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  • Review Article
  • Published:

Polycystic liver diseases: advanced insights into the molecular mechanisms

Nature Reviews Gastroenterology & Hepatology volume 11, pages 750–761 (2014)Cite this article

Subjects

Key Points

  • Proteins encoded by the genes that cause polycystic liver diseases are predominantly localized in the primary cilium, plasma membrane and/or the endoplasmic reticulum of cholangiocytes

  • Current treatments are based on surgical procedures and/or pharmacological management; however, their beneficial effects are modest, leaving liver transplantation as the only definitive remedy

  • Elucidating the molecular mechanisms involved in the pathogenesis of these disorders is crucial in order to identify new potential targets for therapy

  • Hepatic cystogenesis is characterized by ductal plate malformation, abnormalities of the cholangiocyte primary cilium, centrosome amplification, hyperproliferation, hypersecretion, matrix-metalloprotease hyperactivity, angiogenesis, epigenetic alterations and atypical levels of key intracellular mediators

  • Preclinical studies have revealed new potential therapeutic targets that need to be validated in future clinical trials

Abstract

Polycystic liver diseases are genetic disorders characterized by progressive bile duct dilatation and/or cyst development. The large volume of hepatic cysts causes different symptoms and complications such as abdominal distension, local pressure with back pain, hypertension, gastro-oesophageal reflux and dyspnea as well as bleeding, infection and rupture of the cysts. Current therapeutic strategies are based on surgical procedures and pharmacological management, which partially prevent or ameliorate the disease. However, as these treatments only show short-term and/or modest beneficial effects, liver transplantation is the only definitive therapy. Therefore, interest in understanding the molecular mechanisms involved in disease pathogenesis is increasing so that new targets for therapy can be identified. In this Review, the genetic mechanisms underlying polycystic liver diseases and the most relevant molecular pathways of hepatic cystogenesis are discussed. Moreover, the main clinical and preclinical studies are highlighted and future directions in basic as well as clinical research are indicated.

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Figure 1: Cellular alterations and molecular mechanisms involved in hepatic cystogenesis.

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References

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

    Article  CAS  PubMed  Google Scholar 

  2. 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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  5. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. [No authors listed] The polycystic kidney disease 1 gene encodes a 14 kb transcript and lies within a duplicated region on chromosome 16. The European Polycystic Kidney Disease Consortium. Cell 77, 881–894 (1994).

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

    Article  CAS  PubMed  Google Scholar 

  8. Ward, C. J. et al. The gene mutated in autosomal recessive polycystic kidney disease encodes a large, receptor-like protein. Nat. Genet. 30, 259–269 (2002).

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  10. Rossetti, S. et al. Comprehensive molecular diagnostics in autosomal dominant polycystic kidney disease. J. Am. Soc. Nephrol. 18, 2143–2160 (2007).

    Article  CAS  PubMed  Google Scholar 

  11. Waanders, E., te Morsche, R. H., de Man, R. A., Jansen, J. B. & Drenth, J. P. Extensive mutational analysis of PRKCSH and SEC63 broadens the spectrum of polycystic liver disease. Hum. Mutat. 27, 830 (2006).

    Article  PubMed  Google Scholar 

  12. Waanders, E. et al. Secondary and tertiary structure modeling reveals effects of novel mutations in polycystic liver disease genes PRKCSH and SEC63. Clin. Genet. 78, 47–56 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Ong, A. C. & Harris, P. C. Molecular pathogenesis of ADPKD: the polycystin complex gets complex. Kidney Int. 67, 1234–1247 (2005).

    Article  CAS  PubMed  Google Scholar 

  14. Geng, L. et al. Syntaxin 5 regulates the endoplasmic reticulum channel-release properties of polycystin-2. Proc. Natl Acad. Sci. USA 105, 15920–15925 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  16. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. 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).

    Article  CAS  PubMed  Google Scholar 

  18. 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).

