Tectorigenin alleviates intrahepatic cholestasis by inhibiting hepatic inflammation and bile accumulation via activation of PPARγ.

Publisher: Wiley Country of Publication: England NLM ID: 7502536 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-5381 (Electronic) Linking ISSN: 00071188 NLM ISO Abbreviation: Br J Pharmacol Subsets: MEDLINE

Publication: London : Wiley
Original Publication: London, Macmillian Journals Ltd.

Cholestasis*/drug therapy ; Cholestasis, Intrahepatic*/drug therapy; Animals ; Bile ; Bile Acids and Salts ; Inflammation/drug therapy ; Isoflavones ; Liver ; Mice ; PPAR gamma

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.
(© 2021 The British Pharmacological Society.)

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2020M683179 China Postdoctoral Science Foundation; 82000824 National Natural Science Foundation of China; 82003747 National Natural Science Foundation of China; 19JCQNJC12600 Natural Science Foundation of Tianjin City; 2019KJ044 Research project of Tianjin education commission

Keywords: PPARγ; hepatocytes; intrahepatic cholestasis; macrophage; tectorigenin

0 (Bile Acids and Salts)
0 (Isoflavones)
0 (PPAR gamma)
855130H9CO (tectorigenin)

Date Created: 20210304 Date Completed: 20210705 Latest Revision: 20210705

20221213

10.1111/bph.15429

33661551