title: Role of the lipid-regulated NF-κB/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-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.
authors.affiliation: Department of Toxicology, School of Public Health, Tianjin Medical University, 22 Qixiangtai Road, Heping District, Tianjin, 300070, China.|Laboratory of Metabolism, Center for Cancer Research, National Institutes of Health, Building 37, Room 3106, Bethesda, MD, 20892, USA.|Department of Immunology, Tianjin Key Laboratory of Cellular and Molecular Immunology, Tianjin Medical University, Tianjin, 30070, China.|Joint Center for Translational Medicine, Dalian Institute of Chemical Physics, Chinese Academy of Sciences and The First Affiliated Hospital of Liaoning Medical University, No. 457, Zhongshan Road, Dalian, 116023, China.|Key Laborotary of Liaoning Tumor Clinical Metabolomics (KLLTCM), Jinzhou, Liaoning, China.
authors.forename: Zhong-Ze
authors.initials: ZZ
authors.lastname: Fang
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Institutes of Health, Building 37, Room 3106, Bethesda, MD, 20892, USA.|Department of Metabolic Regulation, Shinshu University Graduate School of Medicine, Matsumoto, 390-8621, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Tanaka
authors.affiliation: Department of Immunology, Tianjin Key Laboratory of Cellular and Molecular Immunology, Tianjin Medical University, Tianjin, 30070, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Lu
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Institutes of Health, Building 37, Room 3106, Bethesda, MD, 20892, USA.
authors.forename: Chang-Tao
authors.initials: CT
authors.lastname: Jiang
authors.affiliation: Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin, 300121, China.
authors.forename: Wei-Hua
authors.initials: WH
authors.lastname: Zhang
authors.affiliation: Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin, 300121, China.
authors.forename: Chunze
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Toxicology, School of Public Health, Tianjin Medical University, 22 Qixiangtai Road, Heping District, Tianjin, 300070, China.
authors.forename: Zuo
authors.initials: Z
authors.lastname: Du
authors.affiliation: Department of Toxicology, School of Public Health, Tianjin Medical University, 22 Qixiangtai Road, Heping District, Tianjin, 300070, China.
authors.forename: Zhi-Wei
authors.initials: ZW
authors.lastname: Fu
authors.affiliation: Key Laborotary of Liaoning Tumor Clinical Metabolomics (KLLTCM), Jinzhou, Liaoning, China.|Clinical Laboratory, Dalian Sixth People's Hospital, Dalian, 116031, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Gao
authors.affiliation: Joint Center for Translational Medicine, Dalian Institute of Chemical Physics, Chinese Academy of Sciences and The First Affiliated Hospital of Liaoning Medical University, No. 457, Zhongshan Road, Dalian, 116023, China.|Key Laborotary of Liaoning Tumor Clinical Metabolomics (KLLTCM), Jinzhou, Liaoning, China.
authors.forename: Yun-Feng
authors.initials: YF
authors.lastname: Cao
authors.affiliation: Joint Center for Translational Medicine, Dalian Institute of Chemical Physics, Chinese Academy of Sciences and The First Affiliated Hospital of Liaoning Medical University, No. 457, Zhongshan Road, Dalian, 116023, China.|Key Laborotary of Liaoning Tumor Clinical Metabolomics (KLLTCM), Jinzhou, Liaoning, China.
authors.forename: Hong-Zhi
authors.initials: HZ
authors.lastname: Sun
authors.affiliation: Joint Center for Translational Medicine, Dalian Institute of Chemical Physics, Chinese Academy of Sciences and The First Affiliated Hospital of Liaoning Medical University, No. 457, Zhongshan Road, Dalian, 116023, China.|Key Laborotary of Liaoning Tumor Clinical Metabolomics (KLLTCM), Jinzhou, Liaoning, China.
authors.forename: Zhi-Tu
authors.initials: ZT
authors.lastname: Zhu
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Institutes of Health, Building 37, Room 3106, Bethesda, MD, 20892, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Cai
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Institutes of Health, Building 37, Room 3106, Bethesda, MD, 20892, USA.
authors.forename: Kristopher W
authors.initials: KW
authors.lastname: Krausz
authors.affiliation: Department of Immunology, Tianjin Key Laboratory of Cellular and Molecular Immunology, Tianjin Medical University, Tianjin, 30070, China. yaozhi@tijmu.edu.cn.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Yao
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Institutes of Health, Building 37, Room 3106, Bethesda, MD, 20892, USA. gonzalef@mail.nih.gov.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
mesh_terms: D015058:1-Naphthylisothiocyanate / Q000633:toxicity*; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D015850:Interleukin-6 / Q000378:metabolism*; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D016328:NF-kappa B / Q000378:metabolism*; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000378:metabolism*
chemical_list: D015850:Interleukin-6; D016328:NF-kappa B; D047493:PPAR alpha; D011743:Pyrimidines; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015058:1-Naphthylisothiocyanate; C006253:pirinixic acid
keywords: Alpha-naphthyl isothiocyanate; Drug toxicity; Metabolomics; NF-κB/IL-6/STAT3 axis