Unaltered liver regeneration in post?cholestatic rats treated with the fxr agonist obeticholic acid

LR de Haan, J Verheij, RF van Golen, V Horneffer, MR Lewis, UHW Beuers, TM Gulik, SWM Olde Damink, FG Schaap, M Heger, Pim Olthof

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3 Citations (Scopus)
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Abstract

In a previous study, obeticholic acid (OCA) increased liver growth before partial hepatectomy (PHx) in rats through the bile acid receptor farnesoid X‐receptor (FXR). In that model, OCA was administered during obstructive cholestasis. However, patients normally undergo PHx several days after biliary drainage. The effects of OCA on liver regeneration were therefore studied in post‐cholestatic Wistar rats. Rats underwent sham surgery or reversible bile duct ligation (rBDL), which was relieved after 7 days. PHx was performed one day after restoration of bile flow. Rats received 10 mg/kg OCA per day or were fed vehicle from restoration of bile flow until sacrifice 5 days after PHx. Liver regeneration was comparable between cholestatic and non‐cholestatic livers in PHx‐subjected rats, which paralleled liver regeneration a human validation cohort. OCA treatment induced ileal Fgf15 mRNA expression but did not enhance post‐PHx hepatocyte proliferation through FXR/SHP signaling. OCA treatment neither increased mitosis rates nor recovery of liver weight after PHx but accelerated liver regrowth in rats that had not been subjected to rBDL. OCA did not increase biliary injury. Conclusively, OCA does not induce liver regeneration in post‐cholestatic rats and does not exacerbate biliary damage that results from cholestasis. This study challenges the previously reported beneficial effects of OCA in liver regeneration in cholestatic rats.

Original languageEnglish
Article number260
Pages (from-to)1-22
Number of pages22
JournalBiomolecules
Volume11
Issue number2
DOIs
Publication statusPublished - 2021

Bibliographical note

Funding Information:
This work was supported by grants from the Dutch Cancer Foundation (KWF project #10666), a Zhejiang Provincial Foreign Expert Program Grant, Zhejiang Provincial Key Natural Science Foundation of China (#Z20H160031), the Medical Research Council and National Institute for Health Research (grant number MC_PC_12025), and a grant for the establishment of the Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics to MH.

Funding Information:
Funding: This work was supported by grants from the Dutch Cancer Foundation (KWF project #10666), a Zhejiang Provincial Foreign Expert Program Grant, Zhejiang Provincial Key Natural Sci‐ ence Foundation of China (#Z20H160031), the Medical Research Council and National Institute for Health Research (grant number MC_PC_12025), and a grant for the establishment of the Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics to MH.

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.

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