10.
57. Francis H., Franchitto A., Ueno Y., et al. H3 histamine receptor agonist inhibits biliary growth of BDL rats by downregulation of the cAMP-dependent PKA/ERK1/2/ELK-1 pathway. Lab Invest 2007, 87:473-487.
58. Francis H., Meng F., Gaudio E., et al. Histamine regulation of biliary proliferation. J Hepatol 2012, 56:1204-1206.
59. Francis H., DeMorrow S., Venter J., et al. Inhibition of histidine decarboxylase ablates the autocrine tumorigenic effects of histamine in human cholangiocarcinoma. Gut 2012, 61:753-764.
60. Yu F.X., Meng Z., Plouffe S.W., et al. Hippo pathway regulation of gastrointestinal tissues. Annu Rev Physiol 2015, 77:201-227.
61. Yin F., Yu J., Zheng Y., et al. Spatial organization of Hippo signaling at the plasma membrane mediated by the tumor suppressor Merlin/NF2. Cell 2013, 154:1342-1355.
62. Yimlamai D., Christodoulou C., Galli G.G., et al. Hippo pathway activity influences liver cell fate. Cell 2014, 157:1324-1338.
63. Bai H., Gayyed M.F., Lam-Himlin D.M., et al. Expression of Yes-associated protein modulates Survivin expression in primary liver malignancies. Hum Pathol 2012, 43:1376-1385.
64. Zhang N., Bai H., David K.K., et al. The Merlin/NF2 tumor suppressor functions through the YAP oncoprotein to regulate tissue homeostasis in mammals. Dev Cell 2010, 19:27-38.
65. Fitamant J., Kottakis F., Benhamouche S., et al. YAP inhibition restores hepatocyte differentiation in advanced HCC, leading to tumor regression. Cell Rep 2015, Published online. http://dx/doi.org/10.1016/j.celrep.2015.02.027.
66. Morell C.M., Fiorotto R., Fabris L., et al. Notch signalling beyond liver development: emerging concepts in liver repair and oncogenesis. Clin Res Hepatol Gastroenterol 2013, 37:447-454.
67. Geisler F., Nagl F., Mazur P.K., et al. Liver-specific inactivation of Notch2, but not Notch1, compromises intrahepatic bile duct development in mice. Hepatology 2008, 48:607-616.
68. Fiorotto R., Raizner A., Morell C.M., et al. Notch signaling regulates tubular morphogenesis during repair from biliary damage in mice. J Hepatol 2013, 59:124-130.
69. Lozier J., McCright B., Gridley T. Notch signaling regulates bile duct morphogenesis in mice. PLoS One 2008, 3:e1851.
70. Hofmann J.J., Zovein A.C., Koh H., et al. Jagged1 in the portal vein mesenchyme regulates intrahepatic bile duct development: insights into Alagille syndrome. Development 2010, 137:4061-4072.
71. Loomes K.M., Russo P., Ryan M., et al. Bile duct proliferation in liver-specific Jag1 conditional knockout mice: effects of gene dosage. Hepatology 2007, 45:323-330.
72. Sparks E.E., Huppert K.A., Brown M.A., et al. Notch signaling regulates formation of the three-dimensional architecture of intrahepatic bile ducts in mice. Hepatology 2010, 51:1391-1400.
73. Zong Y., Panikkar A., Xu J., et al. Notch signaling controls liver development by regulating biliary differentiation. Development 2009, 136:1727-1739.
74. Kodama Y., Hijikata M., Kageyama R., et al. The role of notch signaling in the development of intrahepatic bile ducts. Gastroenterology 2004, 127:1775-1786.
75. Antoniou A., Raynaud P., Cordi S., et al. Intrahepatic bile ducts develop according to a new mode of tubulogenesis regulated by the transcription factor SOX9. Gastroenterology 2009, 136:2325-2333.
76. Coffinier C., Gresh L., Fiette L., et al. Bile system morphogenesis defects and liver dysfunction upon targeted deletion of HNF1β. Development 2002, 129:1829-1838.
77. Jeliazkova P., Jors S., Lee M., et al. Canonical Notch2 signaling determines biliary cell fates of embryonic hepatoblasts and adult hepatocytes independent of Hes1. Hepatology 2013, 57:2469-2479.
