The anti-fibrotic effects of epigallocatechin-3-gallate in bile duct-ligated cholestatic rats and human hepatic stellate LX-2 cells are mediated by the PI3K/Akt/Smad pathway |
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Authors: | Dong-ke Yu Cai-xia Zhang Shuang-shuang Zhao Sheng-hua Zhang Hao Zhang Shi-ying Cai Rong-guang Shao Hong-wei He |
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Affiliation: | 1.Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China;2.Sichuan Academy of Medical Sciences & Sichuan Provincial People''s Hospital, Chengdu 610072, China;3.Department of Internal Medicine and Liver Center, School of Medicine, Yale University, New Haven, CT 06520, USA |
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Abstract: | Aim:(−)-Epigallocatechin-3-gallate (EGCG) is one of the most abundant polyphenols in green tea with strong antioxidant activity and various therapeutic effects. In this study, we investigated the anti-fibrotic effects of EGCG and underlying mechanisms in bile duct-ligated (BDL) rats and a liver fibrosis model in vitro.Methods:BDL rats were treated with EGCG (25 mg·kg−1·d−1, po) for 14 d, and then the serum, bile and liver samples were collected. Liver fibrosis was assessed by serum, urine and bile biochemistry analyses and morphological studies of liver tissues. TGF-β1-stimulated human hepatic stellate LX-2 cells were used as a liver fibrosis model in vitro. The expression of liver fibrogenic genes and signaling proteins in the PI3K/Akt/Smad pathway was examined using Western blotting and/or real-time PCR.Results:In BDL rats, EGCG treatment significantly ameliorates liver necrosis, inflammation and fibrosis, and suppressed expression of the genes associated with liver inflammation and fibrogenesis, including TNF-α, IL-1β, TGF-β1, MMP-9, α-SMA, and COL1A1. In LX-2 cells, application of EGCG (10, 25 μmol/L) dose-dependently suppressed TGF-β1-stimulated expression of COL1A1, MMP-2, MMP-9, TGF-β1, TIMP1, and α-SMA. Furthermore, EGCG significantly suppressed the phosphorylation of Smad2/3 and Akt in the livers of BDL rats and in TGF-β1-stimulated LX-2 cells. Application of {"type":"entrez-nucleotide","attrs":{"text":"LY294002","term_id":"1257998346","term_text":"LY294002"}}LY294002, a specific inhibitor of PI3K, produced similar effects as EGCG did in TGF-β1-stimulated LX-2 cells, but co-application of EGCG and {"type":"entrez-nucleotide","attrs":{"text":"LY294002","term_id":"1257998346","term_text":"LY294002"}}LY294002 did not produce additive effects.Conclusion:EGCG exerts anti-fibrotic effects in BDL rats and TGF-β1-stimulated LX-2 cells in vitro via inhibiting the PI3K/Akt/Smad pathway. |
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Keywords: | epigallocatechin-3-gallate, liver fibrosis, cholestasis, bile duct-ligated rats, hepatic stellate cells, TGF-β 1, PI3K/Akt/Smad pathway, G3BP1, __tag_705602209" class=" tag_hotlink" href=" /nuccore/LY294002" ref=" /nuccore/LY294002" >{" type" :" entrez-nucleotide" ," attrs" :{" text" :" LY294002" ," term_id" :" 1257998346" ," term_text" :" LY294002" }}LY294002 |
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