Pathobiology of inherited biliary diseases: a roadmap to understand acquired liver diseases

Abstract

Bile duct epithelial cells, also known as cholangiocytes, regulate the composition of bile and its flow. Acquired, congenital and genetic dysfunctions in these cells give rise to a set of diverse and complex diseases, often of unknown aetiology, called cholangiopathies. New knowledge has been steadily acquired about genetic and congenital cholangiopathies, and this has led to a better understanding of the mechanisms of acquired cholangiopathies. This Review focuses on findings from studies on Alagille syndrome, polycystic liver diseases, fibropolycystic liver diseases (Caroli disease and congenital hepatic fibrosis) and cystic fibrosis-related liver disease. In particular, knowledge on the role of Notch signalling in biliary repair and tubulogenesis has been advanced by work on Alagille syndrome, and investigations in polycystic liver diseases have highlighted the role of primary cilia in biliary pathophysiology and the concept of biliary angiogenic signalling and its role in cyst growth and biliary repair. In fibropolycystic liver disease, research has shown that loss of fibrocystin generates a signalling cascade that increases β-catenin signalling, activates the NOD-, LRR- and pyrin domain-containing 3 inflammasome, and promotes production of IL-1β and other chemokines that attract macrophages and orchestrate the process of pericystic and portal fibrosis, which are the main mechanisms of progression in cholangiopathies. In cystic fibrosis-related liver disease, lack of cystic fibrosis transmembrane conductance regulator increases the sensitivity of epithelial Toll-like receptor 4 that sustains the secretion of nuclear factor-κB-dependent cytokines and peribiliary inflammation in response to gut-derived products, providing a model for primary sclerosing cholangitis. These signalling mechanisms may be targeted therapeutically and they offer a possibility for the development of novel treatments for acquired cholangiopathies.

Key points

  • Reactivation of morphogen signalling (such as Notch, Wnt–β-catenin and Hedgehog) takes place during biliary repair and orchestrates the balance between biliary remodelling and fibrogenesis and transdifferentiation and carcinogenesis.

  • Polycystins control fundamental Ca2+–cAMP-dependent cell signalling processes in cholangiocytes and, when defective, these proteins enhance cell proliferation and activate angiogenic signalling that leads to cystogenesis.

  • Polycystin-2 can be modulated in response to biliary inflammation and mediates vascular endothelial growth factor secretion and cholangiocyte proliferation in acquired cholangiopathies.

  • Genetic defects in fibrocystin are associated with altered β-catenin signalling, which generates an auto-inflammatory response with secretion of chemokines that are able to attract macrophages, resulting in biliary fibrogenesis.

  • Cystic fibrosis transmembrane conductance regulator (CFTR) regulates cholangiocyte innate immunity and maintains Toll-like receptor tolerance; loss of CFTR predisposes the biliary epithelium to inflammation and damage in response to gut-derived microbial components.

  • Pathological mechanisms identified in genetic cholangiopathies can be applied to acquired cholangiopathies and might represent potential targets for the next generation of treatments.

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Fig. 1: Notch signalling in biliary development and disease.
Fig. 2: Signalling mechanisms involved in cyst growth in ADPKD.
Fig. 3: Novel mechanisms of biliary fibrosis in ARPKD.
Fig. 4: CFTR function in cholangiocytes.

References

  1. 1.

    Strazzabosco, M. & Fabris, L. Functional anatomy of normal bile ducts. Anat. Rec. 291, 653–660 (2008).

  2. 2.

    Lazaridis, K. N., Strazzabosco, M. & Larusso, N. F. The cholangiopathies: disorders of biliary epithelia. Gastroenterology 127, 1565–1577 (2004).

  3. 3.

    Strazzabosco, M., Fabris, L. & Spirli, C. Pathophysiology of cholangiopathies. J. Clin. Gastroenterol. 39, S90–S102 (2005).

  4. 4.

    Lazaridis, K. N. & LaRusso, N. F. The cholangiopathies. Mayo Clin. Proc. 90, 791–800 (2015).

  5. 5.

    Spada, M., Riva, S., Maggiore, G., Cintorino, D. & Gridelli, B. Pediatric liver transplantation. World J. Gastroenterol. 15, 648–674 (2009).

  6. 6.

    Srivastava, A. Progressive familial intrahepatic cholestasis. J. Clin. Exp. Hepatol. 4, 25–36 (2014).

  7. 7.

    Falguieres, T., Ait-Slimane, T., Housset, C. & Maurice, M. ABCB4: insights from pathobiology into therapy. Clin. Res. Hepatol. Gastroenterol. 38, 557–563 (2014).

  8. 8.

    Van Haele, M. & Roskams, T. Hepatic progenitor cells: an update. Gastroenterol. Clin. North Am. 46, 409–420 (2017).

  9. 9.

    Duncan, A. W., Dorrell, C. & Grompe, M. Stem cells and liver regeneration. Gastroenterology 137, 466–481 (2009).

  10. 10.

    Cardinale, V. et al. Mucin-producing cholangiocarcinoma might derive from biliary tree stem/progenitor cells located in peribiliary glands. Hepatology 55, 2041–2042 (2012).

  11. 11.

    Fabris, L., Spirli, C., Cadamuro, M., Fiorotto, R. & Strazzabosco, M. Emerging concepts in biliary repair and fibrosis. Am. J. Physiol. Gastrointest. Liver Physiol. 313, G102–G116 (2017).

  12. 12.

    Strazzabosco, M. & Fabris, L. Development of the bile ducts: essentials for the clinical hepatologist. J. Hepatol. 56, 1159–1170 (2012).