78. Tchorz J.S., Kinter J., Muller M., et al. Notch2 signaling promotes biliary epithelial cell fate specification and tubulogenesis during bile duct development in mice. Hepatology 2009, 50:871-879.
79. Omenetti A., Diehl A.M. Hedgehog signaling in cholangiocytes. Curr Opin Gastroenterol 2011, 27:268-275.
80. Omenetti A., Yang L., Li Y.X., et al. Hedgehog-mediated mesenchymal-epithelial interactions modulate hepatic response to bile duct ligation. Lab Invest 2007, 87:499-514.
81. Omenetti A., Porrello A., Jung Y., et al. Hedgehog signaling regulates epithelial-mesenchymal transition during biliary fibrosis in rodents and humans. J Clin Invest 2008, 118:3331-3342.
82. Omenetti A., Popov Y., Jung Y., et al. The hedgehog pathway regulates remodelling responses to biliary obstruction in rats. Gut 2008, 57:1275-1282.
83. -/- mice spontaneously develop severe biliary fibrosis via massive dysregulation of pro- and antifibrogenic genes. J Hepatol 2005, 43:1045-1054.
84. Fickert P., Fuchsbichler A., Wagner M., et al. Regurgitation of bile acids from leaky bile ducts causes sclerosing cholangitis in Mdr2 (Abcb4) knockout mice. Gastroenterology 2004, 127:261-274.
85. Fickert P., Wagner M., Marschall H.U., et al. 24-norUrsodeoxycholic acid is superior to ursodeoxycholic acid in the treatment of sclerosing cholangitis in Mdr2 (Abcb4) knockout mice. Gastroenterology 2006, 130:465-481.
86. Tabibian J.H., Trussoni C.E., O'Hara S.P., et al. Characterization of cultured cholangiocytes isolated from livers of patients with primary sclerosing cholangitis. Lab Invest 2014, 94:1126-1133.
87. Folseraas T., Liaskou E., Anderson C.A., et al. Genetics in PSC: what do the "risk genes" teach us?. Clin Rev Allergy Immunol 2015, 48:154-164.
88. Karlsen T.H., Franke A., Melum E., et al. Genome-wide association analysis in primary sclerosing cholangitis. Gastroenterology 2010, 138:1102-1111.
89. Duboc H., Tache Y., Hofmann A.F. The bile acid TGR5 membrane receptor: from basic research to clinical application. Dig Liver Dis 2014, 46:302-312.
90. Hov J.R., Keitel V., Laerdahl J.K., et al. Mutational characterization of the bile acid receptor TGR5 in primary sclerosing cholangitis. PLoS One 2010, 5:e12403.
91. Keitel V., Haussinger D. TGR5 in the biliary tree. Dig Dis 2011, 29:45-47.
92. Dyson J.K., Hirschfield G.M., Adams D.H., et al. Novel therapeutic targets in primary biliary cirrhosis. Nat Rev Gastroenterol Hepatol 2015, 12:147-158.
93. + memory B cells in primary biliary cirrhosis. Gastroenterology 2005, 128:304-312.
94. Moritoki Y., Lian Z.X., Wulff H., et al. AMA production in primary biliary cirrhosis is promoted by the TLR9 ligand CpG and suppressed by potassium channel blockers. Hepatology 2007, 45:314-322.
95. Manousou P., Kolios G., Drygiannakis I., et al. CXCR3 axis in patients with primary biliary cirrhosis: a possible novel mechanism of the effect of ursodeoxycholic acid. Clin Exp Immunol 2013, 172:9-15.
96. Irie J., Wu Y., Wicker L.S., et al. NOD.c3c4 congenic mice develop autoimmune biliary disease that serologically and pathogenetically models human primary biliary cirrhosis. J Exp Med 2006, 203:1209-1219.
97. Oertelt S., Lian Z.X., Cheng C.M., et al. Anti-mitochondrial antibodies and primary biliary cirrhosis in TGF-β receptor II dominant-negative mice. J Immunol 2006, 177:1655-1660.
98. -/- mice and the development of primary biliary cirrhosis. Hepatology 2006, 44:1240-1249.