    Article  CAS  PubMed  Google Scholar 

  19. 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).

    CAS  PubMed  Google Scholar 

  20. Watnick, T. et al. Mutations of PKD1 in ADPKD2 cysts suggest a pathogenic effect of trans-heterozygous mutations. Nat. Genet. 25, 143–144 (2000).

    Article  CAS  PubMed  Google Scholar 

  21. Banales, J. M., Munoz-Garrido, P. & Bujanda, L. Somatic second-hit mutations leads to polycystic liver diseases. World J. Gastroenterol. 19, 141–143 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Chandok, N. Polycystic liver disease: a clinical review. Ann. Hepatol. 11, 819–826 (2012).

    Article  PubMed  Google Scholar 

  23. Raynaud, P., Carpentier, R., Antoniou, A. & Lemaigre, F. P. Biliary differentiation and bile duct morphogenesis in development and disease. Int. J. Biochem. Cell Biol. 43, 245–256 (2011).

    Article  CAS  PubMed  Google Scholar 

  24. Wills, E. S., Roepman, R. & Drenth, J. P. Polycystic liver disease: ductal plate malformation and the primary cilium. Trends Mol. Med. 20, 261–270 (2014).

    Article  CAS  PubMed  Google Scholar 

  25. Temmerman, F. et al. Systematic review: the pathophysiology and management of polycystic liver disease. Aliment. Pharmacol. Ther. 34, 702–713 (2011).

    Article  CAS  PubMed  Google Scholar 

  26. Gunay-Aygun, M. Liver and kidney disease in ciliopathies. Am. J. Med. Genet. C. Semin. Med. Genet. 151C, 296–306 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Godlewski, G., Gaubert-Cristol, R., Rouy, S. & Prudhomme, M. Liver development in the rat and in man during the embryonic period (Carnegie stages 11–23). Microsc. Res. Tech. 39, 314–327 (1997).

    Article  CAS  PubMed  Google Scholar 

  28. Carpentier, R. et al. Embryonic ductal plate cells give rise to cholangiocytes, periportal hepatocytes, and adult liver progenitor cells. Gastroenterology 141, 1432–1438 (2011).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  31. Crawford, J. M. Development of the intrahepatic biliary tree. Semin. Liver Dis. 22, 213–226 (2002).

    Article  PubMed  Google Scholar 

  32. Ezratty, E. J. et al. A role for the primary cilium in Notch signaling and epidermal differentiation during skin development. Cell 145, 1129–1141 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Lopes, S. S. et al. Notch signalling regulates left-right asymmetry through ciliary length control. Development 137, 3625–3632 (2010).

    Article  CAS  PubMed  Google Scholar 

  34. Shih, H. P. et al. A Notch-dependent molecular circuitry initiates pancreatic endocrine and ductal cell differentiation. Development 139, 2488–2499 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Sato, Y. et al. Cholangiocytes with mesenchymal features contribute to progressive hepatic fibrosis of the polycystic kidney rat. Am. J. Pathol. 171, 1859–1871 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Hassane, S. et al. Elevated TGFβ-Smad signalling in experimental Pkd1 models and human patients with polycystic kidney disease. J. Pathol. 222, 21–31 (2010).

    CAS  PubMed  Google Scholar 

  37. Decaens, T. et al. Stabilization of β-catenin affects mouse embryonic liver growth and hepatoblast fate. Hepatology 47, 247–258 (2008).

    Article  CAS  PubMed  Google Scholar 

  38. May-Simera, H. L. & Kelley, M. W. Cilia, Wnt signaling, and the cytoskeleton. Cilia 1, 7 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Benzing, T., Simons, M. & Walz, G. Wnt signaling in polycystic kidney disease. J. Am. Soc. Nephrol. 18, 1389–1398 (2007).

    Article  CAS  PubMed  Google Scholar 

  40. Yanai, M. et al. FGF signaling segregates biliary cell-lineage from chick hepatoblasts cooperatively with BMP4 and ECM components in vitro. Dev. Dyn. 237, 1268–1283 (2008).

