Da-Chai-Hu-Tang Protects From Acute Intrahepatic Cholestasis by Inhibiting Hepatic Inflammation and Bile Accumulation via Activation of PPARα

Frontiers in Pharmacology

Yin Cai¹  Long Chen²  Jianling Xie³  Christopher G. Proud⁵  Shihao Xu⁶  Kaikai Shen⁶  Jin Xu⁶  Xi Qiao⁶  Ziyi Zhu⁶  Peike Peng⁶  Xinwei Shi⁶  Mengyuan Yu⁷  Yaoting Li⁸ 

[1] Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Kowloon, Hong Kong SAR, China;Experimental Center for Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai, China;Flinders Health and Medical Research Institute, Flinders University, Adelaide, SA, Australia;Lifelong Health Theme, South Australian Health and Medical Research Institute, Adelaide, SA, Australia;Molecular and Biomedical Sciences, School of Biological Sciences, University of Adelaide, Adelaide, SA, Australia;School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China;School of Biosciences, University of Birmingham, Birmingham, United Kingdom;School of Pharmacy, Fudan University, Shanghai, China;

关键词: Da-Chai-Hu-Tang;    intrahepatic cholestasis;    liver injury;    bile acid homeostasis;    peroxisome proliferator-activated receptor alpha;   

DOI  :  10.3389/fphar.2022.847483

来源: DOAJ

【 摘 要 】

Cholestasis is caused by intrahepatic retention of excessive toxic bile acids and ultimately results in hepatic failure. Da-Chai-Hu-Tang (DCHT) has been used in China to treat liver and gallbladder diseases for over 1800 years. Here, we demonstrated that DCHT treatment prevented acute intrahepatic cholestasis with liver injury in response to α-naphthylisothiocyanate (ANIT) not to bile duct ligation (BDL) induced-extrahepatic cholestasis. ANIT (80 mg/kg) increased serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), direct bilirubin (DBiL), total bilirubin (TBiL), and total bile acids (TBA) which was attenuated by DCHT treatment in a dose-dependent manner. DCHT treatment at high dose of 1.875 g/kg restored bile acid homeostasis, as evidenced by the recovery of the transcription of genes implicated in bile acid biosynthesis, uptake and efflux. DCHT treatment (1.875 g/kg) reversed ANIT-evoked disordered glutathione homeostasis (as determined by GSH/GSSG ratio) and increased in the mRNA levels for Il6, Il1b and Tnfa associated with liver inflammation. Using network pharmacology-based approaches, we identified 22 putative targets involved in DCHT treatment for intrahepatic cholestasis not extrahepatic cholestasis. In addition, as evidenced by dual-luciferase reporter assays, compounds from DCHT with high affinity of PPARα increased luciferase levels from a PPARα-driven reporter. PPARα agonist fenofibrate was able to mimic the cytoprotective effect of DCHT on intrahepatic cholestasis, which was abolished by the PPARα antagonist GW6471. KEGG enrichment and western blot analyses showed that signaling axes of JNK/IL-6/NF-κB/STAT3 related to PPARα might be the principal pathway DCHT affects intrahepatic cholestasis. Taken together, the present study provides compelling evidence that DCHT is a promising formula against acute intrahepatic cholestasis with hepatotoxicity which works via PPARα activation.

【 授权许可】

Unknown