Role of the Lipid-regulated NF-κB/IL-6/STAT3 Axis in Alpha-naphthyl Isothiocyanate-induced Liver Injury

Overview

Journal Arch Toxicol

Specialty Toxicology

Date 2016 Nov 18

PMID 27853831

Citations 15

Authors

Zhong-Ze Fang

Naoki Tanaka

Dan Lu

Chang-Tao Jiang

Wei-Hua Zhang

Chunze Zhang

Zuo Du

Zhi-Wei Fu

Peng Gao

Yun-Feng Cao

Hong-Zhi Sun

Zhi-Tu Zhu

Yan Cai

Kristopher W Krausz

Zhi Yao

Frank J Gonzalez

Affiliations

Soon will be listed here.

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-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.

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