    Article  CAS  PubMed  Google Scholar 

  41. Neugebauer, J. M., Amack, J. D., Peterson, A. G., Bisgrove, B. W. & Yost, H. J. FGF signalling during embryo development regulates cilia length in diverse epithelia. Nature 458, 651–654 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Pavik, I. et al. Patients with autosomal dominant polycystic kidney disease have elevated fibroblast growth factor 23 levels and a renal leak of phosphate. Kidney Int. 79, 234–240 (2011).

    Article  CAS  PubMed  Google Scholar 

  43. Clotman, F. et al. The onecut transcription factor HNF6 is required for normal development of the biliary tract. Development 129, 1819–1828 (2002).

    CAS  PubMed  Google Scholar 

  44. Hunter, M. P. et al. The homeobox gene Hhex is essential for proper hepatoblast differentiation and bile duct morphogenesis. Dev. Biol. 308, 355–367 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Pierreux, C. E. et al. The transcription factor hepatocyte nuclear factor-6 controls the development of pancreatic ducts in the mouse. Gastroenterology 130, 532–541 (2006).

    Article  CAS  PubMed  Google Scholar 

  46. Guay-Woodford, L. M., Green, W. J., Lindsey, J. R. & Beier, D. R. Germline and somatic loss of function of the mouse cpk gene causes biliary ductal pathology that is genetically modulated. Hum. Mol. Genet. 9, 769–778 (2000).

    Article  CAS  PubMed  Google Scholar 

  47. Hou, X. et al. Cystin, a novel cilia-associated protein, is disrupted in the cpk mouse model of polycystic kidney disease. J. Clin. Invest. 109, 533–540 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Hiesberger, T. et al. Mutation of hepatocyte nuclear factor-1β inhibits Pkhd1 gene expression and produces renal cysts in mice. J. Clin. Invest. 113, 814–825 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Gresh, L. et al. A transcriptional network in polycystic kidney disease. EMBO J. 23, 1657–1668 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Yamasaki, H. et al. Suppression of C/EBPα expression in periportal hepatoblasts may stimulate biliary cell differentiation through increased Hnf6 and Hnf1b expression. Development 133, 4233–4243 (2006).

    Article  CAS  PubMed  Google Scholar 

  51. Hand, N. J. et al. The microRNA-30 family is required for vertebrate hepatobiliary development. Gastroenterology 136, 1081–1090 (2009).

    Article  CAS  PubMed  Google Scholar 

  52. Masyuk, A. I., Masyuk, T. V. & LaRusso, N. F. Cholangiocyte primary cilia in liver health and disease. Dev. Dyn. 237, 2007–2012 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. 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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  55. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  56. Stroope, A. et al. Hepato-renal pathology in Pkd2ws25/− mice, an animal model of autosomal dominant polycystic kidney disease. Am. J. Pathol. 176, 1282–1291 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  57. Alvaro, D. & Mancino, M. G. New insights on the molecular and cell biology of human cholangiopathies. Mol. Aspects Med. 29, 50–57 (2008).

    Article  CAS  PubMed  Google Scholar 

  58. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Battini, L. et al. Loss of polycystin-1 causes centrosome amplification and genomic instability. Hum. Mol. Genet. 17, 2819–2833 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Woollard, J. R. et al. A mouse model of autosomal recessive polycystic kidney disease with biliary duct and proximal tubule dilatation. Kidney Int. 72, 328–336 (2007).

    Article  CAS  PubMed  Google Scholar 

  61. Torres, V. E. & Harris, P. C. Strategies targeting cAMP signaling in the treatment of polycystic kidney disease. J. Am. Soc. Nephrol. 25, 18–32 (2014).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  63. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Gradilone, S. A. et al. Cholangiocyte cilia express TRPV4 and detect changes in luminal tonicity inducing bicarbonate secretion. Proc. Natl Acad. Sci. USA 104, 19138–19143 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  65. 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).

