Targeted Metabolomics Reveals a Protective Role for Basal PPAR alpha in Cholestasis Induced by alpha-Naphthylisothiocyanate
Dai, Manyun1; Hua, Huiying1; Lin, Hante1; Xu, Gangming1; Hu, Xiaowei1; Li, Fei2; Gonzalez, Frank J.3; Liu, Aiming1; Yang, Julin4
Abstractalpha-Naphthylisothiocyanate (ANIT) is an experimental agent used to induce intrahepatic cholestasis. The Ppara-null mouse line is widely employed to explore the physiological and pathological roles of PPAR alpha. However, little is known about how PPAR alpha influences the hepatotoxicity of ANIT. In the present study, wild-type and Ppara-null mice were orally treated with ANIT to induce cholestasis. The serum metabolome of wild-type mice segregated from that of the Ppara-null mice, driven by changes of bile acid (BA) metabolites. Alkaline phosphatase and total BAs were elevated preferentially in Ppara-null mice, which correlated with changes in Cyp7al, Cyp8b1, Mrp3, Cyp3a11, Cyp2b10, Ugt1a2, and Ugt1a5 genes and showed cross-talk between basal PPAR alpha and potentially adaptive pathways. 116, Tnfa, and target genes in the STAT3 pathway (Socs3, Fga, Fgb, and F4:) were up-regulated in Pparanull mice but not in wild-type mice. The JNK pathway was activated in both mouse lines, while NF-kappa B and STAT3 were activated only in Ppara-null mice. These data suggest protection against cholestasis by basal PPAR alpha involves regulation of BA metabolism and inhibition of NF-kappa B/STAT3 signaling. Considering studies on the protective effects of both basal and activated PPAR alpha, caution should be exercised when one attempts to draw condusions in which the PPAR alpha is modified by genetic manipulation, fasting, or activation in pharmacological and toxicological studies.
KeywordPpar Alpha Nf-kappa b Stat3 Alpha-naphthylisothiocyanate Cholestasis
WOS IDWOS:000429886600015
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Affiliation1.Ningbo Univ, Med Sch, Zhejiang Key Lab Pathophysiol, Ningbo 315211, Zhejiang, Peoples R China
2.Chinese Acad Sci, Kunming Inst Bot, State Key Lab Phytochem & Plant Resources West Ch, Kunming 650201, Yunnan, Peoples R China
3.NCI, Lab Metab, NIH, Bethesda, MD 20892 USA
4.Ningbo Coll Hlth Sci, Ningbo 315100, Zhejiang, Peoples R China
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GB/T 7714
Dai, Manyun,Hua, Huiying,Lin, Hante,et al. Targeted Metabolomics Reveals a Protective Role for Basal PPAR alpha in Cholestasis Induced by alpha-Naphthylisothiocyanate[J]. JOURNAL OF PROTEOME RESEARCH,2018,17(4):1500-1508.
APA Dai, Manyun.,Hua, Huiying.,Lin, Hante.,Xu, Gangming.,Hu, Xiaowei.,...&Yang, Julin.(2018).Targeted Metabolomics Reveals a Protective Role for Basal PPAR alpha in Cholestasis Induced by alpha-Naphthylisothiocyanate.JOURNAL OF PROTEOME RESEARCH,17(4),1500-1508.
MLA Dai, Manyun,et al."Targeted Metabolomics Reveals a Protective Role for Basal PPAR alpha in Cholestasis Induced by alpha-Naphthylisothiocyanate".JOURNAL OF PROTEOME RESEARCH 17.4(2018):1500-1508.
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