Molecular mechanisms of hepatoprotective effect of tectorigenin against ANIT-induced cholestatic liver injury: Role of FXR and Nrf2 pathways

被引：12
作者：
Cao, Peng [1 ,2 ,3 ,4 ]
Gan, Jun [5 ]
Wu, Sanlan [1 ,2 ]
Hu, Yixin [5 ]
Xia, Bin [5 ]
Li, Xiaoyue [5 ]
Zeng, Hongan [1 ,2 ]
Cheng, Bingyu [5 ]
Yu, Huifan [3 ]
Li, Fei [3 ]
Si, Luqin [5 ]
Huang, Jiangeng [5 ]
机构：
[1] Huazhong Univ Sci & Technol, Tongji Med Coll, Union Hosp, Dept Pharm, Wuhan 430022, Peoples R China
[2] Hubei Prov Clin Res Ctr Precis Med Crit Illness, Wuhan 430022, Peoples R China
[3] Hubei Univ Med, Sch Pharmaceut Sci, Hubei Key Lab Wudang Local Chinese Med Res, Shiyan 442000, Hubei, Peoples R China
[4] Huazhong Univ Sci & Technol, Tongji Med Coll, Union Hosp, Hubei Key Lab Biol Targeted Therapy, Wuhan, Peoples R China
[5] Huazhong Univ Sci & Technol, Tongji Med Coll, Sch Pharm, Dept Pharmaceut, Wuhan 430030, Peoples R China
来源：
FOOD AND CHEMICAL TOXICOLOGY | 2023年 / 178卷
基金：
中国国家自然科学基金;
关键词：
Tectorigenin; ANIT; Cholestatic liver injury; Bile acid; FXR; Nrf2; BILE-ACIDS; TRANSPORTERS; FACTOR-2; PROTECTS;
D O I：
10.1016/j.fct.2023.113914
中图分类号：
TS2 [食品工业];
学科分类号：
0832 ;
摘要：
Cholestatic liver injury is caused by toxic action or allergic reaction, resulting in abnormality of bile formation and excretion. Few effective therapies have become available for the treatment of cholestasis. Herein, we found that tectorigenin (TG), a natural isoflavone, showed definite protective effects on alpha-naphthylisothiocyanate (ANIT)-induced cholestatic liver injury, significantly reversing the abnormality of plasma alanine/aspartate aminotransferase, total/direct bilirubin and alkaline phosphatase, as well as hepatic reactive oxygen species, catalase and superoxide dismutase. Importantly, the targeted metabolomic determination found that BA homeostasis could be well maintained in TG-treated cholestatic mice, especially the levels of glycocholic acid, tauromuricholic acid, taurocholic acid, taurolithocholic acid, tauroursodeoxycholic acid and taurodeoxycholic acid. Overall, primary/secondary and amidated/unamidated bile acid (BA) levels were significantly altered upon ANIT stimulation but could be restored by TG intervention to certain extents. In addition, TG boosted the expression of farnesoid x receptor (FXR), which in turn upregulated multidrug resistance protein 2 (MRP2) and bile salt export pump (BSEP) to accelerate the excretion of BA. Meanwhile, TG enhanced the expression of Nrf2 and its upstream genes PI3K/Akt and downstream target genes HO-1, NQO1, GCLC and GCLM to strengthen the antioxidant capacity. Taken together, TG plays a vital role in maintaining BA homeostasis and ameliorating cholestatic liver injury through regulating FXR-mediated BA efflux and Nrf2-mediated antioxidative pathways.
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页数：11
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