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

ABSTRACT: 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-?B/IL-6/STAT3 signaling, and in vitro luciferase reporter gene assays revealed that LPC 18:0 and LPC 18:1 can activate NF-?B in a concentration-dependent manner. Activation of PPAR? 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-?B/IL-6/STAT3 axis in ANIT-induced hepatotoxicity, and that PPAR? may be a potential therapeutic target for the prevention of drug-induced cholestatic liver injury.

SUBMITTER: Fang ZZ 

PROVIDER: S-EPMC6331015 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature