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Farnesoid X receptor contributes to oleanolic acid‐induced cholestatic liver injury in mice

Farnesoid X receptor (FXR) is a nuclear receptor involved in the metabolism of bile acid. However, the molecular signaling of FXR in bile acid homeostasis in cholestatic drug‐induced liver injury remains unclear. Oleanolic acid (OA), a natural triterpenoid, has been reported to produce evident chole...

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Autores principales: Feng, Hong, Hu, Yan, Zhou, Shaoyu, Lu, Yuanfu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9546401/
https://www.ncbi.nlm.nih.gov/pubmed/35128688
http://dx.doi.org/10.1002/jat.4298
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author Feng, Hong
Hu, Yan
Zhou, Shaoyu
Lu, Yuanfu
author_facet Feng, Hong
Hu, Yan
Zhou, Shaoyu
Lu, Yuanfu
author_sort Feng, Hong
collection PubMed
description Farnesoid X receptor (FXR) is a nuclear receptor involved in the metabolism of bile acid. However, the molecular signaling of FXR in bile acid homeostasis in cholestatic drug‐induced liver injury remains unclear. Oleanolic acid (OA), a natural triterpenoid, has been reported to produce evident cholestatic liver injury in mice after a long‐term use. The present study aimed to investigate the role of FXR in OA‐induced cholestatic liver injury in mice using C57BL/6J (WT) mice and FXR knockout (FXR(−/−)) mice. The results showed that a significant alleviation in OA‐induced cholestatic liver injury was observed in FXR(−/−) mice as evidenced by decreases in serum alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase as well as reduced hepatocyte necrosis. UPLC‐MS analysis of bile acids revealed that the contents of bile acids decreased significantly in liver and serum, while increased in the bile in FXR(−/−) mice compared with in WT mice. In addition, the mRNA expressions of hepatic transporter Bsep, bile acid synthesis enzymes Bacs and Baat, and bile acids detoxifying enzymes Cyp3a11, Cyp2b10, Ephx1, Ugt1a1, and Ugt2b5 were increased in liver tissues of FXR(−/−) mice treated with OA. Furthermore, the expression of membrane protein BSEP was significantly higher in livers of FXR(−/−) mice compared with WT mice treated with OA. These results demonstrate that knockout of FXR may alleviate OA‐induced cholestatic liver injury in mice by decreasing accumulation of bile acids both in the liver and serum, increasing the export of bile acids via the bile, and by upregulation of bile acids detoxification enzymes.
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spelling pubmed-95464012022-10-14 Farnesoid X receptor contributes to oleanolic acid‐induced cholestatic liver injury in mice Feng, Hong Hu, Yan Zhou, Shaoyu Lu, Yuanfu J Appl Toxicol Research Articles Farnesoid X receptor (FXR) is a nuclear receptor involved in the metabolism of bile acid. However, the molecular signaling of FXR in bile acid homeostasis in cholestatic drug‐induced liver injury remains unclear. Oleanolic acid (OA), a natural triterpenoid, has been reported to produce evident cholestatic liver injury in mice after a long‐term use. The present study aimed to investigate the role of FXR in OA‐induced cholestatic liver injury in mice using C57BL/6J (WT) mice and FXR knockout (FXR(−/−)) mice. The results showed that a significant alleviation in OA‐induced cholestatic liver injury was observed in FXR(−/−) mice as evidenced by decreases in serum alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase as well as reduced hepatocyte necrosis. UPLC‐MS analysis of bile acids revealed that the contents of bile acids decreased significantly in liver and serum, while increased in the bile in FXR(−/−) mice compared with in WT mice. In addition, the mRNA expressions of hepatic transporter Bsep, bile acid synthesis enzymes Bacs and Baat, and bile acids detoxifying enzymes Cyp3a11, Cyp2b10, Ephx1, Ugt1a1, and Ugt2b5 were increased in liver tissues of FXR(−/−) mice treated with OA. Furthermore, the expression of membrane protein BSEP was significantly higher in livers of FXR(−/−) mice compared with WT mice treated with OA. These results demonstrate that knockout of FXR may alleviate OA‐induced cholestatic liver injury in mice by decreasing accumulation of bile acids both in the liver and serum, increasing the export of bile acids via the bile, and by upregulation of bile acids detoxification enzymes. John Wiley and Sons Inc. 2022-02-23 2022-08 /pmc/articles/PMC9546401/ /pubmed/35128688 http://dx.doi.org/10.1002/jat.4298 Text en © 2022 The Authors. Journal of Applied Toxicology published by John Wiley & Sons Ltd. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Research Articles
Feng, Hong
Hu, Yan
Zhou, Shaoyu
Lu, Yuanfu
Farnesoid X receptor contributes to oleanolic acid‐induced cholestatic liver injury in mice
title Farnesoid X receptor contributes to oleanolic acid‐induced cholestatic liver injury in mice
title_full Farnesoid X receptor contributes to oleanolic acid‐induced cholestatic liver injury in mice
title_fullStr Farnesoid X receptor contributes to oleanolic acid‐induced cholestatic liver injury in mice
title_full_unstemmed Farnesoid X receptor contributes to oleanolic acid‐induced cholestatic liver injury in mice
title_short Farnesoid X receptor contributes to oleanolic acid‐induced cholestatic liver injury in mice
title_sort farnesoid x receptor contributes to oleanolic acid‐induced cholestatic liver injury in mice
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9546401/
https://www.ncbi.nlm.nih.gov/pubmed/35128688
http://dx.doi.org/10.1002/jat.4298
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