  13. 13.

    Ober, E. A. & Lemaigre, F. P. Development of the liver: insights into organ and tissue morphogenesis. J. Hepatol. 68, 1049–1062 (2018).

  14. 14.

    Si-Tayeb, K., Lemaigre, F. P. & Duncan, S. A. Organogenesis and development of the liver. Dev. Cell 18, 175–189 (2010).

  15. 15.

    Fabris, L. et al. Effects of angiogenic factor overexpression by human and rodent cholangiocytes in polycystic liver diseases. Hepatology 43, 1001–1012 (2006).

  16. 16.

    Lemaigre, F. P. Mechanisms of liver development: concepts for understanding liver disorders and design of novel therapies. Gastroenterology 137, 62–79 (2009).

  17. 17.

    Schaub, J. R. et al. De novo formation of the biliary system by TGFbeta-mediated hepatocyte transdifferentiation. Nature 557, 247–251 (2018).

  18. 18.

    Fabris, L. et al. Epithelial expression of angiogenic growth factors modulate arterial vasculogenesis in human liver development. Hepatology 47, 719–728 (2008).

  19. 19.

    Bhattaram, P. et al. Organogenesis relies on SoxC transcription factors for the survival of neural and mesenchymal progenitors. Nat. Commun. 1, 9 (2010).

  20. 20.

    Zhang, N. et al. The Merlin/NF2 tumor suppressor functions through the YAP oncoprotein to regulate tissue homeostasis in mammals. Dev. Cell 19, 27–38 (2010).

  21. 21.

    Yimlamai, D. et al. Hippo pathway activity influences liver cell fate. Cell 157, 1324–1338 (2014).

  22. 22.

    Patel, S. H., Camargo, F. D. & Yimlamai, D. Hippo signaling in the liver regulates organ size, cell fate, and carcinogenesis. Gastroenterology 152, 533–545 (2017).

  23. 23.

    Lemaigre, F. P. Molecular mechanisms of biliary development. Prog. Mol. Biol. Transl Sci. 97, 103–126 (2010).

  24. 24.

    Li, L. et al. Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1. Nat. Genet. 16, 243–251 (1997).

  25. 25.

    Oda, T. et al. Mutations in the human Jagged1 gene are responsible for Alagille syndrome. Nat. Genet. 16, 235–242 (1997).

  26. 26.

    McDaniell, R. et al. NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the notch signaling pathway. Am. J. Hum. Genet. 79, 169–173 (2006).

  27. 27.

    Lykavieris, P., Hadchouel, M., Chardot, C. & Bernard, O. Outcome of liver disease in children with Alagille syndrome: a study of 163 patients. Gut 49, 431–435 (2001).

  28. 28.

    Kamath, B. M. et al. Outcomes of liver transplantation for patients with Alagille syndrome: the studies of pediatric liver transplantation experience. Liver Transpl. 18, 940–948 (2012).

  29. 29.

    Artavanis-Tsakonas, S., Rand, M. D. & Lake, R. J. Notch signaling: cell fate control and signal integration in development. Science 284, 770–776 (1999).

  30. 30.

    Lai, E. C. Notch signaling: control of cell communication and cell fate. Development 131, 965–973 (2004).

  31. 31.

    Geisler, F. & Strazzabosco, M. Emerging roles of Notch signaling in liver disease. Hepatology 61, 382–392 (2015).

  32. 32.

    Borggrefe, T. & Oswald, F. The Notch signaling pathway: transcriptional regulation at Notch target genes. Cell. Mol. Life Sci. 66, 1631–1646 (2009).

  33. 33.

    Bray, S. J. Notch signalling: a simple pathway becomes complex. Nat. Rev. Mol. Cell Biol. 7, 678–689 (2006).

  34. 34.

    Morell, C. M., Fiorotto, R., Fabris, L. & Strazzabosco, M. Notch signalling beyond liver development: emerging concepts in liver repair and oncogenesis. Clin. Res. Hepatol. Gastroenterol. 37, 447–454 (2013).

  35. 35.

    Zong, Y. et al. Notch signaling controls liver development by regulating biliary differentiation. Development 136, 1727–1739 (2009).

  36. 36.

    Kodama, Y., Hijikata, M., Kageyama, R., Shimotohno, K. & Chiba, T. The role of notch signaling in the development of intrahepatic bile ducts. Gastroenterology 127, 1775–1786 (2004).

  37. 37.

    Gerard, C., Tys, J. & Lemaigre, F. P. Gene regulatory networks in differentiation and direct reprogramming of hepatic cells. Semin. Cell Dev. Biol. 66, 43–50 (2017).

  38. 38.

    Boulter, L. et al. Macrophage-derived Wnt opposes Notch signaling to specify hepatic progenitor cell fate in chronic liver disease. Nat. Med. 18, 572–579 (2012).

  39. 39.

    Fiorotto, R. et al. Notch signaling regulates tubular morphogenesis during repair from biliary damage in mice. J. Hepatol. 59, 124–130 (2013).

  40. 40.

    Fan, B. et al. Cholangiocarcinomas can originate from hepatocytes in mice. J. Clin. Invest. 122, 2911–2915 (2012).

  41. 41.

    Sekiya, S. & Suzuki, A. Intrahepatic cholangiocarcinoma can arise from Notch-mediated conversion of hepatocytes. J. Clin. Invest. 122, 3914–3918 (2012).

  42. 42.

    Morell, C. M. et al. Notch signaling and progenitor/ductular reaction in steatohepatitis. PLOS ONE 12, e0187384 (2017).

