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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

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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.

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Abbreviations

AB23A:

Alisol B 23-acetate

ALP:

Alkaline phosphatase

Bsep:

Bile salt export pump

CAR:

Constitutive androstane receptor

CDCA:

Chenodeoxycholic acid

Cyp7a1:

Cholesterol 7α-hydroxylase

Cyp8b1:

Sterol-12α-hydroxylase

EE:

17α-ethinylestradiol

Fgf15:

fibroblast growth factor 15

FXR:

Farnesoid X receptor

GS:

Guggulsterone

H&E:

Haematoxylin & eosin

Mrp2:

Multidrug resistance-related protein 2

Ntcp:

Na+/taurocholate cotransporting polypeptide

PXR:

Pregnane X receptor

Shp:

Small heterodimer partner

Sult2a1:

Hydroxysteroid sulfotransferase 2a1

Ugt1a1:

UDP-glucuronosyltransferase 1a1

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ACKNOWLEDGMENTS AND DISCLOSURES

This present study was financially supported by a grant from the National Natural Science Foundation of China (Nos. 81302826, 81273580). The authors declare that there are no conflicts of interest.

Author Contributions

Qiang Meng: Study conception and design; Drafting/revision of the work for intellectual content and contex

Xinli Chen: Acquisition, analysis of data

Changyuan Wang: Acquisition, analysis of data

Qi Liu: Drafting/revision of the work for intellectual content and context

Huijun Sun: Study conception and design

Pengyuan Sun: Acquisition, analysis of data

Xiaokui Huo: Drafting/revision of the work for intellectual content and contex

Zhihao Liu: Acquisition, analysis of data

Jihong Yao: Drafting/revision of the work for intellectual content and contex

Kexin Liu: Final approval and overall responsibility for the published work

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Authors and Affiliations

  1. Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Dalian, 116044, China

    Qiang Meng, Xinli Chen, Changyuan Wang, Qi Liu, Huijun Sun, Pengyuan Sun, Xiaokui Huo, Zhihao Liu, Jihong Yao & Kexin Liu

  2. Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, Dalian, Liaoning, China

    Qiang Meng, Xinli Chen, Changyuan Wang, Qi Liu, Huijun Sun, Pengyuan Sun, Xiaokui Huo, Zhihao Liu, Jihong Yao & Kexin Liu

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  1. Qiang Meng
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Correspondence to Kexin Liu.

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Meng, Q., Chen, X., Wang, C. et al. 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 32, 3688–3698 (2015). https://doi.org/10.1007/s11095-015-1727-x

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  • DOI: https://doi.org/10.1007/s11095-015-1727-x

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