99. Jones D.E. Pathogenesis of primary biliary cirrhosis. Gut 2007, 56:1615-1624.
100. Dhirapong A., Yang G.X., Nadler S., et al. Therapeutic effect of cytotoxic T lymphocyte antigen 4/immunoglobulin on a murine model of primary biliary cirrhosis. Hepatology 2013, 57:708-715.
101. + regulatory T cells. Clin Exp Immunol 2014, 178:253-261.
102. Myers R.P., Swain M.G., Lee S.S., et al. B-cell depletion with rituximab in patients with primary biliary cirrhosis refractory to ursodeoxycholic acid. Am J Gastroenterol 2013, 108:933-941.
103. Coots A., Donnelly B., Mohanty S.K., et al. Rotavirus infection of human cholangiocytes parallels the murine model of biliary atresia. J Surg Res 2012, 177:275-281.
104. Tyler K.L., Sokol R.J., Oberhaus S.M., et al. Detection of reovirus RNA in hepatobiliary tissues from patients with extrahepatic biliary atresia and choledochal cysts. Hepatology 1998, 27:1475-1482.
105. Drut R., Drut R.M., Gomez M.A., et al. Presence of human papillomavirus in extrahepatic biliary atresia. J Pediatr Gastroenterol Nutr 1998, 27:530-535.
106. Fischler B., Woxenius S., Nemeth A., et al. Immunoglobulin deposits in liver tissue from infants with biliary atresia and the correlation to cytomegalovirus infection. J Pediatr Surg 2005, 40:541-546.
107. Karjoo S., Hand N.J., Loarca L., et al. Extrahepatic cholangiocyte cilia are abnormal in biliary atresia. J Pediatr Gastroenterol Nutr 2013, 57:96-101.
108. Chu A.S., Russo P.A., Wells R.G. Cholangiocyte cilia are abnormal in syndromic and non-syndromic biliary atresia. Mod Pathol 2012, 25:751-757.
109. Jafri M., Donnelly B., Bondoc A., et al. Cholangiocyte secretion of chemokines in experimental biliary atresia. J Pediatr Surg 2009, 44:500-507.
110. Li J., Razumilava N., Gores G.J., et al. Biliary repair and carcinogenesis are mediated by IL-33-dependent cholangiocyte proliferation. J Clin Invest 2014, 124:3241-3251.
111. Shivakumar P., Mourya R., Bezerra J.A. Perforin and granzymes work in synergy to mediate cholangiocyte injury in experimental biliary atresia. J Hepatol 2014, 60:370-376.
112. Finch M.L., Marquardt J.U., Yeoh G.C., et al. Regulation of microRNAs and their role in liver development, regeneration and disease. Int J Biochem Cell Biol 2014, 54:288-303.
113. Marquez R.T., Wendlandt E., Galle C.S., et al. MicroRNA-21 is upregulated during the proliferative phase of liver regeneration, targets Pellino-1, and inhibits NF-κB signaling. Am J Physiol Gastrointest Liver Physiol 2010, 298:G535-G541.
114. Bessho K., Shanmukhappa K., Sheridan R., et al. Integrative genomics identifies candidate microRNAs for pathogenesis of experimental biliary atresia. BMC Syst Biol 2013, 7:104.
115. Carrion A.F., Bhamidimarri K.R. Liver transplant for cholestatic liver diseases. Clin Liver Dis 2013, 17:345-359.
116. Griffiths L., Jones D.E. Pathogenesis of primary biliary cirrhosis and its fatigue. Dig Dis 2014, 32:615-625.
117. Beuers U., Kremer A.E., Bolier R., et al. Pruritus in cholestasis: facts and fiction. Hepatology 2014, 60:399-407.
118. Roma M.G., Toledo F.D., Boaglio A.C., et al. Ursodeoxycholic acid in cholestasis: linking action mechanisms to therapeutic applications. Clin Sci (Lond) 2011, 121:523-544.
119. Beuers U. Drug insight: Mechanisms and sites of action of ursodeoxycholic acid in cholestasis. Nat Clin Pract Gastroenterol Hepatol 2006, 3:318-328.
120. Poupon R.E., Lindor K.D., Cauch-Dudek K., et al. Combined analysis of randomized controlled trials of ursodeoxycholic acid in primary biliary cirrhosis. Gastroenterology 1997, 113:884-890.