  43. 43.

    Fabris, L. et al. Analysis of liver repair mechanisms in Alagille syndrome and biliary atresia reveals a role for notch signaling. Am. J. Pathol. 171, 641–653 (2007).

  44. 44.

    Xie, G. et al. Cross-talk between Notch and Hedgehog regulates hepatic stellate cell fate in mice. Hepatology 58, 1801–1813 (2013).

  45. 45.

    Strazzabosco, M. & Fabris, L. The balance between Notch/Wnt signaling regulates progenitor cells’ commitment during liver repair: mystery solved? J. Hepatol. 58, 181–183 (2013).

  46. 46.

    Walter, T. J., Vanderpool, C., Cast, A. E. & Huppert, S. S. Intrahepatic bile duct regeneration in mice does not require Hnf6 or Notch signaling through Rbpj. Am. J. Pathol. 184, 1479–1488 (2014).

  47. 47.

    Andersson, E. R. et al. Mouse model of Alagille syndrome and mechanisms of Jagged1 missense mutations. Gastroenterology 154, 1080–1095 (2018).

  48. 48.

    Hofmann, J. J. et al. Jagged1 in the portal vein mesenchyme regulates intrahepatic bile duct development: insights into Alagille syndrome. Development 137, 4061–4072 (2010).

  49. 49.

    Masek, J. & Andersson, E. R. The developmental biology of genetic Notch disorders. Development 144, 1743–1763 (2017).

  50. 50.

    Mitchell, E., Gilbert, M. & Loomes, K. M. Alagille syndrome. Clin. Liver Dis. 22, 625–641 (2018).

  51. 51.

    Tsai, E. A. et al. THBS2 is a candidate modifier of liver disease severity in Alagille syndrome. Cell. Mol. Gastroenterol. Hepatol. 2, 663–675 (2016).

  52. 52.

    Thakurdas, S. M. et al. Jagged1 heterozygosity in mice results in a congenital cholangiopathy which is reversed by concomitant deletion of one copy of Poglut1 (Rumi). Hepatology 63, 550–565 (2016).

  53. 53.

    Ryan, M. J. et al. Bile duct proliferation in Jag1/fringe heterozygous mice identifies candidate modifiers of the Alagille syndrome hepatic phenotype. Hepatology 48, 1989–1997 (2008).

  54. 54.

    Strazzabosco, M. & Fabris, L. Notch signaling in hepatocellular carcinoma: guilty in association! Gastroenterology 143, 1430–1434 (2012).

  55. 55.

    Villanueva, A. et al. Notch signaling is activated in human hepatocellular carcinoma and induces tumor formation in mice. Gastroenterology 143, 1660–1669 (2012).

  56. 56.

    Dill, M. T. et al. Constitutive Notch2 signaling induces hepatic tumors in mice. Hepatology 57, 1607–1619 (2013).

  57. 57.

    Guest, R. V. et al. Notch3 drives development and progression of cholangiocarcinoma. Proc. Natl Acad. Sci. USA 113, 12250–12255 (2016).

  58. 58.

    Nijjar, S. S., Crosby, H. A., Wallace, L., Hubscher, S. G. & Strain, A. J. Notch receptor expression in adult human liver: a possible role in bile duct formation and hepatic neovascularization. Hepatology 34, 1184–1192 (2001).

  59. 59.

    Nijjar, S. S., Wallace, L., Crosby, H. A., Hubscher, S. G. & Strain, A. J. Altered Notch ligand expression in human liver disease: further evidence for a role of the Notch signaling pathway in hepatic neovascularization and biliary ductular defects. Am. J. Pathol. 160, 1695–1703 (2002).

  60. 60.

    Andersson, E. R. & Lendahl, U. Therapeutic modulation of Notch signalling—are we there yet? Nat. Rev. Drug Discov. 13, 357–378 (2014).

  61. 61.

    Morell, C. M. & Strazzabosco, M. Notch signaling and new therapeutic options in liver disease. J. Hepatol. 60, 885–890 (2014).

  62. 62.

    van Aerts, R. M. M., van de Laarschot, L. F. M., Banales, J. M. & Drenth, J. P. H. Clinical management of polycystic liver disease. J. Hepatol. 68, 827–837 (2017).

  63. 63.

    Gevers, T. J. & Drenth, J. P. Diagnosis and management of polycystic liver disease. Nat. Rev. Gastroenterol. Hepatol. 10, 101–108 (2013).

  64. 64.

    Masyuk, T., Masyuk, A. & LaRusso, N. Cholangiociliopathies: genetics, molecular mechanisms and potential therapies. Curr. Opin. Gastroenterol. 25, 265–271 (2009).

  65. 65.

    Strazzabosco, M. & Somlo, S. Polycystic liver diseases: congenital disorders of cholangiocyte signaling. Gastroenterology 140, 1855–1859 (2011).

  66. 66.

    Masyuk, A. I. et al. Cholangiocyte cilia detect changes in luminal fluid flow and transmit them into intracellular Ca2+ and cAMP signaling. Gastroenterology 131, 911–920 (2006).

  67. 67.

    Masyuk, A. I. et al. Cholangiocyte primary cilia are chemosensory organelles that detect biliary nucleotides via P2Y12 purinergic receptors. Am. J. Physiol. Gastrointest. Liver Physiol. 295, G725–G734 (2008).

  68. 68.

    Masyuk, A. I. et al. Biliary exosomes influence cholangiocyte regulatory mechanisms and proliferation through interaction with primary cilia. Am. J. Physiol. Gastrointest. Liver Physiol. 299, G990–G999 (2010).

