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FXR agonist obeticholic acid induces liver growth but exacerbates biliary injury in rats with obstructive cholestasis

Cholestasis impairs liver regeneration following partial liver resection (PHx). Bile acid receptor farnesoid X-receptor (FXR) is a key mediator of liver regeneration. The effects of FXR agonist obeticholic acid (OCA) on liver (re)growth were therefore studied in cholestatic rats. Animals underwent s...

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Autores principales: van Golen, Rowan F., Olthof, Pim B., Lionarons, Daniël A., Reiniers, Megan J., Alles, Lindy K., Uz, Zehra, de Haan, Lianne, Ergin, Bulent, de Waart, Dirk R., Maas, Adrie, Verheij, Joanne, Jansen, Peter L., Damink, Steven W. Olde, Schaap, Frank G., van Gulik, Thomas M., Heger, Michal
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6224438/
https://www.ncbi.nlm.nih.gov/pubmed/30409980
http://dx.doi.org/10.1038/s41598-018-33070-1
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author van Golen, Rowan F.
Olthof, Pim B.
Lionarons, Daniël A.
Reiniers, Megan J.
Alles, Lindy K.
Uz, Zehra
de Haan, Lianne
Ergin, Bulent
de Waart, Dirk R.
Maas, Adrie
Verheij, Joanne
Jansen, Peter L.
Damink, Steven W. Olde
Schaap, Frank G.
van Gulik, Thomas M.
Heger, Michal
author_facet van Golen, Rowan F.
Olthof, Pim B.
Lionarons, Daniël A.
Reiniers, Megan J.
Alles, Lindy K.
Uz, Zehra
de Haan, Lianne
Ergin, Bulent
de Waart, Dirk R.
Maas, Adrie
Verheij, Joanne
Jansen, Peter L.
Damink, Steven W. Olde
Schaap, Frank G.
van Gulik, Thomas M.
Heger, Michal
author_sort van Golen, Rowan F.
collection PubMed
description Cholestasis impairs liver regeneration following partial liver resection (PHx). Bile acid receptor farnesoid X-receptor (FXR) is a key mediator of liver regeneration. The effects of FXR agonist obeticholic acid (OCA) on liver (re)growth were therefore studied in cholestatic rats. Animals underwent sham surgery or reversible bile duct ligation (rBDL). PHx with concurrent internal biliary drainage was performed 7 days after rBDL. Animals were untreated or received OCA (10 mg/kg/day) per oral gavage from rBDL until sacrifice. After 7 days of OCA treatment, dry liver weight increased in the rBDL + OCA group, indicating OCA-mediated liver growth. Enhanced proliferation in the rBDL + OCA group prior to PHx concurred with a rise in Ki67-positive hepatocytes, elevated hepatic Ccnd1 and Cdc25b expression, and an induction of intestinal fibroblast growth factor 15 expression. Liver regrowth after PHx was initially stagnant in the rBDL + OCA group, possibly due to hepatomegaly prior to PHx. OCA increased hepatobiliary injury markers during BDL, which was accompanied by upregulation of the bile salt export pump. There were no differences in histological liver injury. In conclusion, OCA induces liver growth in cholestatic rats prior to PHx but exacerbates biliary injury during cholestasis, likely by forced pumping of bile acids into an obstructed biliary tree.
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spelling pubmed-62244382018-11-13 FXR agonist obeticholic acid induces liver growth but exacerbates biliary injury in rats with obstructive cholestasis van Golen, Rowan F. Olthof, Pim B. Lionarons, Daniël A. Reiniers, Megan J. Alles, Lindy K. Uz, Zehra de Haan, Lianne Ergin, Bulent de Waart, Dirk R. Maas, Adrie Verheij, Joanne Jansen, Peter L. Damink, Steven W. Olde Schaap, Frank G. van Gulik, Thomas M. Heger, Michal Sci Rep Article Cholestasis impairs liver regeneration following partial liver resection (PHx). Bile acid receptor farnesoid X-receptor (FXR) is a key mediator of liver regeneration. The effects of FXR agonist obeticholic acid (OCA) on liver (re)growth were therefore studied in cholestatic rats. Animals underwent sham surgery or reversible bile duct ligation (rBDL). PHx with concurrent internal biliary drainage was performed 7 days after rBDL. Animals were untreated or received OCA (10 mg/kg/day) per oral gavage from rBDL until sacrifice. After 7 days of OCA treatment, dry liver weight increased in the rBDL + OCA group, indicating OCA-mediated liver growth. Enhanced proliferation in the rBDL + OCA group prior to PHx concurred with a rise in Ki67-positive hepatocytes, elevated hepatic Ccnd1 and Cdc25b expression, and an induction of intestinal fibroblast growth factor 15 expression. Liver regrowth after PHx was initially stagnant in the rBDL + OCA group, possibly due to hepatomegaly prior to PHx. OCA increased hepatobiliary injury markers during BDL, which was accompanied by upregulation of the bile salt export pump. There were no differences in histological liver injury. In conclusion, OCA induces liver growth in cholestatic rats prior to PHx but exacerbates biliary injury during cholestasis, likely by forced pumping of bile acids into an obstructed biliary tree. Nature Publishing Group UK 2018-11-08 /pmc/articles/PMC6224438/ /pubmed/30409980 http://dx.doi.org/10.1038/s41598-018-33070-1 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
van Golen, Rowan F.
Olthof, Pim B.
Lionarons, Daniël A.
Reiniers, Megan J.
Alles, Lindy K.
Uz, Zehra
de Haan, Lianne
Ergin, Bulent
de Waart, Dirk R.
Maas, Adrie
Verheij, Joanne
Jansen, Peter L.
Damink, Steven W. Olde
Schaap, Frank G.
van Gulik, Thomas M.
Heger, Michal
FXR agonist obeticholic acid induces liver growth but exacerbates biliary injury in rats with obstructive cholestasis
title FXR agonist obeticholic acid induces liver growth but exacerbates biliary injury in rats with obstructive cholestasis
title_full FXR agonist obeticholic acid induces liver growth but exacerbates biliary injury in rats with obstructive cholestasis
title_fullStr FXR agonist obeticholic acid induces liver growth but exacerbates biliary injury in rats with obstructive cholestasis
title_full_unstemmed FXR agonist obeticholic acid induces liver growth but exacerbates biliary injury in rats with obstructive cholestasis
title_short FXR agonist obeticholic acid induces liver growth but exacerbates biliary injury in rats with obstructive cholestasis
title_sort fxr agonist obeticholic acid induces liver growth but exacerbates biliary injury in rats with obstructive cholestasis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6224438/
https://www.ncbi.nlm.nih.gov/pubmed/30409980
http://dx.doi.org/10.1038/s41598-018-33070-1
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