title: 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: OBJECTIVE
  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.affiliation: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Dalian, 116044, China.|Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, Dalian, Liaoning, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Meng
authors.affiliation: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Dalian, 116044, China.|Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, Dalian, Liaoning, China.
authors.forename: Xinli
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Dalian, 116044, China.|Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, Dalian, Liaoning, China.
authors.forename: Changyuan
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Dalian, 116044, China.|Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, Dalian, Liaoning, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Dalian, 116044, China.|Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, Dalian, Liaoning, China.
authors.forename: Huijun
authors.initials: H
authors.lastname: Sun
authors.affiliation: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Dalian, 116044, China.|Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, Dalian, Liaoning, China.
authors.forename: Pengyuan
authors.initials: P
authors.lastname: Sun
authors.affiliation: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Dalian, 116044, China.|Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, Dalian, Liaoning, China.
authors.forename: Xiaokui
authors.initials: X
authors.lastname: Huo
authors.affiliation: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Dalian, 116044, China.|Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, Dalian, Liaoning, China.
authors.forename: Zhihao
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Dalian, 116044, China.|Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, Dalian, Liaoning, China.
authors.forename: Jihong
authors.initials: J
authors.lastname: Yao
authors.affiliation: Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, 9 West Section, Lvshun South Road, Dalian, 116044, China. kexinliu@dlmedu.edu.cn.|Provincial Key Laboratory for Pharmacokinetics and Transport, Liaoning, Dalian Medical University, Dalian, Liaoning, China. kexinliu@dlmedu.edu.cn.
authors.forename: Kexin
authors.initials: K
authors.lastname: Liu
mesh_terms: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology* / Q000473:pathology / Q000517:prevention & control*; D002779:Cholestasis / Q000139:chemically induced* / Q000150:complications / Q000473:pathology; D002783:Cholestenones / Q000008:administration & dosage / Q000627:therapeutic use*; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004997:Ethinyl Estradiol / Q000633:toxicity; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D008111:Liver Function Tests; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism; D029363:Organic Anion Transporters, Sodium-Dependent / Q000235:genetics / Q000378:metabolism; D061251:Primary Cell Culture; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D013253:Steroid 12-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism; D027981:Symporters / Q000235:genetics / Q000378:metabolism; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D002783:Cholestenones; D002790:Cholesterol 7-alpha-Hydroxylase; D004997:Ethinyl Estradiol; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D029363:Organic Anion Transporters, Sodium-Dependent; D018160:Receptors, Cytoplasmic and Nuclear; D013253:Steroid 12-alpha-Hydroxylase; D027981:Symporters; D000099150:Receptor, Farnesoid X-Activated; C490549:Abcb11 protein, mouse; C526957:alisol B 23-acetate; C071908:sodium-bile acid cotransporter
keywords: EE; FXR; alisol B 23-acetate; cholestasis; transporter