  69. 69.

    Masyuk, A. I. et al. Ciliary subcellular localization of TGR5 determines the cholangiocyte functional response to bile acid signaling. Am. J. Physiol. Gastrointest. Liver Physiol. 304, G1013–G1024 (2013).

  70. 70.

    Gradilone, S. A. et al. Activation of Trpv4 reduces the hyperproliferative phenotype of cystic cholangiocytes from an animal model of ARPKD. Gastroenterology 139, 304–314 (2010).

  71. 71.

    Hildebrandt, F., Benzing, T. & Katsanis, N. Ciliopathies. N. Engl. J. Med. 364, 1533–1543 (2011).

  72. 72.

    Bezerra, J. A. et al. Biliary atresia: clinical and research challenges for the twenty-first century. Hepatology 68, 1163–1173 (2018).

  73. 73.

    Rock, N. & McLin, V. Liver involvement in children with ciliopathies. Clin. Res. Hepatol. Gastroenterol. 38, 407–414 (2014).

  74. 74.

    van de Laarschot, L. F. M. & Drenth, J. P. H. Genetics and mechanisms of hepatic cystogenesis. Biochim. Biophys. Acta Mol. Basis Dis. 1864, 1491–1497 (2018).

  75. 75.

    Perugorria, M. J. et al. Polycystic liver diseases: advanced insights into the molecular mechanisms. Nat. Rev. Gastroenterol. Hepatol. 11, 750–761 (2014).

  76. 76.

    Perugorria, M. J. & Banales, J. M. Genetics: novel causative genes for polycystic liver disease. Nat. Rev. Gastroenterol. Hepatol. 14, 391–392 (2017).

  77. 77.

    The European Polycystic Kidney Disease Consortium. The polycystic kidney disease 1 gene encodes a 14 kb transcript and lies within a duplicated region on chromosome 16. Cell 77, 881–894 (1994).

  78. 78.

    Mochizuki, T. et al. PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein. Science 272, 1339–1342 (1996).

  79. 79.

    Harris, R. A., Gray, D. W., Britton, B. J., Toogood, G. J. & Morris, P. J. Hepatic cystic disease in an adult polycystic kidney disease transplant population. Aust. NZ J. Surg. 66, 166–168 (1996).

  80. 80.

    Drenth, J. P., te Morsche, R. H., Smink, R., Bonifacino, J. S. & Jansen, J. B. Germline mutations in PRKCSH are associated with autosomal dominant polycystic liver disease. Nat. Genet. 33, 345–347 (2003).

  81. 81.

    Li, A. et al. Mutations in PRKCSH cause isolated autosomal dominant polycystic liver disease. Am. J. Hum. Genet. 72, 691–703 (2003).

  82. 82.

    Davila, S. et al. Mutations in SEC63 cause autosomal dominant polycystic liver disease. Nat. Genet. 36, 575–577 (2004).

  83. 83.

    Besse, W. et al. Isolated polycystic liver disease genes define effectors of polycystin-1 function. J. Clin. Invest. 127, 1772–1785 (2017).

  84. 84.

    Porath, B. et al. Mutations in GANAB, encoding the glucosidase IIalpha subunit, cause autosomal-dominant polycystic kidney and liver disease. Am. J. Hum. Genet. 98, 1193–1207 (2016).

  85. 85.

    Cnossen, W. R. et al. Whole-exome sequencing reveals LRP5 mutations and canonical Wnt signaling associated with hepatic cystogenesis. Proc. Natl Acad. Sci. USA 111, 5343–5348 (2014).

  86. 86.

    Fedeles, S. V. et al. A genetic interaction network of five genes for human polycystic kidney and liver diseases defines polycystin-1 as the central determinant of cyst formation. Nat. Genet. 43, 639–647 (2011).

  87. 87.

    Kim, S. et al. The polycystin complex mediates Wnt/Ca2+ signalling. Nat. Cell Biol. 18, 752–764 (2016).

  88. 88.

    Raynaud, P. et al. A classification of ductal plate malformations based on distinct pathogenic mechanisms of biliary dysmorphogenesis. Hepatology 53, 1959–1966 (2011).

  89. 89.

    Janssen, M. J., Salomon, J., Te Morsche, R. H. & Drenth, J. P. Loss of heterozygosity is present in SEC63 germline carriers with polycystic liver disease. PLOS ONE 7, e50324 (2012).

  90. 90.

    Janssen, M. J. et al. Secondary, somatic mutations might promote cyst formation in patients with autosomal dominant polycystic liver disease. Gastroenterology 141, 2056–2063 (2011).

  91. 91.

    Pei, Y. et al. Somatic PKD2 mutations in individual kidney and liver cysts support a “two-hit” model of cystogenesis in type 2 autosomal dominant polycystic kidney disease. J. Am. Soc. Nephrol. 10, 1524–1529 (1999).

  92. 92.

    Watnick, T. J. et al. Somatic mutation in individual liver cysts supports a two-hit model of cystogenesis in autosomal dominant polycystic kidney disease. Mol. Cell 2, 247–251 (1998).

  93. 93.

    Banales, J. M. et al. The cAMP effectors Epac and protein kinase A (PKA) are involved in the hepatic cystogenesis of an animal model of autosomal recessive polycystic kidney disease (ARPKD). Hepatology 49, 160–174 (2009).

  94. 94.

    Banales, J. M. et al. Hepatic cystogenesis is associated with abnormal expression and location of ion transporters and water channels in an animal model of autosomal recessive polycystic kidney disease. Am. J. Pathol. 173, 1637–1646 (2008).

