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 La Russo, Jesús PrietoLuis Bujanda, Joost P H Drenth, Jesús M. Banales

Research output: Contribution to journalArticle

23 Citations (Scopus)

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 ([Ca<sup>2+</sup>]<inf>i</inf>). 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

Fingerprint

Ursodeoxycholic Acid
Bile Acids and Salts
Theoretical Models
Liver
Bile
Glycodeoxycholic Acid
Fibrosis
Polycystic liver disease
Kidney
Inborn Genetic Diseases
Wild Animals
Mitogen-Activated Protein Kinase Kinases
Therapeutics
Serum
Phosphatidylinositol 3-Kinases
Liver Diseases
High Pressure Liquid Chromatography
Apoptosis
Calcium

Keywords

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

ASJC Scopus subject areas

  • Hepatology

Cite this

Munoz-Garrido, P., Marin, J. J. G., Perugorria, M. J., Urribarri, A. D., Erice, O., Sáez, E., ... 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

Ursodeoxycholic acid inhibits hepatic cystogenesis in experimental models of polycystic liver disease. / Munoz-Garrido, Patricia; Marin, José J G; Perugorria, María J.; Urribarri, Aura D.; Erice, Oihane; Sáez, Elena; Úriz, Miriam; Sarvide, Sarai; Portu, Ainhoa; Concepcion, Axel R.; Romero, Marta R.; Monte, María J.; Santos-Laso, Álvaro; Hijona, Elizabeth; Jimenez-Agüero, Raúl; Marzioni, Marco; Beuers, Ulrich; Masyuk, Tatyana V.; La Russo, Nicholas F; Prieto, Jesús; Bujanda, Luis; Drenth, Joost P H; Banales, Jesús M.

In: Journal of Hepatology, Vol. 63, No. 4, 01.10.2015, p. 952-961.

Research output: Contribution to journalArticle

Munoz-Garrido, P, Marin, JJG, Perugorria, MJ, Urribarri, AD, Erice, O, Sáez, E, Úriz, M, Sarvide, S, Portu, A, Concepcion, AR, Romero, MR, Monte, MJ, Santos-Laso, Á, Hijona, E, Jimenez-Agüero, R, Marzioni, M, Beuers, U, Masyuk, TV, La Russo, NF, Prieto, J, Bujanda, L, Drenth, JPH & Banales, JM 2015, 'Ursodeoxycholic acid inhibits hepatic cystogenesis in experimental models of polycystic liver disease', Journal of Hepatology, vol. 63, no. 4, pp. 952-961. https://doi.org/10.1016/j.jhep.2015.05.023
Munoz-Garrido P, Marin JJG, Perugorria MJ, Urribarri AD, Erice O, Sáez E et al. Ursodeoxycholic acid inhibits hepatic cystogenesis in experimental models of polycystic liver disease. Journal of Hepatology. 2015 Oct 1;63(4):952-961. https://doi.org/10.1016/j.jhep.2015.05.023
Munoz-Garrido, Patricia ; Marin, José J G ; Perugorria, María J. ; Urribarri, Aura D. ; Erice, Oihane ; Sáez, Elena ; Úriz, Miriam ; Sarvide, Sarai ; Portu, Ainhoa ; Concepcion, Axel R. ; Romero, Marta R. ; Monte, María J. ; Santos-Laso, Álvaro ; Hijona, Elizabeth ; Jimenez-Agüero, Raúl ; Marzioni, Marco ; Beuers, Ulrich ; Masyuk, Tatyana V. ; La Russo, Nicholas F ; Prieto, Jesús ; Bujanda, Luis ; Drenth, Joost P H ; Banales, Jesús M. / Ursodeoxycholic acid inhibits hepatic cystogenesis in experimental models of polycystic liver disease. In: Journal of Hepatology. 2015 ; Vol. 63, No. 4. pp. 952-961.
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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.",
keywords = "Cholangiocyte, Cystogenesis, Intracellular calcium, Polycystic liver diseases (PLDs), Therapy, Ursodeoxycholic acid (UDCA)",
author = "Patricia Munoz-Garrido and Marin, {Jos{\'e} J G} and Perugorria, {Mar{\'i}a J.} and Urribarri, {Aura D.} and Oihane Erice and Elena S{\'a}ez and Miriam {\'U}riz and Sarai Sarvide and Ainhoa Portu and Concepcion, {Axel R.} and Romero, {Marta R.} and Monte, {Mar{\'i}a J.} and {\'A}lvaro Santos-Laso and Elizabeth Hijona and Ra{\'u}l Jimenez-Ag{\"u}ero and Marco Marzioni and Ulrich Beuers and Masyuk, {Tatyana V.} and {La Russo}, {Nicholas F} and Jes{\'u}s Prieto and Luis Bujanda and Drenth, {Joost P H} and Banales, {Jes{\'u}s M.}",
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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 - La Russo, Nicholas F

AU - Prieto, Jesús

AU - Bujanda, Luis

AU - Drenth, Joost P H

AU - Banales, Jesús M.

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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