Alisol B 23-acetate protects against ANIT-induced hepatotoxity and cholestasis, due to FXR-mediated regulation of transporters and enzymes involved in bile acid homeostasis

Toxicol Appl Pharmacol. 2015 Mar 15;283(3):178-86. doi: 10.1016/j.taap.2015.01.020. Epub 2015 Feb 3.

Abstract

Intrahepatic cholestasis is a clinical syndrome with systemic and intrahepatic accumulation of excessive toxic bile acids that ultimately cause hepatobiliary injury. Appropriate regulation of bile acids in hepatocytes is critically important for protection against liver injury. In the present study, we characterized the protective effect of alisol B 23-acetate (AB23A), a natural triterpenoid, on alpha-naphthylisothiocyanate (ANIT)-induced liver injury and intrahepatic cholestasis in mice and further elucidated the mechanisms in vivo and in vitro. AB23A treatment dose-dependently protected against liver injury induced by ANIT through reducing hepatic uptake and increasing efflux of bile acid via down-regulation of hepatic uptake transporters (Ntcp) and up-regulation of efflux transporter (Bsep, Mrp2 and Mdr2) expression. Furthermore, AB23A reduced bile acid synthesis through repressing Cyp7a1 and Cyp8b1, increased bile acid conjugation through inducing Bal, Baat and bile acid metabolism through an induction in gene expression of Sult2a1. We further demonstrate the involvement of farnesoid X receptor (FXR) in the hepatoprotective effect of AB23A. The changes in transporters and enzymes, as well as ameliorative liver histology in AB23A-treated mice were abrogated by FXR antagonist guggulsterone in vivo. In vitro evidences also directly demonstrated the effect of AB23A on FXR activation in a dose-dependent manner using luciferase reporter assay in HepG2 cells. In conclusion, AB23A produces protective effect against ANIT-induced hepatotoxity and cholestasis, due to FXR-mediated regulation of transporters and enzymes.

Keywords: ANIT; Alisol B 23-acetate; Enzymes; FXR; Liver injury; Transporters.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Naphthylisothiocyanate*
  • Animals
  • Bile Acids and Salts / metabolism*
  • Chemical and Drug Induced Liver Injury / genetics
  • Chemical and Drug Induced Liver Injury / metabolism
  • Chemical and Drug Induced Liver Injury / pathology
  • Chemical and Drug Induced Liver Injury / prevention & control*
  • Cholestasis, Intrahepatic / genetics
  • Cholestasis, Intrahepatic / metabolism
  • Cholestasis, Intrahepatic / pathology
  • Cholestasis, Intrahepatic / prevention & control*
  • Cholestenones / pharmacology*
  • Cytoprotection
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Gene Expression Regulation, Enzymologic
  • Hep G2 Cells
  • Homeostasis
  • Humans
  • Liver / drug effects*
  • Liver / metabolism
  • Liver / pathology
  • Male
  • Membrane Transport Proteins / metabolism*
  • Mice, Inbred C57BL
  • Protective Agents / pharmacology*
  • Receptors, Cytoplasmic and Nuclear / drug effects*
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Signal Transduction / drug effects
  • Time Factors
  • Transfection

Substances

  • Bile Acids and Salts
  • Cholestenones
  • Membrane Transport Proteins
  • Protective Agents
  • Receptors, Cytoplasmic and Nuclear
  • alisol B 23-acetate
  • nuclear receptor subfamily 0, group B, member 2
  • farnesoid X-activated receptor
  • 1-Naphthylisothiocyanate