    Article  CAS  PubMed  Google Scholar 

  66. Onori, P. et al. Polycystic liver diseases. Dig. Liver Dis. 42, 261–271 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Muchatuta, M. N., Gattone, V. H. 2nd, Witzmann, F. A. & Blazer-Yost, B. L. Structural and functional analyses of liver cysts from the BALB/c-cpk mouse model of polycystic kidney disease. Exp. Biol. Med. (Maywood) 234, 17–27 (2009).

    Article  CAS  Google Scholar 

  68. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Fedeles, S. V., Gallagher, A. R. & Somlo, S. Polycystin-1: a master regulator of intersecting cystic pathways. Trends Mol. Med. 20, 251–260 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Ma, M., Tian, X., Igarashi, P., Pazour, G. J. & Somlo, S. Loss of cilia suppresses cyst growth in genetic models of autosomal dominant polycystic kidney disease. Nat. Genet. 45, 1004–1012 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Alvaro, D. et al. Morphological and functional features of hepatic cyst epithelium in autosomal dominant polycystic kidney disease. Am. J. Pathol. 172, 321–332 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. 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).

    Article  CAS  PubMed  Google Scholar 

  74. 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).

    Article  CAS  PubMed  Google Scholar 

  75. 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).

    Article  CAS  PubMed  Google Scholar 

  76. Waanders, E., Van Krieken, J. H., Lameris, A. L. & Drenth, J. P. Disrupted cell adhesion but not proliferation mediates cyst formation in polycystic liver disease. Mod. Pathol. 21, 1293–1302 (2008).

    Article  CAS  PubMed  Google Scholar 

  77. Nichols, M. T. et al. Secretion of cytokines and growth factors into autosomal dominant polycystic kidney disease liver cyst fluid. Hepatology 40, 836–846 (2004).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  79. Amura, C. R. et al. CXCR2 agonists in ADPKD liver cyst fluids promote cell proliferation. Am. J. Physiol. Cell Physiol. 294, C786–C796 (2008).

    Article  CAS  PubMed  Google Scholar 

  80. Sato, Y. et al. Activation of the MEK5/ERK5 cascade is responsible for biliary dysgenesis in a rat model of Caroli's disease. Am. J. Pathol. 166, 49–60 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Torres, V. E. et al. Epidermal growth factor receptor tyrosine kinase inhibition is not protective in PCK rats. Kidney Int. 66, 1766–1773 (2004).

    Article  CAS  PubMed  Google Scholar 

  82. Amura, C. R. et al. VEGF receptor inhibition blocks liver cyst growth in pkd2WS25/− mice. Am. J. Physiol. Cell Physiol. 293, C419–C428 (2007).

    Article  CAS  PubMed  Google Scholar 

  83. 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. (Maywood) 234, 1155–1165 (2009).

    Article  CAS  Google Scholar 

  84. Renken, C., Fischer, D. C., Kundt, G., Gretz, N. & Haffner, D. Inhibition of mTOR with sirolimus does not attenuate progression of liver and kidney disease in PCK rats. Nephrol. Dial. Transplant 26, 92–100 (2011).

    Article  CAS  PubMed  Google Scholar 

  85. Qian, Q. et al. Sirolimus reduces polycystic liver volume in ADPKD patients. J. Am. Soc. Nephrol. 19, 631–638 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Walz, G. et al. Everolimus in patients with autosomal dominant polycystic kidney disease. N. Engl. J. Med. 363, 830–840 (2010).

    Article  CAS  PubMed  Google Scholar 

  87. Serra, A. L. et al. Sirolimus and kidney growth in autosomal dominant polycystic kidney disease. N. Engl. J. Med. 363, 820–829 (2010).

    Article  CAS  PubMed  Google Scholar 

  88. Chrispijn, M. et al. Everolimus does not further reduce polycystic liver volume when added to long acting octreotide: results from a randomized controlled trial. J. Hepatol. 59, 153–159 (2013).

