Protective effects of alisol B 23-acetate from edible botanical Rhizoma alismatis against carbon tetrachloride-induced hepatotoxicity in mice.
Carbon tetrachloride (CCl4)-induced hepatotoxicity is a common syndrome with simultaneous severe hepatocyte death and acute cholestasis. The purpose of the present study is to investigate the hepatoprotective effect of alisol B 23-acetate (AB23A), a natural triterpenoid from edible botanical Rhizoma alismatis, on acute hepatotoxicity induced by CCl4 in mice, and further to elucidate the involvement of farnesoid X receptor (FXR), signal transducers and activators of transcription 3 (STAT3) in the hepatoprotective effect. H&E staining, BrdU immunohistochemistry and TUNEL assay were used to identify the amelioration of histopathological changes, hepatocyte proliferation and apoptosis. Real-time PCR and western blot assay were used to elucidate the mechanisms underlying AB23A hepatoprotection. The results indicated that AB23A treatment in a dose-dependent manner resulted in protection against hepatotoxicity induced by CCl4via FXR activation. Through FXR activation, AB23A promoted hepatocyte proliferation via an induction in hepatic levels of FoxM1b, Cyclin D1 and Cyclin B1. AB23A also reduced hepatic bile acids through a decrease in hepatic uptake transporter Ntcp, bile acid synthetic enzymes Cyp7a1, Cyp8b1, and an increase in efflux transporter Bsep, Mrp2 expression. In addition, AB23A induced the expression of STAT3 phosphorylation, and STAT3 target genes Bcl-xl and SOCS3, resulting in decreased hepatocyte apoptosis. In conclusion, AB23A produces a protective effect against CCl4-induced hepatotoxicity, due to FXR and STAT3-mediated gene regulation.
Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, China. kexinliu@dlmedu.edu.cn.
Qiang
Q
Meng
Xinli
X
Chen
Changyuan
C
Wang
Qi
Q
Liu
Huijun
H
Sun
Pengyuan
P
Sun
Xiaokui
X
Huo
Zhihao
Z
Liu
Kexin
K
Liu
D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000410:Alanine Transaminase / Q000097:blood; D034902:Alisma / Q000737:chemistry*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001219:Aspartate Aminotransferases / Q000097:blood; D001647:Bile Acids and Salts / Q000097:blood; D002251:Carbon Tetrachloride / Q000009:adverse effects; D049109:Cell Proliferation / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy*; D002783:Cholestenones / Q000494:pharmacology*; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism; D056744:Cyclin B1 / Q000235:genetics / Q000378:metabolism; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D027343:Rhizome / Q000737:chemistry*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D013253:Steroid 12-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; C490549:Abcb11 protein, mouse; C494812:Bcl2l1 protein, mouse; D001647:Bile Acids and Salts; C534700:Ccnb1 protein, mouse; D002783:Cholestenones; D056744:Cyclin B1; D051858:Forkhead Transcription Factors; D050796:STAT3 Transcription Factor; C491411:Socs3 protein, mouse; C494087:Stat3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C526957:alisol B 23-acetate; D051020:bcl-X Protein; D019938:Cyclin D1; D002251:Carbon Tetrachloride; D002790:Cholesterol 7-alpha-Hydroxylase; C502772:Cyp7a1 protein, mouse; D013253:Steroid 12-alpha-Hydroxylase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase