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Ibuprofen induces hepatic Cyp7a1 expression in mice via the intestinal FXR-FGF15 signaling.

Authors :
Li H
Xiong H
Wang X
Xu T
Zhang C
Zhang W
Zhang Y
Source :
Toxicology letters [Toxicol Lett] 2024 Jul; Vol. 398, pp. 1-12. Date of Electronic Publication: 2024 May 28.
Publication Year :
2024

Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) may cause drug-induced liver injury (DILI). However, the molecular mechanisms underlying NSAIDs hepatotoxicity remain elusive. Dysregulations of bile acids (BAs) have been implicated in various DILI. In this study, we systematically investigated the effects of ibuprofen, the most commonly used NSAID, on BA metabolism and signaling in adult male C57/BL6 mice after oral administration of ibuprofen (IBU) at clinically relevant doses (30, 100, and 200 mg/kg) for one week. Notably, IBU significantly decreased BA concentrations in the liver in a dose-dependent manner, with a concomitant increase in both mRNA and protein expression of cholesterol 7alpha-hydoxylase (CYP7A1), the rate-limiting enzyme for BA synthesis. Mechanically, IBU altered the composition of gut microbiota and increased cecal BAs, leading to reduced intestinal absorption of BAs and thus deactivated ileal farnesoid X receptor-fibroblast growth factor 15 (FXR-FGF15) signaling. Additionally, diclofenac and indomethacin also induced hepatic Cyp7a1 expression in mice via their effects on gut microbiota and intestinal BA signaling. To conclude, the current findings suggest that NSAIDs-induced liver injury could be at least partially attributable to the dysregulation of BA metabolism and signaling.<br />Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Copyright © 2024 Elsevier B.V. All rights reserved.)

Details

Language :
English
ISSN :
1879-3169
Volume :
398
Database :
MEDLINE
Journal :
Toxicology letters
Publication Type :
Academic Journal
Accession number :
38815664
Full Text :
https://doi.org/10.1016/j.toxlet.2024.05.015