title: Ursodeoxycholic acid inhibits hepatic cystogenesis in experimental models of polycystic liver disease.
abstract: OBJECTIVE
  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.
authors.affiliation: 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.
authors.forename: Patricia
authors.initials: P
authors.lastname: Munoz-Garrido
authors.affiliation: 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.
authors.forename: José J G
authors.initials: JJ
authors.lastname: Marin
authors.affiliation: 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.
authors.forename: María J
authors.initials: MJ
authors.lastname: Perugorria
authors.affiliation: Division of Gene Therapy and Hepatology, CIMA of the University of Navarra, Pamplona, Spain.
authors.forename: Aura D
authors.initials: AD
authors.lastname: Urribarri
authors.affiliation: Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastián, Spain.
authors.forename: Oihane
authors.initials: O
authors.lastname: Erice
authors.affiliation: Division of Gene Therapy and Hepatology, CIMA of the University of Navarra, Pamplona, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Sáez
authors.affiliation: Division of Gene Therapy and Hepatology, CIMA of the University of Navarra, Pamplona, Spain.
authors.forename: Miriam
authors.initials: M
authors.lastname: Úriz
authors.affiliation: Division of Gene Therapy and Hepatology, CIMA of the University of Navarra, Pamplona, Spain.
authors.forename: Sarai
authors.initials: S
authors.lastname: Sarvide
authors.affiliation: 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.
authors.forename: Ainhoa
authors.initials: A
authors.lastname: Portu
authors.affiliation: Division of Gene Therapy and Hepatology, CIMA of the University of Navarra, Pamplona, Spain.
authors.forename: Axel R
authors.initials: AR
authors.lastname: Concepcion
authors.affiliation: 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.
authors.forename: Marta R
authors.initials: MR
authors.lastname: Romero
authors.affiliation: 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.
authors.forename: María J
authors.initials: MJ
authors.lastname: Monte
authors.affiliation: Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastián, Spain.
authors.forename: Álvaro
authors.initials: Á
authors.lastname: Santos-Laso
authors.affiliation: 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.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hijona
authors.affiliation: Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastián, Spain.
authors.forename: Raúl
authors.initials: R
authors.lastname: Jimenez-Agüero
authors.affiliation: Department of Gastroenterology, "Università Politecnica delle Marche", Ancona, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Marzioni
authors.affiliation: Department of Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Beuers
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Tatyana V
authors.initials: TV
authors.lastname: Masyuk
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Nicholas F
authors.initials: NF
authors.lastname: LaRusso
authors.affiliation: 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.
authors.forename: Jesús
authors.initials: J
authors.lastname: Prieto
authors.affiliation: 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.
authors.forename: Luis
authors.initials: L
authors.lastname: Bujanda
authors.affiliation: Department of Gastroenterology & Hepatology, Radboud University Nijmegen Medical Center, The Netherlands.
authors.forename: Joost P H
authors.initials: JP
authors.lastname: Drenth
authors.affiliation: 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: jesus.banales@biodonostia.org.
authors.forename: Jesús M
authors.initials: JM
authors.lastname: Banales
mesh_terms: D000818:Animals; D017209:Apoptosis; D001647:Bile Acids and Salts / Q000378:metabolism; D001652:Bile Ducts / Q000378:metabolism / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002756:Cholagogues and Choleretics / Q000494:pharmacology; D003560:Cysts / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008107:Liver Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D053719:Tandem Mass Spectrometry; D014580:Ursodeoxycholic Acid / Q000494:pharmacology*
chemical_list: D001647:Bile Acids and Salts; D002756:Cholagogues and Choleretics; D014580:Ursodeoxycholic Acid; D002118:Calcium
keywords: Cholangiocyte; Cystogenesis; Intracellular calcium; Polycystic liver diseases (PLDs); Therapy; Ursodeoxycholic acid (UDCA)