  95. 95.

    Urribarri, A. D. et al. Inhibition of metalloprotease hyperactivity in cystic cholangiocytes halts the development of polycystic liver diseases. Gut 63, 1658–1667 (2014).

  96. 96.

    Masyuk, A. I. et al. Cholangiocyte autophagy contributes to hepatic cystogenesis in polycystic liver disease and represents a potential therapeutic target. Hepatology 67, 1088–1108 (2018).

  97. 97.

    Masyuk, T. V. et al. Defects in cholangiocyte fibrocystin expression and ciliary structure in the PCK rat. Gastroenterology 125, 1303–1310 (2003).

  98. 98.

    Masyuk, T. V. et al. Centrosomal abnormalities characterize human and rodent cystic cholangiocytes and are associated with Cdc25A overexpression. Am. J. Pathol. 184, 110–121 (2014).

  99. 99.

    Lee, S. O. et al. MicroRNA15a modulates expression of the cell-cycle regulator Cdc25A and affects hepatic cystogenesis in a rat model of polycystic kidney disease. J. Clin. Invest. 118, 3714–3724 (2008).

  100. 100.

    Beaudry, J. B. et al. Proliferation-independent initiation of biliary cysts in polycystic liver diseases. PLOS ONE 10, e0132295 (2015).

  101. 101.

    Benhamouche-Trouillet, S. et al. Proliferation-independent role of NF2 (Merlin) in limiting biliary morphogenesis. Development 145, dev162123 (2018).

  102. 102.

    Chebib, F. T., Sussman, C. R., Wang, X., Harris, P. C. & Torres, V. E. Vasopressin and disruption of calcium signalling in polycystic kidney disease. Nat. Rev. Nephrol. 11, 451–464 (2015).

  103. 103.

    Spirli, C. et al. Altered store operated calcium entry increases cyclic 3′,5′-adenosine monophosphate production and extracellular signal-regulated kinases 1 and 2 phosphorylation in polycystin-2-defective cholangiocytes. Hepatology 55, 856–868 (2012).

  104. 104.

    Spirli, C. et al. Adenylyl cyclase 5 links changes in calcium homeostasis to cAMP-dependent cyst growth in polycystic liver disease. J. Hepatol. 66, 571–580 (2017).

  105. 105.

    Wang, Y., Deng, X. & Gill, D. L. Calcium signaling by STIM and Orai: intimate coupling details revealed. Sci. Signal. 3, pe42 (2010).

  106. 106.

    Wang, Y. et al. STIM protein coupling in the activation of Orai channels. Proc. Natl Acad. Sci. USA 106, 7391–7396 (2009).

  107. 107.

    Spirli, C. et al. Cyclic AMP/PKA-dependent paradoxical activation of Raf/MEK/ERK signaling in polycystin-2 defective mice treated with sorafenib. Hepatology 56, 2363–2374 (2012).

  108. 108.

    Masyuk, T. V. et al. Pasireotide is more effective than octreotide in reducing hepatorenal cystogenesis in rodents with polycystic kidney and liver diseases. Hepatology 58, 409–421 (2013).

  109. 109.

    Khan, S., Dennison, A. & Garcea, G. Medical therapy for polycystic liver disease. Ann. R. Coll. Surg. Engl. 98, 18–23 (2016).

  110. 110.

    D’Agnolo, H. M. et al. Ursodeoxycholic acid in advanced polycystic liver disease: a phase 2 multicenter randomized controlled trial. J. Hepatol. 65, 601–607 (2016).

  111. 111.

    Munoz-Garrido, P. et al. Ursodeoxycholic acid inhibits hepatic cystogenesis in experimental models of polycystic liver disease. J. Hepatol. 63, 952–961 (2015).

  112. 112.

    Brodsky, K. S., McWilliams, R. R., Amura, C. R., Barry, N. P. & Doctor, R. B. Liver cyst cytokines promote endothelial cell proliferation and development. Exp. Biol. Med. 234, 1155–1165 (2009).

  113. 113.

    Amura, C. R. et al. VEGF receptor inhibition blocks liver cyst growth in pkd2(WS25/–) mice. Am. J. Physiol. Cell Physiol. 293, C419–C428 (2007).

  114. 114.

    Spirli, C. et al. ERK1/2-dependent vascular endothelial growth factor signaling sustains cyst growth in polycystin-2 defective mice. Gastroenterology 138, 360–371 (2010).

  115. 115.

    Spirli, C. et al. Mammalian target of rapamycin regulates vascular endothelial growth factor-dependent liver cyst growth in polycystin-2-defective mice. Hepatology 51, 1778–1788 (2010).

  116. 116.

    Spirli, C. et al. Posttranslational regulation of polycystin-2 protein expression as a novel mechanism of cholangiocyte reaction and repair from biliary damage. Hepatology 62, 1828–1839 (2015).

  117. 117.

    Torrice, A. et al. Polycystins play a key role in the modulation of cholangiocyte proliferation. Dig. Liver Dis. 42, 377–385 (2010).

  118. 118.

    Novo, E. et al. Proangiogenic cytokines as hypoxia-dependent factors stimulating migration of human hepatic stellate cells. Am. J. Pathol. 170, 1942–1953 (2007).

  119. 119.

    Yoshiji, H. et al. Vascular endothelial growth factor and receptor interaction is a prerequisite for murine hepatic fibrogenesis. Gut 52, 1347–1354 (2003).

  120. 120.

    Brancatelli, G. et al. Fibropolycystic liver disease: CT and MR imaging findings. Radiographics 25, 659–670 (2005).

