Oleanolic acid alters bile acid metabolism and produces cholestatic liver injury in mice |
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Authors: | Jie Liu Yuan-Fu Lu Youcai Zhang Kai Connie Wu Fang Fan Curtis D Klaassen |
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Affiliation: | 1. University of Kansas Medical Center, Kansas City, KS 66160, USA;2. Zunyi Medical College, Zunyi 563003, China;3. Cytopathology, University of Kansas Medical Center, Kansas City, KS 66160, USA |
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Abstract: | Oleanolic acid (OA) is a triterpenoids that exists widely in plants. OA is effective in protecting against hepatotoxicants. Whereas a low dose of OA is hepatoprotective, higher doses and longer-term use of OA produce liver injury. This study characterized OA-induced liver injury in mice. Adult C57BL/6 mice were given OA at doses of 0, 22.5, 45, 90, and 135 mg/kg, s.c., daily for 5 days, and liver injury was observed at doses of 90 mg/kg and above, as evidenced by increases in serum activities of alanine aminotransferase and alkaline phosphatase, increases in serum total bilirubin, as well as by liver histopathology. OA-induced cholestatic liver injury was further evidenced by marked increases of both unconjugated and conjugated bile acids (BAs) in serum. Gene and protein expression analysis suggested that livers of OA-treated mice had adaptive responses to prevent BA accumulation by suppressing BA biosynthetic enzyme genes (Cyp7a1, 8b1, 27a1, and 7b1); lowering BA uptake transporters (Ntcp and Oatp1b2); and increasing a BA efflux transporter (Ostβ). OA increased the expression of Nrf2 and its target gene, Nqo1, but decreased the expression of AhR, CAR and PPARα along with their target genes, Cyp1a2, Cyp2b10 and Cyp4a10. OA had minimal effects on PXR and Cyp3a11. Taken together, the present study characterized OA-induced liver injury, which is associated with altered BA homeostasis, and alerts its toxicity potential. |
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Keywords: | OA oleanolic acid ALT alanine aminotransferase UPLC-MS/MS ultra performance liquid chromatography tandem mass spectrometry Ntcp Na+-taurocholate co-transporting ploypeptide Oatp1b2 organic anion-transporting polypeptide 1b2 Bsep bile salt export pump Nrf2 Nuclear factor erythroid-derived 2-like 2 Nqo1 NAD(P)H:quinone oxidoreductase 1 (Nqo1) AhR Aryl hydrocarbon Receptor CAR Constitutive androstane receptor PXR Pregnane X receptor PPAR Peroxisome proliferator-activated receptor |
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