Ursodeoxycholic acid inhibits hepatic cystogenesis in experimental models of polycystic liver disease

Patricia Munoz-Garrido, José J.G. Marin, María J. Perugorria, Aura D. Urribarri, Oihane Erice, Elena Sáez, Miriam Úriz, Sarai Sarvide, Ainhoa Portu, Axel R. Concepcion, Marta R. Romero, María J. Monte, Álvaro Santos-Laso, Elizabeth Hijona, Raúl Jimenez-Agüero, Marco Marzioni, Ulrich Beuers, Tatyana V. Masyuk, Nicholas F. Larusso, Jesús PrietoLuis Bujanda, Joost P.H. Drenth, Jesús M. Banales

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

Background & Aims Polycystic liver diseases (PLDs) are genetic disorders characterized by progressive biliary cystogenesis. Current therapies show short-term and/or modest beneficial effects. Cystic cholangiocytes hyperproliferate as a consequence of diminished intracellular calcium levels ([Ca2+]i). Here, the therapeutic value of ursodeoxycholic acid (UDCA) was investigated. Methods Effect of UDCA was examined in vitro and in polycystic (PCK) rats. Hepatic cystogenesis and fibrosis, and the bile acid (BA) content were evaluated from the liver, bile, serum, and kidneys by HPLC-MS/MS. Results Chronic treatment of PCK rats with UDCA inhibits hepatic cystogenesis and fibrosis, and improves their motor behaviour. As compared to wild-type animals, PCK rats show increased BA concentration ([BA]) in liver, similar hepatic Cyp7a1 mRNA levels, and diminished [BA] in bile. Likewise, [BA] is increased in cystic fluid of PLD patients compared to their matched serum levels. In PCK rats, UDCA decreases the intrahepatic accumulation of cytotoxic BA, normalizes their diminished [BA] in bile, increases the BA secretion in bile and diminishes the increased [BA] in kidneys. In vitro, UDCA inhibits the hyperproliferation of polycystic human cholangiocytes via a PI3K/AKT/MEK/ERK1/2-dependent mechanism without affecting apoptosis. Finally, the presence of glycodeoxycholic acid promotes the proliferation of polycystic human cholangiocytes, which is inhibited by both UDCA and tauro-UDCA. Conclusions UDCA was able to halt the liver disease of a rat model of PLD through inhibiting cystic cholangiocyte hyperproliferation and decreasing the levels of cytotoxic BA species in the liver, which suggests the use of UDCA as a potential therapeutic tool for PLD patients.

Original languageEnglish (US)
Pages (from-to)952-961
Number of pages10
JournalJournal of hepatology
Volume63
Issue number4
DOIs
StatePublished - Oct 1 2015

Keywords

  • Cholangiocyte
  • Cystogenesis
  • Intracellular calcium
  • Polycystic liver diseases (PLDs)
  • Therapy
  • Ursodeoxycholic acid (UDCA)

ASJC Scopus subject areas

  • Hepatology

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    Munoz-Garrido, P., Marin, J. J. G., Perugorria, M. J., Urribarri, A. D., Erice, O., Sáez, E., Úriz, M., Sarvide, S., Portu, A., Concepcion, A. R., Romero, M. R., Monte, M. J., Santos-Laso, Á., Hijona, E., Jimenez-Agüero, R., Marzioni, M., Beuers, U., Masyuk, T. V., Larusso, N. F., ... Banales, J. M. (2015). Ursodeoxycholic acid inhibits hepatic cystogenesis in experimental models of polycystic liver disease. Journal of hepatology, 63(4), 952-961. https://doi.org/10.1016/j.jhep.2015.05.023