2. Academic Validation
  3. Protective Effects of Alisol B 23-Acetate Via Farnesoid X Receptor-Mediated Regulation of Transporters and Enzymes in Estrogen-Induced Cholestatic Liver Injury in Mice

Protective Effects of Alisol B 23-Acetate Via Farnesoid X Receptor-Mediated Regulation of Transporters and Enzymes in Estrogen-Induced Cholestatic Liver Injury in Mice

  • Pharm Res. 2015 Nov;32(11):3688-98. doi: 10.1007/s11095-015-1727-x.
Qiang Meng 1 2,  Xinli Chen 1 2,  Changyuan Wang 1 2,  Qi Liu 1 2,  Huijun Sun 1 2,  Pengyuan Sun 1 2,  Xiaokui Huo 1 2,  Zhihao Liu 1 2,  Jihong Yao 1 2,  Kexin Liu 3 4
Affiliations

Affiliations

  • 1 Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Dalian, 116044, China.
  • 2 Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, Dalian, Liaoning, China.
  • 3 Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Dalian, 116044, China. [email protected].
  • 4 Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, Dalian, Liaoning, China. [email protected].
PMID: 26040663 DOI: 10.1007/s11095-015-1727-x
Abstract

Purpose: To investigate protective effects of alisol B 23-acetate (AB23A) against hepatotoxity and cholestasis induced by 17α-ethinylestradiol (EE) in association with farnesoid X receptor (FXR) activation in vivo and in vitro.

Methods: The cholestatic liver injury model was established by subcutaneous injections of EE in C57BL/6 mice. Serum biomarkers, bile flow assay and H&E staining were used to identify the amelioration of cholestasis after AB23A treatment. Mice primary hepatocytes culture, gene silencing experiment, Real-Time PCR and Western blot assay were used to elucidate the mechanisms underlying AB23A hepatoprotection.

Results: AB23A treatment protected against liver injury induced by EE through increasing hepatic efflux and reducing uptake of bile acid via an induction in efflux transporters (Bsep and Mrp2) and an inhibition in hepatic uptake transporter (Ntcp) expression. AB23A also reduced bile acid synthesis through repressing Cyp7a1 and Cyp8b1, and increased bile acid metabolism through an induction in gene expression of Sult2a1. We further demonstrated that the changes in transporters and enzymes, as well as ameliorative liver histology in AB23A-treated mice were abrogated by FXR antagonist guggulsterone in vivo and were abrogated after FXR was silenced in vitro.

Conclusions: AB23A produces protective effects against EE-induced cholestasis, due to FXR-mediated gene regulation.

Keywords

EE; FXR; alisol B 23-acetate; cholestasis; transporter.

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