Pharmaceutical research · 2015
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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Meng Qiang, Chen Xinli, Wang Changyuan, Liu Qi, Sun Huijun, Sun Pengyuan, Huo Xiaokui, Liu Zhihao, Yao Jihong, Liu Kexin
Аннотация
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.
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.
Предметные рубрики MeSH
ATP Binding Cassette Transporter, Subfamily B, Member 11ATP-Binding Cassette TransportersAnimalsChemical and Drug Induced Liver InjuryCholestasisCholestenonesCholesterol 7-alpha-HydroxylaseDisease Models, AnimalEthinyl EstradiolHepatocytesLiver Function TestsMaleMembrane Transport ProteinsMice, Inbred C57BLMultidrug Resistance-Associated Protein 2ATP-Binding Cassette, Sub-Family C ProteinsOrganic Anion Transporters, Sodium-DependentPrimary Cell CultureReceptors, Cytoplasmic and NuclearSteroid 12-alpha-HydroxylaseSymportersReceptor, Farnesoid X-Activated