    Article  CAS  PubMed  Google Scholar 

  89. 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).

    Article  CAS  PubMed  Google Scholar 

  90. Yoshihara, D. et al. PPAR-γ 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).

    Article  CAS  PubMed  Google Scholar 

  91. Yoshihara, D. et al. Global gene expression profiling in PPAR-γ agonist-treated kidneys in an orthologous rat model of human autosomal recessive polycystic kidney disease. PPAR Res. 2012, 695898 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Chapman, A. B. Cystic disease in women: clinical characteristics and medical management. Adv. Ren. Replace. Ther. 10, 24–30 (2003).

    Article  PubMed  Google Scholar 

  94. Gabow, P. A. et al. Risk factors for the development of hepatic cysts in autosomal dominant polycystic kidney disease. Hepatology 11, 1033–1037 (1990).

    Article  CAS  PubMed  Google Scholar 

  95. Sherstha, R. et al. Postmenopausal estrogen therapy selectively stimulates hepatic enlargement in women with autosomal dominant polycystic kidney disease. Hepatology 26, 1282–1286 (1997).

    CAS  PubMed  Google Scholar 

  96. Alvaro, D. et al. Estrogens and the pathophysiology of the biliary tree. World J. Gastroenterol. 12, 3537–3545 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. 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).

    Article  CAS  PubMed  Google Scholar 

  98. 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).

    Article  CAS  PubMed  Google Scholar 

  99. 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).

    Article  CAS  PubMed  Google Scholar 

  100. Caroli, A. et al. Reducing polycystic liver volume in ADPKD: effects of somatostatin analogue octreotide. Clin. J. Am. Soc. Nephrol. 5, 783–789 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Hogan, M. C. et al. Randomized clinical trial of long-acting somatostatin for autosomal dominant polycystic kidney and liver disease. J. Am. Soc. Nephrol. 21, 1052–1061 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Hogan, M. C. et al. Somatostatin analog therapy for severe polycystic liver disease: results after 2 years. Nephrol. Dial. Transplant 27, 3532–3539 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. van Keimpema, L. et al. Lanreotide reduces the volume of polycystic liver: a randomized, double-blind, placebo-controlled trial. Gastroenterology 137, 1661–1668 (2009).

    Article  CAS  PubMed  Google Scholar 

  104. Chrispijn, M. et al. The long-term outcome of patients with polycystic liver disease treated with lanreotide. Aliment. Pharmacol. Ther. 35, 266–274 (2012).

    Article  CAS  PubMed  Google Scholar 

  105. Temmerman, F. et al. Safety and efficacy of different lanreotide doses in the treatment of polycystic liver disease: pooled analysis of individual patient data. Aliment. Pharmacol. Ther. 38, 397–406 (2013).

    Article  CAS  PubMed  Google Scholar 

  106. Gevers, T. J. et al. Young women with polycystic liver disease respond best to somatostatin analogues: a pooled analysis of individual patient data. Gastroenterology 145, 357–365 (2013).

    Article  CAS  PubMed  Google Scholar 

  107. US National Library of Medicine. ClincalTrials.gov [online], (2012).

  108. 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).

    Article  CAS  PubMed  Google Scholar 

  109. Banales, J. M., Prieto, J. & Medina, J. F. Cholangiocyte anion exchange and biliary bicarbonate excretion. World J. Gastroenterol. 12, 3496–3511 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Banales, J. M. et al. Bicarbonate-rich choleresis induced by secretin in normal rat is taurocholate-dependent and involves AE2 anion exchanger. Hepatology 43, 266–275 (2006).

    Article  CAS  PubMed  Google Scholar 

  111. Tietz, P. S. et al. Agonist-induced coordinated trafficking of functionally related transport proteins for water and ions in cholangiocytes. J. Biol. Chem. 278, 20413–20419 (2003).

