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

文献类型： 外文期刊

第一作者： Xiang, Jiaqing

作者： Xiang, Jiaqing;Yang, Guangyan;Wu, Han;Jiang, Lingyun;Liang, Zhen;Kang, Lin;Yang, Shu;Ma, Chuanrui;Ma, Chuanrui;Wei, Lingling;Wu, Han;Zhang, Wei;Tao, Xiuhua;Yang, Shu

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关键词： hepatocytes; intrahepatic cholestasis; macrophage; PPARγ tectorigenin

期刊名称：BRITISH JOURNAL OF PHARMACOLOGY （ 影响因子：7.73； 五年影响因子：6.148 ）

ISSN： 0007-1188

年卷期： 2021 年 178 卷 12 期

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收录情况： SCI

摘要： 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 PPAR gamma exerts liver protective effects in cholestatic liver disease (CLD), particularly by ameliorating inflammation and fibrosis, thus limiting disease progression. However, existing PPAR gamma 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 PPAR gamma. Experimental Approach Wild-type mice were intragastrically administered alpha-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, PPAR gamma-deficient mice were administered ANIT and/or tectorigenin to determine whether tectorigenin exerts its liver protective effect by activating PPAR gamma. 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 PPAR gamma. Furthermore, tectorigenin increased expression of the bile salt export pump (BSEP) through enhanced PPAR gamma binding to the BSEP promoter. In PPAR gamma-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 PPAR gamma. Taken together, our results suggest that tectorigenin is a candidate compound for cholestasis treatment.

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