121. Lindor K.D., Therneau T.M., Jorgensen R.A., et al. Effects of ursodeoxycholic acid on survival in patients with primary biliary cirrhosis. Gastroenterology 1996, 110:1515-1518.
122. Corpechot C., Carrat F., Bahr A., et al. The effect of ursodeoxycholic acid therapy on the natural course of primary biliary cirrhosis. Gastroenterology 2005, 128:297-303.
123. ter Borg P.C., Schalm S.W., Hansen B.E., et al. Prognosis of ursodeoxycholic acid-treated patients with primary biliary cirrhosis. Results of a 10-yr cohort study involving 297 patients. Am J Gastroenterol 2006, 101:2044-2050.
124. Corpechot C., Abenavoli L., Rabahi N., et al. Biochemical response to ursodeoxycholic acid and long-term prognosis in primary biliary cirrhosis. Hepatology 2008, 48:871-877.
125. Lindor K.D., Kowdley K.V., Luketic V.A., et al. High-dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis. Hepatology 2009, 50:808-814.
126. EASL Clinical practice guidelines: management of cholestatic liver diseases. J Hepatol 2009, 51:237-267. European Association for the Study of the Liver.
127. Pellicciari R., Fiorucci S., Camaioni E., et al. 6α-ethyl-chenodeoxycholic acid (6-ECDCA), a potent and selective FXR agonist endowed with anticholestatic activity. J Med Chem 2002, 45:3569-3572.
128. Sinal C.J., Tohkin M., Miyata M., et al. Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis. Cell 2000, 102:731-744.
129. Hirschfield G.M., Mason A., Luketic V., et al. Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid. Gastroenterology 2015, 148:751-761.e8.
130. Nevens F., Andreone P., Mazzella G., et al. O168 The first primary biliary cirrhosis (PBC) phase 3 trial in two decades-an international study of the FXR agonist obeticholic acid in PBC patients. J Hepatol 2014, 60(Suppl):S525-S526.
131. Cohen B.I., Hofmann A.F., Mosbach E.H., et al. Differing effects of nor-ursodeoxycholic or ursodeoxycholic acid on hepatic histology and bile acid metabolism in the rabbit. Gastroenterology 1986, 91:189-197.
132. Hohenester S., Wenniger L.M., Paulusma C.C., et al. A biliary HCO3- umbrella constitutes a protective mechanism against bile acid-induced injury in human cholangiocytes. Hepatology 2012, 55:173-183.
133. Fickert P., Pollheimer M.J., Silbert D., et al. Differential effects of norUDCA and UDCA in obstructive cholestasis in mice. J Hepatol 2013, 58:1201-1208.
134. Moritoki Y., Lian Z.X., Lindor K., et al. B-cell depletion with anti-CD20 ameliorates autoimmune cholangitis but exacerbates colitis in transforming growth factor-beta receptor II dominant negative mice. Hepatology 2009, 50:1893-1903.
135. Tsuda M., Moritoki Y., Lian Z.X., et al. Biochemical and immunologic effects of rituximab in patients with primary biliary cirrhosis and an incomplete response to ursodeoxycholic acid. Hepatology 2012, 55:512-521.
136. Lleo A., Gershwin M.E., Mantovani A., et al. Towards common denominators in primary biliary cirrhosis: the role of IL-12. J Hepatol 2012, 56:731-733.
137. Hirschfield G.M., Liu X., Xu C., et al. Primary biliary cirrhosis associated with HLA, IL12A, and IL12RB2 variants. N Engl J Med 2009, 360:2544-2555.
138. Eaton J.E., Talwalkar J.A., Lazaridis K.N., et al. Pathogenesis of primary sclerosing cholangitis and advances in diagnosis and management. Gastroenterology 2013, 145:521-536.
139. Liaskou E., Karikoski M., Reynolds G.M., et al. Regulation of mucosal addressin cell adhesion molecule 1 expression in human and mice by vascular adhesion protein 1 amine oxidase activity. Hepatology 2011, 53:661-672.
140. Moon H.J., Finney J., Ronnebaum T., et al. Human lysyl oxidase-like 2. Bioorg Chem 2014, 57:231-241.
141. O'Hara S.P., Tabibian J.H., Splinter P.L., et al. The dynamic biliary epithelia: molecules, pathways, and disease. J Hepatol 2013, 58:575-582.