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

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

Br J Pharmacol 2021 Mar 4. Epub 2021 Mar 4.

Department of Endocrinology, The Second Clinical Medical College, Jinan University (Shenzhen People's Hospital), Shenzhen, 518020, China.

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 peroxisome proliferator-activated receptor-γ (PPARγ) exerts liver protective effects in cholestatic liver disease (CLD), particularly by ameliorating inflammation and fibrosis, thus limiting disease progression. However, the existing PPARγ agonists, such as troglitazone and rosiglitazone, have significant side effects that impede their clinical application in the treatment of CLD. In this study, we found that tectorigenin (TEC) 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 TEC intervention, followed by determination of intrahepatic cholestasis and the mechanisms involved. In addition, PPARγ-deficient mice were administered ANIT and/or TEC to determine whether TEC exerts its liver protective effect by activating PPARγ.

Key Results: We demonstrated that TEC intervention alleviated intrahepatic cholestasis by inhibiting the recruitment and activation of hepatic macrophages as well as by promoting the expression of bile transporters via activation of PPARγ. Furthermore, our results show that TEC increased bile salt export pump (BSEP) expression through enhanced PPARγ binding to the BSEP promoter. We also demonstrated that PPARγ deficiency blocked the hepatoprotective effect of TEC during cholestasis.

Conclusions And Implications: In conclusion, TEC reduced the recruitment and activation of hepatic macrophages, and enhanced the export of bile acids by activating PPARγ. Taken together, our results suggest that TEC is a candidate compound for cholestasis treatment.

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http://dx.doi.org/10.1111/bph.15429DOI Listing
March 2021

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