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

• Published in: Toxicology and applied pharmacology 2013-11, Vol.272 (3), p.816-824
• Main Authors: Liu, Jie, Lu, Yuan-Fu, Zhang, Youcai, Wu, Kai Connie, Fan, Fang, Klaassen, Curtis D.
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; ALANINES; ALKALINE PHOSPHATASE; Animals; APOPTOSIS; BENZOQUINONES; BILE; Bile acid synthesis genes; Bile acid transporters; BILE ACIDS; Bile Acids and Salts - metabolism; BILIRUBIN; Biological and medical sciences; Chemical and Drug Induced Liver Injury - metabolism; Cholestasis; Cholestasis - chemically induced; Cholestasis - metabolism; Dose-Response Relationship, Drug; Female; Gastroenterology. Liver. Pancreas. Abdomen; INFLAMMATION; INJURIES; LIQUID COLUMN CHROMATOGRAPHY; LIVER; Liver. Biliary tract. Portal circulation. Exocrine pancreas; MASS SPECTROSCOPY; Medical sciences; MICE; Mice, Inbred C57BL; Nuclear receptors; Oleanolic acid; Oleanolic Acid - toxicity; Other diseases. Semiology; POLYPEPTIDES; RECEPTORS; Serum bile acids; TOXICITY; Toxicology
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2013.08.003

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 135mg/kg, s.c., daily for 5days, and liver injury was observed at doses of 90mg/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. [Display omitted] •Oleanolic acid at higher doses and long-term use may produce liver injury.•Oleanolic acid increased serum ALT, ALP, bilirubin and bile acid concentrations.•OA produced feathery degeneration, inflammation and cell death in the liver.•OA altered bile acid homeostasis, affecting bile acid synthesis and transport.