FXR-Deoxycholic Acid-TNF-α Axis Modulates Acetaminophen-Induced Hepatotoxicity

Tingting Yan, Nana Yan, Hong Wang, Tomoki Yagai, Yuhong Luo, Shogo Takahashi, Min Zhao, Kristopher W. Krausz, Guangji Wang, Haiping Hao, Frank J. Gonzalez

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

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.

Original languageEnglish
Pages (from-to)273-284
Number of pages12
JournalToxicological Sciences
Volume181
Issue number2
DOIs
Publication statusPublished - 2021 Jun 1

Keywords

  • DCA
  • FXR
  • acetaminophen
  • acute liver failure
  • drug-induced liver injury

ASJC Scopus subject areas

  • Toxicology

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