Tectorigenin alleviates intrahepatic cholestasis by inhibiting hepatic inflammation and bile accumulation via activation of PPARγ.
PPARγ
hepatocytes
intrahepatic cholestasis
macrophage
tectorigenin
Journal
British journal of pharmacology
ISSN: 1476-5381
Titre abrégé: Br J Pharmacol
Pays: England
ID NLM: 7502536
Informations de publication
Date de publication:
06 2021
06 2021
Historique:
revised:
07
02
2021
received:
04
09
2020
accepted:
21
02
2021
pubmed:
5
3
2021
medline:
6
7
2021
entrez:
4
3
2021
Statut:
ppublish
Résumé
Increasing evidence suggests that human cholestasis is closely associated with the accumulation and activation of hepatic macrophages. Research indicates that activation of PPARγ exerts liver protective effects in cholestatic liver disease (CLD), particularly by ameliorating inflammation and fibrosis, thus limiting disease progression. However, existing PPARγ agonists, such as troglitazone and rosiglitazone, have significant side effects that prevent their clinical application in the treatment of CLD. In this study, we found that tectorigenin alleviates intrahepatic cholestasis in mice by activating PPARγ. Wild-type mice were intragastrically administered α-naphthylisothiocyanate (ANIT) or fed a diet containing 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) to simultaneously establish an experimental model of intrahepatic cholestasis and tectorigenin intervention, followed by determination of intrahepatic cholestasis and the mechanisms involved. In addition, PPARγ-deficient mice were administered ANIT and/or tectorigenin to determine whether tectorigenin exerts its liver protective effect by activating PPARγ. Treatment with tectorigenin alleviated intrahepatic cholestasis by inhibiting the recruitment and activation of hepatic macrophages and by promoting the expression of bile transporters via activation of PPARγ. Furthermore, tectorigenin increased expression of the bile salt export pump (BSEP) through enhanced PPARγ binding to the BSEP promoter. In PPARγ-deficient mice, the hepatoprotective effect of tectorigenin during cholestasis was blocked. In conclusion, tectorigenin reduced the recruitment and activation of hepatic macrophages and enhanced the export of bile acids by activating PPARγ. Taken together, our results suggest that tectorigenin is a candidate compound for cholestasis treatment.
Sections du résumé
BACKGROUND AND PURPOSE
Increasing evidence suggests that human cholestasis is closely associated with the accumulation and activation of hepatic macrophages. Research indicates that activation of PPARγ exerts liver protective effects in cholestatic liver disease (CLD), particularly by ameliorating inflammation and fibrosis, thus limiting disease progression. However, existing PPARγ agonists, such as troglitazone and rosiglitazone, have significant side effects that prevent their clinical application in the treatment of CLD. In this study, we found that tectorigenin alleviates intrahepatic cholestasis in mice by activating PPARγ.
EXPERIMENTAL APPROACH
Wild-type mice were intragastrically administered α-naphthylisothiocyanate (ANIT) or fed a diet containing 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) to simultaneously establish an experimental model of intrahepatic cholestasis and tectorigenin intervention, followed by determination of intrahepatic cholestasis and the mechanisms involved. In addition, PPARγ-deficient mice were administered ANIT and/or tectorigenin to determine whether tectorigenin exerts its liver protective effect by activating PPARγ.
KEY RESULTS
Treatment with tectorigenin alleviated intrahepatic cholestasis by inhibiting the recruitment and activation of hepatic macrophages and by promoting the expression of bile transporters via activation of PPARγ. Furthermore, tectorigenin increased expression of the bile salt export pump (BSEP) through enhanced PPARγ binding to the BSEP promoter. In PPARγ-deficient mice, the hepatoprotective effect of tectorigenin during cholestasis was blocked.
CONCLUSION AND IMPLICATIONS
In conclusion, tectorigenin reduced the recruitment and activation of hepatic macrophages and enhanced the export of bile acids by activating PPARγ. Taken together, our results suggest that tectorigenin is a candidate compound for cholestasis treatment.
Substances chimiques
Bile Acids and Salts
0
Isoflavones
0
PPAR gamma
0
tectorigenin
855130H9CO
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2443-2460Subventions
Organisme : China Postdoctoral Science Foundation
ID : 2020M683179
Organisme : National Natural Science Foundation of China
ID : 82000824
Organisme : National Natural Science Foundation of China
ID : 82003747
Organisme : Natural Science Foundation of Tianjin City
ID : 19JCQNJC12600
Organisme : Research project of Tianjin education commission
ID : 2019KJ044
Informations de copyright
© 2021 The British Pharmacological Society.
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