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Lipidomics reveal aryl hydrocarbon receptor (Ahr)-regulated lipid metabolic pathway in alpha-naphthyl isothiocyanate (ANIT)-induced intrahepatic cholestasis |
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| Authors: | Bao-Long Wang Chang-Wen Zhang Liang Wang Kun-Long Tang Naoki Tanaka Frank J Gonzalez |
| Institution: | 1. Department of Urology, The Second Hospital of Tianjin Medical University, Tianjin Institute of Urology, Tianjin, China;2. Department of Urology, General Hospital of Tianjin Medical University, Tianjin, China;3. Department of Urology, General Hospital of Tianjin Medical University, Tianjin, China;4. Laboratory of Metabolism, Center for Cancer Research, National Institutes of Health, Bethesda, MD, USA;5. Department of Metabolic Regulation, Shinshu University Graduate School of Medicine, Matsumoto, Japan |
| Abstract: | 1. Ultra-performance liquid chromatography coupled with electrospray ionization quadrupole mass spectrometry (UPLC-ESI-QTOF MS)-based lipidomics was employed to elucidate new mechanism of alpha-naphthyl isothiocyanate (ANIT)-induced intrahepatic cholestasis in mice. 2. Multiple lipid components significantly increased in ANIT-induced intrahepatic cholestasis, including PC 16:0, 20:4, PC 16:0, 22:6, PC 16:0, 18:2, LPC 18:2, PC 18:2, LPC 18:1, PC 18:1, 14:0, SM 18:1, 16:0, oleoylcarnitine and palmitoylcarnitine. This alteration of lipid profile was induced by the changed expression of genes choline kinase (Chk) a, sphingomyelin phosphodiesterase (SMPD) and stearoyl-coenzyme A desaturase 1 (SCD1). 3. Knockout of aryl hydrocarbon receptor (Ahr) in mice can significantly reverse ANIT-induced intrahepatic cholestasis, as indicated by lowered ALT, AST and ALP activity, and liver histology. Aryl hydrocarbon receptor knockout significantly reversed ANIT-induced lipid metabolism alteration through regulating the expression of Chka. 4. In conclusion, this study demonstrated ANIT-induced lipid metabolism disruption might be the potential pathogenesis of ANIT-induced intrahepatic cholestasis in mice. |
| Keywords: | Intrahepatic cholestasis alpha-naphthyl isothiocyanate (ANIT) lipidomics aryl hydrocarbon receptor (Ahr) |