  121. 121.

    Veigel, M. C. et al. Fibropolycystic liver disease in children. Pediatr. Radiol. 39, 317–327 (2009).

  122. 122.

    Menezes, L. F. et al. Polyductin, the PKHD1 gene product, comprises isoforms expressed in plasma membrane, primary cilium, and cytoplasm. Kidney Int. 66, 1345–1355 (2004).

  123. 123.

    Zhang, M. Z. et al. PKHD1 protein encoded by the gene for autosomal recessive polycystic kidney disease associates with basal bodies and primary cilia in renal epithelial cells. Proc. Natl Acad. Sci. USA 101, 2311–2316 (2004).

  124. 124.

    Locatelli, L. et al. Macrophage recruitment by fibrocystin-defective biliary epithelial cells promotes portal fibrosis in congenital hepatic fibrosis. Hepatology 63, 965–982 (2016).

  125. 125.

    Harris, P. C. & Torres, V. E. Polycystic kidney disease. Annu. Rev. Med. 60, 321–337 (2009).

  126. 126.

    Bergmann, C. Genetics of autosomal recessive polycystic kidney disease and its differential diagnoses. Front. Pediatr. 5, 221 (2017).

  127. 127.

    Yonem, O. & Bayraktar, Y. Clinical characteristics of Caroli’s syndrome. World J. Gastroenterol. 13, 1934–1937 (2007).

  128. 128.

    Mai, W. et al. Inhibition of Pkhd1 impairs tubulomorphogenesis of cultured IMCD cells. Mol. Biol. Cell 16, 4398–4409 (2005).

  129. 129.

    Al-Bhalal, L. & Akhtar, M. Molecular basis of autosomal recessive polycystic kidney disease (ARPKD). Adv. Anat. Pathol. 15, 54–58 (2008).

  130. 130.

    Kaimori, J. Y. et al. Polyductin undergoes notch-like processing and regulated release from primary cilia. Hum. Mol. Genet. 16, 942–956 (2007).

  131. 131.

    Cerwenka, H. Bile duct cyst in adults: interventional treatment, resection, or transplantation? World J. Gastroenterol. 19, 5207–5211 (2013).

  132. 132.

    Moslim, M. A., Gunasekaran, G., Vogt, D., Cruise, M. & Morris-Stiff, G. Surgical management of Caroli’s disease: single center experience and review of the literature. J. Gastrointest. Surg. 19, 2019–2027 (2015).

  133. 133.

    Desmet, V. J. Ludwig symposium on biliary disorders—part I. Pathogenesis of ductal plate abnormalities. Mayo Clin. Proc. 73, 80–89 (1998).

  134. 134.

    Masyuk, T. V. et al. Biliary dysgenesis in the PCK rat, an orthologous model of autosomal recessive polycystic kidney disease. Am. J. Pathol. 165, 1719–1730 (2004).

  135. 135.

    Masyuk, T. V., Masyuk, A. I., Torres, V. E., Harris, P. C. & Larusso, N. F. Octreotide inhibits hepatic cystogenesis in a rodent model of polycystic liver disease by reducing cholangiocyte adenosine 3′,5′-cyclic monophosphate. Gastroenterology 132, 1104–1116 (2007).

  136. 136.

    Kaffe, E. et al. beta-Catenin and interleukin-1beta-dependent chemokine (C-X-C motif) ligand 10 production drives progression of disease in a mouse model of congenital hepatic fibrosis. Hepatology 67, 1903–1919 (2018).

  137. 137.

    Spirli, C. et al. Protein kinase A-dependent pSer(675)-beta-catenin, a novel signaling defect in a mouse model of congenital hepatic fibrosis. Hepatology 58, 1713–1723 (2013).

  138. 138.

    Niehrs, C. The complex world of WNT receptor signalling. Nat. Rev. Mol. Cell Biol. 13, 767–779 (2012).

  139. 139.

    Dunach, M., Del Valle-Perez, B. & Garcia de Herreros, A. p120-catenin in canonical Wnt signaling. Crit. Rev. Biochem. Mol. Biol. 52, 327–339 (2017).

  140. 140.

    Strazzabosco, M. et al. Pathophysiologic implications of innate immunity and autoinflammation in the biliary epithelium. Biochim. Biophys. Acta 1864, 1374–1379 (2018).

  141. 141.

    Park, H., Bourla, A. B., Kastner, D. L., Colbert, R. A. & Siegel, R. M. Lighting the fires within: the cell biology of autoinflammatory diseases. Nat. Rev. Immunol. 12, 570–580 (2012).

  142. 142.

    Masyuk, T. V. et al. Inhibition of Cdc25A suppresses hepato-renal cystogenesis in rodent models of polycystic kidney and liver disease. Gastroenterology 142, 622–633 (2012).

  143. 143.

    Yoshihara, D. et al. Telmisartan ameliorates fibrocystic liver disease in an orthologous rat model of human autosomal recessive polycystic kidney disease. PLOS ONE 8, e81480 (2013).

  144. 144.

    Yoshihara, D. et al. PPAR-gamma agonist ameliorates kidney and liver disease in an orthologous rat model of human autosomal recessive polycystic kidney disease. Am. J. Physiol. Renal Physiol. 300, F465–F474 (2011).

  145. 145.

    Chuang, Y. H. et al. Increased levels of chemokine receptor CXCR3 and chemokines IP-10 and MIG in patients with primary biliary cirrhosis and their first degree relatives. J. Autoimmun. 25, 126–132 (2005).

