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Low dose of oleanolic acid protects against lithocholic acid-induced cholestasis in mice: potential involvement of nuclear factor-E2-related factor 2-mediated upregulation of multidrug resistance-associated proteins.

Abstract
Oleanolic acid (OA) is a natural triterpenoid and has been demonstrated to protect against varieties of hepatotoxicants. Recently, however, OA at high doses was reported to produce apparent cholestasis in mice. In this study, we characterized the protective effect of OA at low doses against lithocholic acid (LCA)-induced cholestasis in mice and explored further mechanisms. OA cotreatment (5, 10, and 20 mg/kg, i.p.) significantly improved mouse survival rate, attenuated liver necrosis, and decreased serum alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase; more importantly, serum total bile acids and bilirubin, as well as hepatic total bile acids were also remarkably reduced. Gene and protein expression analysis showed that hepatic expression of multidrug resistance-associated protein 2 (Mrp2), Mrp3, and Mrp4 was significantly increased by OA cotreatment, whereas other bile acid metabolism- and transport-related genes, including Na+/taurocholate cotransporter, organic anion transporter 1b2, bile salt export pump, multidrug resistance protein 3, Cyp3a11, Cyp2b10, Sulfotransferase 2a1 (Sult2a1), and UDP-glucuronosyltransferase 1a1 (Ugt1a1), were only slightly changed. OA also caused increased nuclear factor-E2-related factor (Nrf2) mRNA expression and nuclear protein accumulation, whereas nuclear receptors farnesoid X receptor (FXR), pregnane X receptor (PXR), and constitutive androstane receptor were not significantly influenced by OA. Luciferase (Luc) assays performed in HepG2 cells illustrated that OA was a strong Nrf2 agonist with moderate PXR and weak FXR agonism. Finally, in mouse primary cultured hepatocytes, OA dose- and time-dependently induced expression of Mrp2, Mrp3, and Mrp4; however, this upregulation was abrogated when Nrf2 was silenced. In conclusion, OA produces a protective effect against LCA-induced hepatotoxicity and cholestasis, possibly due to Nrf2-mediated upregulation of Mrp2, Mrp3, and Mrp4.
AuthorsPan Chen, Hang Zeng, Yongtao Wang, Xiaomei Fan, Chenshu Xu, Rongrong Deng, Xunian Zhou, Huichang Bi, Min Huang
JournalDrug metabolism and disposition: the biological fate of chemicals (Drug Metab Dispos) Vol. 42 Issue 5 Pg. 844-52 (May 2014) ISSN: 1521-009X [Electronic] United States
PMID24510383 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Multidrug Resistance-Associated Proteins
  • NF-E2-Related Factor 2
  • Lithocholic Acid
  • Oleanolic Acid
Topics
  • Animals
  • Chemical and Drug Induced Liver Injury (metabolism, prevention & control)
  • Cholestasis (chemically induced, metabolism, prevention & control)
  • Dose-Response Relationship, Drug
  • Gene Expression (drug effects)
  • Hep G2 Cells
  • Hepatocytes (drug effects, metabolism)
  • Humans
  • Lithocholic Acid (pharmacology)
  • Liver Function Tests
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Multidrug Resistance-Associated Proteins (genetics)
  • NF-E2-Related Factor 2 (agonists, metabolism)
  • Oleanolic Acid (administration & dosage, therapeutic use)
  • Primary Cell Culture
  • Up-Regulation

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