Farnesoid X receptor protects against chemically-induced liver injury through the taurocholate-JNK pathway

Authors

• S Takahashi
• N Tanaka
• S Golla
• T Fukami
• KW Krausz
• MA Polunas
• BC Weig
• Y Masuo
• C Xie
• C Jiang
• FJ Gonzalez

Abstract

Hepatotoxicity is of major concern for human exposure to industrial chemicals and drugs, and clarifying the molecular pathogenesis of chemically-induced liver damage may lead to novel therapeutic interventions. Farnesoid X receptor (FXR), a ligand-activated transcription factor and a member of the nuclear receptor superfamily, is expressed in intestine and liver where it is activated by bile acid metabolites and controls bile acid homeostasis. Disruption of FXR was reported to enhance the sensitivity to acute liver injury in mice after toxicant exposure, but the precise mechanism remains unclear. A single low-dose intraperitoneal injection of carbon tetrachloride (CCl4), an inducer of acute hepatitis in mice, resulted in more severe hepatocyte damage and higher induction of pro-inflammatory mediators, such as chemokine (C-C motif) ligand 2 (Ccl2), in Fxr-null mice compared with wild-type mice. Serum metabolomics analysis revealed marked increases in circulating taurocholic acid (TCA) and tauro-beta-muricholic acid (T-b-MCA) in these mice, and forced expression of bile salt export protein by adenovirus in Fxr-null mice ameliorated CCl4-induced liver damage and increases in these serum bile acids. Treatment of Fxr-null hepatocytes with TCA, but not T-b-MCA, significantly increased c-Jun-N-terminal kinase (JNK) activation and Ccl2 mRNA, and up-regulation of Ccl2 mRNA was attenuated by co-treatment with the JNK inhibitor SP600125, indicating that TCA directly amplifies hepatocyte inflammatory signaling mainly mediated by JNK in the absence of FXR signaling. Additionally, pre-treatment with SP600125 or restoration of hepatic FXR, by forced expression with recombinant adenovirus, attenuated CCl4-induced liver injury in Fxr-null mice. Collectively, these results suggest that the TCA-JNK axis is likely associated with increased susceptibility to CCl4-induced acute liver injury, and provide clues to the mechanism by which FXR and its downstream targets such as bile salt export protein, protects against chemically-induced hepatotoxicity.

Scientific Focus Area: Molecular Biology and Biochemistry

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