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Eupatilin attenuates bile acid-induced hepatocyte apoptosis

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Abstract

Background

In cases of cholestasis, bile acids induce hepatocyte apoptosis by activating death receptor-mediated apoptotic signaling cascades. Eupatilin (5,7-dihydroxy-3,4,6-trimethoxyflavone) is a pharmacologically active ingredient found in Artemisia asiatica and exhibits cytoprotective effects against experimentally induced gastrointestinal, pancreatic, and hepatic damage. This study was undertaken to examine if eupatilin modulates bile acid-induced hepatocyte apoptosis.

Methods

Huh-BAT cells, a human hepatocellular carcinoma cell line stably transfected with a bile acid transporter, were used in this study. Apoptosis was quantified using 4′,6-diamidino-2-phenylindole dihydrochloride staining, and its signaling cascades were explored by immunoblot analysis. Kinase signaling was evaluated by immunoblotting and by using selective inhibitors. Eupatilin's in vivo effect on bile acid-induced hepatocyte apoptosis was explored in bile duct-ligated rats.

Results

Eupatilin significantly reduced bile acid-mediated hepatocyte apoptosis by attenuating bile acid-induced caspase 8 cleavage. Eupatilin diminished the bile acid-induced activation of mitogen-activated protein kinases, including p38 mitogen-activated protein kinase and c-Jun N-terminal kinase. In particular, the eupatilin-mediated inhibition of bile acid-induced c-Jun N-terminal kinase activation was found to be responsible for attenuating caspase 8 cleavage. Moreover, eupatilin diminished hepatocyte apoptosis in bile duct-ligated rats.

Conclusions

Eupatilin attenuates bile acid-induced hepatocyte apoptosis by suppressing bile acid-induced kinase activation. Therefore, eupatilin might be therapeutically efficacious in a variety of human liver diseases associated with cholestasis.

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Authors and Affiliations

  1. Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, 28 Yungun-dong Chongno-gu, Seoul, 110-744, Republic of Korea

    Su Cheol Park, Jung-Hwan Yoon, Won Kim, Geum-Youn Gwak, Sung-Hee Lee, Soo-Mi Lee & Hyo-Suk Lee

  2. Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Ulsan, Republic of Korea

    Kang Mo Kim

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  1. Su Cheol Park
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Park, S., Yoon, JH., Kim, W. et al. Eupatilin attenuates bile acid-induced hepatocyte apoptosis. J Gastroenterol 41, 772–778 (2006). https://doi.org/10.1007/s00535-006-1854-6

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  • DOI: https://doi.org/10.1007/s00535-006-1854-6

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