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Toxicol Appl Pharmacol. 2013 Nov 1;272(3):816-24. doi: 10.1016/j.taap.2013.08.003. Epub 2013 Aug 13.

Oleanolic acid alters bile acid metabolism and produces cholestatic liver injury in mice.

Author information

1
University of Kansas Medical Center, Kansas City, KS 66160, USA; Zunyi Medical College, Zunyi 563003, China. Electronic address: JLiu@kumc.edu.

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.

KEYWORDS:

ALT; AhR; Aryl hydrocarbon Receptor; Bile acid synthesis genes; Bile acid transporters; Bsep; CAR; Cholestasis; Constitutive androstane receptor; NAD(P)H:quinone oxidoreductase 1 (Nqo1); Na(+)-taurocholate co-transporting ploypeptide; Nqo1; Nrf2; Ntcp; Nuclear factor erythroid-derived 2-like 2; Nuclear receptors; OA; Oatp1b2; Oleanolic acid; PPAR; PXR; Peroxisome proliferator-activated receptor; Pregnane X receptor; Serum bile acids; UPLC-MS/MS; alanine aminotransferase; bile salt export pump; oleanolic acid; organic anion-transporting polypeptide 1b2; ultra performance liquid chromatography tandem mass spectrometry

PMID:
23948738
PMCID:
PMC3857557
DOI:
10.1016/j.taap.2013.08.003
[Indexed for MEDLINE]
Free PMC Article

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