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

Alpha-naphthyl isothiocyanate (ANIT)-induced liver damage is regarded as a useful model to study druginduced 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-hydroxysn- 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-kappa B/IL-6/STAT3 signaling, and in vitro luciferase reporter gene assays revealed that LPC 18: 0 and LPC 18: 1 can activate NF-kappa B in a concentrationdependent manner. Activation of PPARa 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-kappa B/IL-6/STAT3 axis in ANIT-induced hepatotoxicity, and that PPARa may be a potential therapeutic target for the prevention of drug-induced cholestatic liver injury.