  146. 146.

    de Graaf, K. L. et al. NI-0801, an anti-chemokine (C-X-C motif) ligand 10 antibody, in patients with primary biliary cholangitis and an incomplete response to ursodeoxycholic acid. Hepatol. Commun. 2, 492–503 (2018).

  147. 147.

    Guicciardi, M. E. et al. Macrophages contribute to the pathogenesis of sclerosing cholangitis in mice. J. Hepatol. 69, 676–686 (2018).

  148. 148.

    Yu, D., Cai, S. Y., Mennone, A., Vig, P. & Boyer, J. L. Cenicriviroc, a cytokine receptor antagonist, potentiates all-trans retinoic acid in reducing liver injury in cholestatic rodents. Liver Int. 38, 1128–1138 (2018).

  149. 149.

    Castellani, C. & Assael, B. M. Cystic fibrosis: a clinical view. Cell. Mol. Life Sci. 74, 129–140 (2017).

  150. 150.

    O’Sullivan, B. P. & Freedman, S. D. Cystic fibrosis. Lancet 373, 1891–1904 (2009).

  151. 151.

    Veit, G. et al. From CFTR biology toward combinatorial pharmacotherapy: expanded classification of cystic fibrosis mutations. Mol. Biol. Cell 27, 424–433 (2016).

  152. 152.

    Cohn, J. A. et al. Localization of the cystic fibrosis transmembrane conductance regulator in human bile duct epithelial cells. Gastroenterology 105, 1857–1864 (1993).

  153. 153.

    Kinnman, N. et al. Expression of cystic fibrosis transmembrane conductance regulator in liver tissue from patients with cystic fibrosis. Hepatology 32, 334–340 (2000).

  154. 154.

    Ooi, C. Y. & Durie, P. R. Cystic fibrosis from the gastroenterologist’s perspective. Nat. Rev. Gastroenterol. Hepatol. 13, 175–185 (2016).

  155. 155.

    Debray, D. et al. Cystic fibrosis-related liver disease: research challenges and future perspectives. J. Pediatr. Gastroenterol. Nutr. 65, 443–448 (2017).

  156. 156.

    Rowland, M. et al. Outcome in patients with cystic fibrosis liver disease. J. Cyst. Fibros. 14, 120–126 (2015).

  157. 157.

    Chryssostalis, A. et al. Liver disease in adult patients with cystic fibrosis: a frequent and independent prognostic factor associated with death or lung transplantation. J. Hepatol. 55, 1377–1382 (2011).

  158. 158.

    Debray, D., Kelly, D., Houwen, R., Strandvik, B. & Colombo, C. Best practice guidance for the diagnosis and management of cystic fibrosis-associated liver disease. J. Cyst. Fibros. 10 (Suppl. 2), S29–S36 (2011).

  159. 159.

    Beuers, U. Drug insight: mechanisms and sites of action of ursodeoxycholic acid in cholestasis. Nat. Clin. Pract. Gastroenterol. Hepatol. 3, 318–328 (2006).

  160. 160.

    Lindblad, A., Glaumann, H. & Strandvik, B. A two-year prospective study of the effect of ursodeoxycholic acid on urinary bile acid excretion and liver morphology in cystic fibrosis-associated liver disease. Hepatology 27, 166–174 (1998).

  161. 161.

    Cheng, K., Ashby, D. & Smyth, R. L. Ursodeoxycholic acid for cystic fibrosis-related liver disease. Cochrane Database Syst. Rev. 9, CD000222 (2017).

  162. 162.

    Fajac, I. & Wainwright, C. E. New treatments targeting the basic defects in cystic fibrosis. Presse Med. 46, e165–e175 (2017).

  163. 163.

    Strug, L. J., Stephenson, A. L., Panjwani, N. & Harris, A. Recent advances in developing therapeutics for cystic fibrosis. Hum. Mol. Genet. 27, R173–R186 (2018).

  164. 164.

    Fiorotto, R. et al. Src kinase inhibition reduces inflammatory and cytoskeletal changes in DeltaF508 human cholangiocytes and improves cystic fibrosis transmembrane conductance regulator correctors efficacy. Hepatology 67, 972–988 (2018).

  165. 165.

    Huch, M. et al. Long-term culture of genome-stable bipotent stem cells from adult human liver. Cell 160, 299–312 (2015).

  166. 166.

    Sampaziotis, F. et al. Directed differentiation of human induced pluripotent stem cells into functional cholangiocyte-like cells. Nat. Protoc. 12, 814–827 (2017).

  167. 167.

    Staufer, K., Halilbasic, E., Trauner, M. & Kazemi-Shirazi, L. Cystic fibrosis related liver disease—another black box in hepatology. Int. J. Mol. Sci. 15, 13529–13549 (2014).

  168. 168.

    Guggino, W. B. The cystic fibrosis transmembrane regulator forms macromolecular complexes with PDZ domain scaffold proteins. Proc. Am. Thorac. Soc. 1, 28–32 (2004).

  169. 169.

    Li, C. & Naren, A. P. CFTR chloride channel in the apical compartments: spatiotemporal coupling to its interacting partners. Integr. Biol. 2, 161–177 (2010).

  170. 170.

    Fiorotto, R. et al. The cystic fibrosis transmembrane conductance regulator controls biliary epithelial inflammation and permeability by regulating Src tyrosine kinase activity. Hepatology 64, 2118–2134 (2016).

  171. 171.

    Akira, S. Toll-like receptors and innate immunity. Adv. Immunol. 78, 1–56 (2001).

  172. 172.

