Oleanolic acid alters bile acid metabolism and produces cholestatic liver injury in mice.
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.
University of Kansas Medical Center, Kansas City, KS 66160, USA; Zunyi Medical College, Zunyi 563003, China. Electronic address: JLiu@kumc.edu.
Jie
J
Liu
Yuan-Fu
YF
Lu
Youcai
Y
Zhang
Kai Connie
KC
Wu
Fang
F
Fan
Curtis D
CD
Klaassen
D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism*; D002779:Cholestasis / Q000139:chemically induced* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D009828:Oleanolic Acid / Q000633:toxicity*
D001647:Bile Acids and Salts; D009828:Oleanolic Acid
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