Role of the lipid-regulated NF-κB/IL-6/STAT3 axis in alpha-naphthyl isothiocyanate-induced liver injury

Arch Toxicol. 2017 May;91(5):2235-2244. doi: 10.1007/s00204-016-1877-6. Epub 2016 Nov 16.


Alpha-naphthyl isothiocyanate (ANIT)-induced liver damage is regarded as a useful model to study drug-induced cholestatic hepatitis. Ultra-performance liquid chromatography coupled with electrospray ionization quadrupole mass spectrometry (UPLC-ESI-QTOF MS)-based metabolomics revealed clues to the mechanism of ANIT-induced liver injury, which facilitates the elucidation of drug-induced liver toxicity. 1-Stearoyl-2-hydroxy-sn-glycero-3-phosphocholine (LPC 18:0) and 1-oleoyl-2-hydroxy-sn-glycero-3-phosphocholine (LPC 18:1) were significantly increased in serum from ANIT-treated mice, and this increase resulted from altered expression of genes encoding the lipid metabolism enzymes Chka and Scd1. ANIT also increased NF-κB/IL-6/STAT3 signaling, and in vitro luciferase reporter gene assays revealed that LPC 18:0 and LPC 18:1 can activate NF-κB in a concentration-dependent manner. Activation of PPARα through feeding mice a Wy-14,643-containing diet (0.1%) reduced ANIT-induced liver injury, as indicated by lowered ALT and AST levels, and liver histology. In conclusion, the present study demonstrated a role for the lipid-regulated NF-κB/IL-6/STAT3 axis in ANIT-induced hepatotoxicity, and that PPARα may be a potential therapeutic target for the prevention of drug-induced cholestatic liver injury.

Keywords: Alpha-naphthyl isothiocyanate; Drug toxicity; Metabolomics; NF-κB/IL-6/STAT3 axis.

MeSH terms

  • 1-Naphthylisothiocyanate / toxicity*
  • Animals
  • Chemical and Drug Induced Liver Injury / etiology
  • Chemical and Drug Induced Liver Injury / metabolism*
  • Chemical and Drug Induced Liver Injury / pathology
  • Disease Models, Animal
  • Interleukin-6 / metabolism*
  • Lipid Metabolism / drug effects
  • Male
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • NF-kappa B / metabolism*
  • PPAR alpha / genetics
  • PPAR alpha / metabolism
  • Pyrimidines / pharmacology
  • STAT3 Transcription Factor / metabolism*


  • Interleukin-6
  • NF-kappa B
  • PPAR alpha
  • Pyrimidines
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • 1-Naphthylisothiocyanate
  • pirinixic acid