TY - JOUR
T1 - Ursodeoxycholic acid inhibits hepatic cystogenesis in experimental models of polycystic liver disease
AU - Munoz-Garrido, Patricia
AU - Marin, José J.G.
AU - Perugorria, María J.
AU - Urribarri, Aura D.
AU - Erice, Oihane
AU - Sáez, Elena
AU - Úriz, Miriam
AU - Sarvide, Sarai
AU - Portu, Ainhoa
AU - Concepcion, Axel R.
AU - Romero, Marta R.
AU - Monte, María J.
AU - Santos-Laso, Álvaro
AU - Hijona, Elizabeth
AU - Jimenez-Agüero, Raúl
AU - Marzioni, Marco
AU - Beuers, Ulrich
AU - Masyuk, Tatyana V.
AU - Larusso, Nicholas F.
AU - Prieto, Jesús
AU - Bujanda, Luis
AU - Drenth, Joost P.H.
AU - Banales, Jesús M.
N1 - Funding Information:
Spanish Ministries of Economy and Competitiveness (J.M. Banales: FIS PI12/00380 and PI15/01132 ; M.J. Perugorria: PI14/00399 ) cofinanced by “Fondo Europeo de Desarrollo Regional” (FEDER), and Science and Technology (J.J.G. Marin: SAF2010-15517 and SAF2013-40620-R ), and “ Instituto de Salud Carlos III ” (J.M. Banales, L. Bujanda, J.J.G. Marín, and J. Prieto: Ciberehd; J.M. Banales: Miguel Servet Program CON14/00129), Spain; Department of Industry of the Basque Government (J.M. Banales: SAIO12-PE12BN002 ), Spanish UTE for CIMA Project (J.M. Banales and J. Prieto), NIH of United States of America (N.F. LaRusso: DK24031 ), Mayo Translational Polycystic Kidney Disease Center grant (T.V. Masyuk: NIH P30 DK090728 ) and Mayo Center for Cell Signaling in Gastroenterology (N.F. LaRusso: NIH P30 DK084567). J.M.B. is funded by the “Asociación Española Contra el Cancer ( AECC ), Spain”.
Publisher Copyright:
© 2015 European Association for the Study of the Liver.
PY - 2015/10/1
Y1 - 2015/10/1
N2 - 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.
AB - 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.
KW - Cholangiocyte
KW - Cystogenesis
KW - Intracellular calcium
KW - Polycystic liver diseases (PLDs)
KW - Therapy
KW - Ursodeoxycholic acid (UDCA)
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U2 - 10.1016/j.jhep.2015.05.023
DO - 10.1016/j.jhep.2015.05.023
M3 - Article
C2 - 26044126
AN - SCOPUS:84941933532
SN - 0168-8278
VL - 63
SP - 952
EP - 961
JO - Journal of hepatology
JF - Journal of hepatology
IS - 4
ER -