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.

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.

• Authors: Qiang Meng, Xinli Chen, Changyuan Wang, Qi Liu, Huijun Sun, Pengyuan Sun, Xiaokui Huo, Zhihao Liu, Jihong Yao, Kexin Liu
• Journal: Pharmaceutical research (Pharm Res) Vol. 32 Issue 11 Pg. 3688-98 (Nov 2015) ISSN: 1573-904X [Electronic] United States
• PMID: 26040663 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 11
• ATP-Binding Cassette Transporters
• Abcb11 protein, mouse
• Cholestenones
• Membrane Transport Proteins
• Multidrug Resistance-Associated Protein 2
• Multidrug Resistance-Associated Proteins
• Organic Anion Transporters, Sodium-Dependent
• Receptors, Cytoplasmic and Nuclear
• Symporters
• alisol B 23-acetate
• farnesoid X-activated receptor
• sodium-bile acid cotransporter
• Ethinyl Estradiol
• Cholesterol 7-alpha-Hydroxylase
• Steroid 12-alpha-Hydroxylase

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 11
• ATP-Binding Cassette Transporters (genetics, metabolism)
• Animals
• Chemical and Drug Induced Liver Injury (enzymology, pathology, prevention & control)
• Cholestasis (chemically induced, complications, pathology)
• Cholestenones (administration & dosage, therapeutic use)
• Cholesterol 7-alpha-Hydroxylase (genetics, metabolism)
• Disease Models, Animal
• Ethinyl Estradiol (toxicity)
• Hepatocytes (drug effects, metabolism)
• Liver Function Tests
• Male
• Membrane Transport Proteins (genetics, metabolism)
• Mice, Inbred C57BL
• Multidrug Resistance-Associated Protein 2
• Multidrug Resistance-Associated Proteins (genetics, metabolism)
• Organic Anion Transporters, Sodium-Dependent (genetics, metabolism)
• Primary Cell Culture
• Receptors, Cytoplasmic and Nuclear (metabolism)
• Steroid 12-alpha-Hydroxylase (genetics, metabolism)
• Symporters (genetics, metabolism)