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

JOURNAL OF HEPATOLOGY

卷:63

Article

Munoz-Garrido, Patricia^1,2  Marin, Jose J. G.^2,3  Perugorria, Maria J.^1,2,4  Urribarri, Aura D.⁵  Erice, Oihane¹  Saez, Elena⁵  Uriz, Miriam⁵  Sarvide, Sarai⁵  Portu, Ainhoa^2,5  Concepcion, Axel R.⁵  Romero, Marta R.^2,3  Monte, Maria J.^2,3  Santos-Laso, Alvaro¹  Hijona, Elizabeth^1,2  Jimenez-Agueero, Raul¹  Marzioni, Marco⁶  Beuers, Ulrich⁷  Masyuk, Tatyana V.⁸  LaRusso, Nicholas F.⁸  Prieto, Jesus^2,5  Bujanda, Luis^1,2  Drenth, Joost P. H.⁹  Banales, Jesus M.^1,2,4,5 

[1] Univ Basque Country UPV EHU, Donostia Univ Hosp, Biodonostia Hlth Res Inst, Dept Liver & Gastrointestinal Dis, San Sebastian, Spain

[2] Inst Salud Carlos III, CIBERehd, Natl Inst Study Liver & Gastrointestinal Dis, Madrid, Spain

[3] Univ Salamanca, Expt Hepatol & Drug Targeting HEVEFARM, Biomed Res Inst Salamanca IBSAL, E-37008 Salamanca, Spain

[4] Basque Fdn Sci, IKERBASQUE, Bilbao, Spain

[5] Univ Navarra, CIMA, Div Gene Therapy & Hepatol, E-31080 Pamplona, Spain

[6] Univ Politecn Marche, Dept Gastroenterol, Ancona, Italy

[7] Univ Amsterdam, Acad Med Ctr, Dept Gastroenterol & Hepatol, Tytgat Inst Liver & Intestinal Res, NL-1105 AZ Amsterdam, Netherlands

[8] Mayo Clin, Div Gastroenterol & Hepatol, Rochester, MN USA

[9] Radboud Univ Nijmegen, Med Ctr, Dept Gastroenterol & Hepatol, NL-6525 ED Nijmegen, Netherlands

关键词: Polycystic liver diseases (PLDs);    Ursodeoxycholic acid (UDCA);    Cystogenesis;    Cholangiocyte;    Intracellular calcium;    Therapy;   

DOI  :  10.1016/j.jhep.2015.05.023

来源: Elsevier

【 摘 要 】

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. (C) 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

【 授权许可】

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