Ursodeoxycholic acid inhibits hepatic cystogenesis in experimental models of polycystic liver disease
Authors: Oihane Erice
Patricia Munoz-Garrido
Elizabeth Hijona
Raúl Jimenez-Agüero
Sarai Sarvide
Miriam Úriz
Álvaro Santos-Laso
María J Monte
Jesús Prieto
Ainhoa Portu
Ulrich Beuers
José J G Marin
Nicholas F LaRusso
Marco Marzioni
Joost P H Drenth
Elena Sáez
Luis Bujanda
Jesús M Banales
Aura D Urribarri
María J Perugorria
Tatyana V Masyuk
Axel R Concepcion
Marta R Romero
Journal: Journal of hepatology (2015)
Discipline: CLINICAL MEDICINE
Keywords: Cholangiocyte; Cystogenesis; Intracellular calcium; Polycystic liver diseases (PLDs); Therapy
Affiliations: Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastián, Spain; National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Instituto de Salud Carlos III), Spain., National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Instituto de Salud Carlos III), Spain; Experimental Hepatology and Drug Targeting (HEVEFARM), Biomedical Research Institute of Salamanca (IBSAL), University of Salamanca, Salamanca, Spain., Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastián, Spain; National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Instituto de Salud Carlos III), Spain; IKERBASQUE, Basque Foundation for Science, Spain., Division of Gene Therapy and Hepatology, CIMA of the University of Navarra, Pamplona, Spain., Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastián, Spain., National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Instituto de Salud Carlos III), Spain; Division of Gene Therapy and Hepatology, CIMA of the University of Navarra, Pamplona, Spain., Department of Gastroenterology, "Università Politecnica delle Marche", Ancona, Italy., Department of Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands., Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA., Department of Gastroenterology & Hepatology, Radboud University Nijmegen Medical Center, The Netherlands., Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastián, Spain; National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Instituto de Salud Carlos III), Spain; IKERBASQUE, Basque Foundation for Science, Spain; Division of Gene Therapy and Hepatology, CIMA of the University of Navarra, Pamplona, Spain. Electronic address: .

Abstract:  Background &amp; 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 ([Ca(2+)]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. 

Retracted: No

PubPeer comments:
 Can the authors please check Figure 1D?. Some WB bands look similar (see squares). ![file] ,