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

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

  • Br J Pharmacol. 2021 Jun;178(12):2443-2460. doi: 10.1111/bph.15429.
Jiaqing Xiang 1 Guangyan Yang 1 Chuanrui Ma 2 3 Lingling Wei 4 Han Wu 1 5 Wei Zhang 6 Xiuhua Tao 7 Lingyun Jiang 1 Zhen Liang 1 Lin Kang 1 Shu Yang 1 8
Affiliations

Affiliations

  • 1 Department of Endocrinology, The Second Clinical Medical College, Jinan University (Shenzhen People's Hospital), Shenzhen, China.
  • 2 First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.
  • 3 Tianjin Key Laboratory of Translational Research of TCM Prescription and Syndrome, Tianjin, China.
  • 4 Institute of Agricultural Economics and Information, Jiangxi Academy of Agricultural Sciences, Jiangxi, China.
  • 5 Department of Endocrinology, Key Laboratory of Endocrinology, National Health Commission, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
  • 6 State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for Cell Responses, College of Life Sciences, Nankai University, Tianjin, China.
  • 7 Institute of Vegetables and Flowers, Jiangxi Academy of Agricultural Sciences, Jiangxi, China.
  • 8 Integrated Chinese and Western Medicine Postdoctoral Research Station, Jinan University, Guangzhou, China.
Abstract

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.

Keywords

PPARγ; hepatocytes; intrahepatic cholestasis; macrophage; tectorigenin.

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