Editor’s Highlight: Farnesoid X Receptor Protects Against Low-Dose Carbon Tetrachloride-Induced Liver Injury Through the Taurocholate-JNK Pathway
| Autor: | Srujana Golla, Changtao Jiang, Cen Xie, Naoki Tanaka, Frank J. Gonzalez, Kristopher W. Krausz, Shogo Takahashi, Yusuke Masuo, Marianne Polunas, Blair C. Weig, Tatsuki Fukami |
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| Rok vydání: | 2017 |
| Předmět: |
Male
Taurocholic Acid 0301 basic medicine Chemokine medicine.medical_specialty MAP Kinase Kinase 4 medicine.drug_class Farnesoid X Receptor and Carbon Tetrachloride-Induced Liver Injury Receptors Cytoplasmic and Nuclear CCL4 Pharmacology CCL2 Toxicology Mice 03 medical and health sciences Internal medicine medicine Animals Carbon Tetrachloride Cells Cultured Liver injury Dose-Response Relationship Drug biology Bile acid Chemistry Kinase medicine.disease Mice Inbred C57BL 030104 developmental biology Endocrinology medicine.anatomical_structure Hepatocyte biology.protein Farnesoid X receptor Chemical and Drug Induced Liver Injury |
| Zdroj: | Toxicological Sciences. 158:334-346 |
| ISSN: | 1096-0929 1096-6080 |
| DOI: | 10.1093/toxsci/kfx094 |
| Popis: | Hepatotoxicity is of major concern for humans exposed to industrial chemicals and drugs. Disruption of farnesoid X receptor (FXR), a master regulator of bile acid (BA) metabolism, enhanced the sensitivity to liver injury in mice after toxicant exposure, but the precise mechanism remains unclear. In this study, the interconnection between BA metabolism, FXR, and chemically induced hepatotoxicity was investigated using metabolomics, Fxr-null mice (Fxr−/−) and hepatocytes, and recombinant adenoviruses. 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−/−. Serum metabolomics analysis revealed marked increases in circulating taurocholate (TCA) and tauro-β-muricholate (T-β-MCA) in these mice, and forced expression of bile salt export protein (BSEP) by recombinant adenovirus in Fxr−/− ameliorated CCl4-induced liver damage. Treatment of Fxr-null hepatocytes with TCA, but not T-β-MCA, significantly increased c-Jun-N-terminal kinase (JNK) activation and Ccl2 mRNA levels, and up-regulation of Ccl2 mRNA was attenuated by co-treatment with a JNK inhibitor SP600125, indicating that TCA directly amplifies hepatocyte inflammatory signaling mainly mediated by JNK under FXR-deficiency. Additionally, pretreatment with SP600125 or restoration of FXR expression in liver by use of recombinant adenovirus, attenuated CCl4-induced liver injury. Collectively, these results suggest that the TCA–JNK axis is likely associated with increased susceptibility to CCl4-induced acute liver injury in Fxr−/−, and provide clues to the mechanism by which FXR and its downstream gene targets, such as BSEP, protects against chemically induced hepatotoxicity. |
| Databáze: | OpenAIRE |
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