    Chattopadhyay, S. & Sen, G. C. Tyrosine phosphorylation in Toll-like receptor signaling. Cytokine Growth Factor Rev. 25, 533–541 (2014).

  173. 173.

    Medvedev, A. E. et al. Role of TLR4 tyrosine phosphorylation in signal transduction and endotoxin tolerance. J. Biol. Chem. 282, 16042–16053 (2007).

  174. 174.

    Szabo, G., Dolganiuc, A. & Mandrekar, P. Pattern recognition receptors: a contemporary view on liver diseases. Hepatology 44, 287–298 (2006).

  175. 175.

    Chen, X. M. et al. Multiple TLRs are expressed in human cholangiocytes and mediate host epithelial defense responses to Cryptosporidium parvum via activation of NF-kappaB. J. Immunol. 175, 7447–7456 (2005).

  176. 176.

    Fiorotto, R. et al. Loss of CFTR affects biliary epithelium innate immunity and causes TLR4-NF-kappaB-mediated inflammatory response in mice. Gastroenterology 141, 1498–1508 (2011).

  177. 177.

    Scirpo, R. et al. Stimulation of nuclear receptor peroxisome proliferator-activated receptor-gamma limits NF-kappaB-dependent inflammation in mouse cystic fibrosis biliary epithelium. Hepatology 62, 1551–1562 (2015).

  178. 178.

    Schnabl, B. & Brenner, D. A. Interactions between the intestinal microbiome and liver diseases. Gastroenterology 146, 1513–1524 (2014).

  179. 179.

    Wiest, R., Albillos, A., Trauner, M., Bajaj, J. S. & Jalan, R. Targeting the gut-liver axis in liver disease. J. Hepatol. 67, 1084–1103 (2017).

  180. 180.

    De Lisle, R. C. & Borowitz, D. The cystic fibrosis intestine. Cold Spring Harb. Perspect. Med. 3, a009753 (2013).

  181. 181.

    Flass, T. et al. Intestinal lesions are associated with altered intestinal microbiome and are more frequent in children and young adults with cystic fibrosis and cirrhosis. PLOS ONE 10, e0116967 (2015).

  182. 182.

    Lynch, S. V. et al. Cystic fibrosis transmembrane conductance regulator knockout mice exhibit aberrant gastrointestinal microbiota. Gut Microbes 4, 41–47 (2013).

  183. 183.

    Hirschfield, G. M., Karlsen, T. H., Lindor, K. D. & Adams, D. H. Primary sclerosing cholangitis. Lancet 382, 1587–1599 (2013).

  184. 184.

    Ellinghaus, D. et al. Genome-wide association analysis in primary sclerosing cholangitis and ulcerative colitis identifies risk loci at GPR35 and TCF4. Hepatology 58, 1074–1083 (2013).

  185. 185.

    Folseraas, T. et al. Extended analysis of a genome-wide association study in primary sclerosing cholangitis detects multiple novel risk loci. J. Hepatol. 57, 366–375 (2012).

  186. 186.

    Katt, J. et al. Increased T helper type 17 response to pathogen stimulation in patients with primary sclerosing cholangitis. Hepatology 58, 1084–1093 (2013).

  187. 187.

    Mueller, T. et al. Enhanced innate immune responsiveness and intolerance to intestinal endotoxins in human biliary epithelial cells contributes to chronic cholangitis. Liver Int. 31, 1574–1588 (2011).

  188. 188.

    Banales, J. M. et al. Cholangiocyte pathobiology. Nat. Rev. Gastroenterol. Hepatol. 16, 269–281 (2019).

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Acknowledgements

This work was supported by the National Institutes of Health (RO1DK096096 (M.S.), RO1DK-079005-07 (M.S.) and RO1DK101528 (C.S.)); by DK034989 Silvio O. Conte Digestive Diseases Research Core Center (M.S., C.S. and R.F.); by PSC Partners Seeking a Cure (M.S.); by a grant from Connecticut Innovations (16-RMA-YALE-26) (M.S.); by a grant from Cystic Fibrosis Foundation (FIOROT18GO) (R.F.); by the University of Padua, Progetti di Ricerca di Dipartimento (PRID) 2017 (L.F.); by the Spanish Ministry of Economy and Competitiveness and “Instituto de Salud Carlos III” grants PI14/00399, PI17/00022 and Ramon y Cajal Programme RYC-2015-17755 (M.J.P.) and by PI15/01132, PI18/01075 and Miguel Servet Programme CON14/00129 co-financed by “Fondo Europeo de Desarrollo Regional” (FEDER) (J.M.B.); by CIBERehd, Spain (M.J.P. and J.M.B.); by IKERBASQUE, Basque foundation for Science, Spain (M.J.P. and J.M.B.); by “Diputación Foral de Gipuzkoa” DFG18/114 (M.J.P.), DFG15/010 and DFG16/004 (J.M.B.); by BIOEF (Basque Foundation for Innovation and Health Research): EiTB Maratoia BIO15/CA/016/BD (J.M.B.); by the Department of Health of the Basque Country (2015111100 (M.J.P.) and 2017111010 (J.M.B.)); and by AECC Scientific Foundation (J.M.B.).

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Nature Reviews Gastroenterology & Hepatology thanks S. Karpen and the other anonymous reviewers for their contribution to the peer review of this work.

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Correspondence to Mario Strazzabosco.

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Fabris, L., Fiorotto, R., Spirli, C. et al. Pathobiology of inherited biliary diseases: a roadmap to understand acquired liver diseases. Nat Rev Gastroenterol Hepatol 16, 497–511 (2019) doi:10.1038/s41575-019-0156-4

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