    Article  CAS  PubMed  Google Scholar 

  112. Perrone, R. D. et al. Autosomal dominant polycystic kidney disease decreases anion exchanger activity. Am. J. Physiol. 272, C1748–C1756 (1997).

    Article  CAS  PubMed  Google Scholar 

  113. Wang, X. et al. Insignificant effect of secretin in rodent models of polycystic kidney and liver disease. Am. J. Physiol. Renal. Physiol. 303, F1089–F1098 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Urribarri, A. D. et al. Inhibition of metalloprotease hyperactivity in cystic cholangiocytes halts the development of polycystic liver diseases. Gut http://dx.doi.org/10.1136/gutjnl-2013-305281.

  115. Yasoshima, M. et al. Matrix proteins of basement membrane of intrahepatic bile ducts are degraded in congenital hepatic fibrosis and Caroli's disease. J. Pathol. 217, 442–451 (2009).

    Article  CAS  PubMed  Google Scholar 

  116. Nemunaitis, J. et al. Combined analysis of studies of the effects of the matrix metalloproteinase inhibitor marimastat on serum tumor markers in advanced cancer: selection of a biologically active and tolerable dose for longer-term studies. Clin. Cancer Res. 4, 1101–1109 (1998).

    CAS  PubMed  Google Scholar 

  117. Rosenbaum, E. et al. Marimastat in the treatment of patients with biochemically relapsed prostate cancer: a prospective randomized, double-blind, phase I/II trial. Clin. Cancer Res. 11, 4437–4443 (2005).

    Article  CAS  PubMed  Google Scholar 

  118. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Gradilone, S. A. et al. HDAC6 is overexpressed in cystic cholangiocytes and its inhibition reduces cystogenesis. Am. J. Pathol. 184, 600–608 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Gevers, T. J. & Drenth, J. P. Somatostatin analogues for treatment of polycystic liver disease. Curr. Opin. Gastroenterol. 27, 294–300 (2011).

    Article  CAS  PubMed  Google Scholar 

  121. Takiar, V. & Caplan, M. J. Polycystic kidney disease: pathogenesis and potential therapies. Biochim. Biophys. Acta 1812, 1337–1343 (2011).

    Article  CAS  PubMed  Google Scholar 

  122. Abu-Wasel, B., Walsh, C., Keough, V. & Molinari, M. Pathophysiology, epidemiology, classification and treatment options for polycystic liver diseases. World J. Gastroenterol. 19, 5775–5786 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute, Donostia University Hospital, University of the Basque Country (UPV-EHU), CIBERehd, IKERBASQUE, Paseo del Doctor Beguiristain, 20014, San Sebastián, Spain

    Maria J. Perugorria, Luis Bujanda & Jesus M. Banales

  2. Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, 55905, MN, USA

    Tatyana V. Masyuk & Nicholas F. LaRusso

  3. Department of Physiology and Pharmacology, Experimental Hepatology and Drug Targeting (HEVEFARM), Biomedical Research Institute of Salamanca (IBSAL), Campus Miguel de Unamuno, University of Salamanca, 37007, Salamanca, Spain

    Jose J. Marin

  4. Department of Gastroenterology, “Università Politecnica delle Marche”, Piazza Roma 22, Ancona, 60121, Italy

    Marco Marzioni

Authors
  1. Maria J. Perugorria
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  2. Tatyana V. Masyuk
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  3. Jose J. Marin
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  4. Marco Marzioni
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  5. Luis Bujanda
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  6. Nicholas F. LaRusso
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  7. Jesus M. Banales
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All authors contributed equally to all aspects of this manuscript.

Corresponding author

Correspondence to Jesus M. Banales.

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Perugorria, M., Masyuk, T., Marin, J. et al. Polycystic liver diseases: advanced insights into the molecular mechanisms. Nat Rev Gastroenterol Hepatol 11, 750–761 (2014). https://doi.org/10.1038/nrgastro.2014.155

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