Targeted Metabolomics Reveals a Protective Role for Basal PPAR? in Cholestasis Induced by ?-Naphthylisothiocyanate.
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ABSTRACT: ?-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?. However, little is known about how PPAR? 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 Cyp7a1, Cyp8b1, Mrp3, Cyp3a11, Cyp2b10, Ugt1a2, and Ugt1a5 genes and showed cross-talk between basal PPAR? and potentially adaptive pathways. Il6, Tnfa, and target genes in the STAT3 pathway ( Socs3, Fga, Fgb, and Fgg) were up-regulated in Ppara-null mice but not in wild-type mice. The JNK pathway was activated in both mouse lines, while NF-?B and STAT3 were activated only in Ppara-null mice. These data suggest protection against cholestasis by basal PPAR? involves regulation of BA metabolism and inhibition of NF-?B/STAT3 signaling. Considering studies on the protective effects of both basal and activated PPAR?, caution should be exercised when one attempts to draw conclusions in which the PPAR? is modified by genetic manipulation, fasting, or activation in pharmacological and toxicological studies.
SUBMITTER: Dai M
PROVIDER: S-EPMC6628934 | biostudies-literature | 2018 Apr
REPOSITORIES: biostudies-literature
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