ArticleToxicological sciences : an official journal of the Society of Toxicology2021
FXR-Deoxycholic Acid-TNF-α Axis Modulates Acetaminophen-Induced Hepatotoxicity.
Article in Toxicological sciences : an official journal of the Society of Toxicology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed.
- Extract from Eucommia ulmoides Oliv. Leaves alleviates APAP-induced acute liver injury via reshaping gut microbiota and attenuating microbial bile acids metabolism disorder.Chinese medicine · 2026Article
- Microbiota-gut-brain axis and bile acids-driven neuromodulation.Neural regeneration research · 2026Article
- Captivating Synergistic, Dose-Dependent Anticancer Effects of Tumor-Regulation Modulators Chloroquine and Ivermectin Completely Abolished by an Opposing Modulator, Deoxycholic Acid, in Hamster Fibrosarcoma: In Vivo, In Vitro, and Literature Review.Pharmaceuticals (Basel, Switzerland) · 2026Article
- Integrated Analysis of Serum and Fecal Metabolites Reveals the Role of Bile Acid Metabolism in Drug-induced Liver Injury: Implications for Diagnostic and Prognostic Biomarkers.Journal of clinical and translational hepatology · 2025Article
- The Protective Role of Baicalin in the Regulation of NLRP3 Inflammasome in Different Diseases.Cell biochemistry and biophysics · 2025Review
- Infection‑associated bile acid disturbance contributes to macrophage activation in patients with cirrhosis.Molecular medicine reports · 2024Article
- Functional metabolomics characterizes the contribution of farnesoid X receptor in pyrrolizidine alkaloid-induced hepatic sinusoidal obstruction syndrome.Archives of toxicology · 2024Article
- Article
- Multi-omics analysis reveals the associations between altered gut microbiota, metabolites, and cytokines during pregnancy.mSystems · 2024Article
- Gut-Liver Axis as a Therapeutic Target for Drug-Induced Liver Injury.Current issues in molecular biology · 2024Review
- Gut microbiota depletion and FXR inhibition exacerbates zonal hepatotoxicity of sunitinib.Theranostics · 2024Article
- Alterations in the gut microbiome and metabolism with doxorubicin-induced heart failure severity.Frontiers in microbiology · 2024Article
- Gut microbiota and tumor-associated macrophages: potential in tumor diagnosis and treatment.Gut microbes · 2023Review
- Microbial Metabolites as Ligands to Xenobiotic Receptors: Chemical Mimicry as Potential Drugs of the Future.Drug metabolism and disposition: the biological fate of chemicals · 2023Review
- Dissection of cellular and molecular mechanisms of aristolochic acid-induced hepatotoxicity via single-cell transcriptomics.Precision clinical medicine · 2022Article
- The immunological mechanisms and therapeutic potential in drug-induced liver injury: lessons learned from acetaminophen hepatotoxicity.Cell & bioscience · 2022Review
- The Farnesoid X Receptor as a Master Regulator of Hepatotoxicity.International journal of molecular sciences · 2022Review
- Roles of Cofactors in Drug-Induced Liver Injury: Drug Metabolism and Beyond.Drug metabolism and disposition: the biological fate of chemicals · 2022Review
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Authors and funding
11 authors.
Funding
Abstract
The idiosyncratic characteristics and severity of acetaminophen (APAP) overdose-induced hepatotoxicity render identifying the predisposing factors and mechanisms of APAP-induced liver toxicity necessary and urgent. Farnesoid X receptor (FXR) controls bile acid homeostasis and modulates the progression of various liver diseases. Although global FXR deficiency in mice enhances APAP intoxication, the mechanism remains elusive. In this study, an increased sensitivity to APAP-induced toxicity was found in global Fxr-null (Fxr-/-) mice, but was not observed in hepatocyte-specific or macrophage-specific Fxr-null mice, suggesting that global FXR deficiency enhances APAP hepatotoxicity via disruption of systematic bile acid homeostasis. Indeed, more bile acid accumulation was found in global Fxr-/- mice, while 2% cholestyramine diet feeding decreased serum bile acids and alleviated APAP hepatotoxicity in global Fxr-/- mice, suggesting that bile acid accumulation contributes to APAP toxicity. Bile acids were suspected to induce macrophage to release tumor necrosis factor-α (TNF-α), which is known to enhance the APAP hepatotoxicity. In vitro, deoxycholic acid (DCA), a secondary bile acid metabolite, significantly induced Tnfa mRNA and dose-dependently enhanced TNF-α release from macrophage, while the same dose of DCA did not directly potentiate APAP toxicity in cultured primary hepatocytes. In vivo, DCA enhanced TNF-α release and potentiated APAP toxicity, both of which were abolished by the specific TNF-α antagonist infliximab. These results reveal an FXR-DCA-TNF-α axis that potentiates APAP hepatotoxicity, which could guide the clinical safe use of APAP.
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