The anti-hepatic fibrosis effects of dihydrotanshinone I are mediated by disrupting the YAP and TEAD2 complex and stimulating autophagy.

Ge M, Liu H, Zhang Y et al.

Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.

British journal of pharmacology. Mar 2017.

Dihydrotanshinone I (DHI), a lipophilic component of traditional Chinese medicine Salvia miltiorrhiza Bunge, has various therapeutic effects. In this study, we investigated the anti-fibrotic effects of DHI and its underlying mechanisms in vitro and in vivo.Rats that underwent bile duct ligation (BDL) were treated with DHI (25 mg·kg(-1) ·d(-1) , ip) for 14 d. Serum biochemical and liver tissue morphological analyses were performed. The human hepatic stellate cell line LX-2 served as a liver fibrosis model in vitro. Liver fibrogenic genes, YAP downstream genes and autophagy markers were examined using western blot and real-time PCR analyses. Similar results were also obtained in rat primary hepatic stellate cells (rat pHSCs). Autophagy flux was assessed by immunofluorescence.In BDL rats, DHI administration attenuated liver necrosis, bile duct proliferation and collagen accumulation, and reduced expression of the genes associated with fibrogenesis, including Tgfb1, Mmp-2, Acta2, and Col1a1. DHI (1, 5, 10 μmol/L) time- and dose-dependently suppressed the protein level of COL1A1, TGFβ1 and α-SMA in LX-2 cells and rat pHSCs. Furthermore, DHI blocked the nuclear translocation of YAP, which inhibited the YAP/TEAD2 interaction and its downstream fibrogenic genes, such as CTGF, SOX4 and Survivin. This stimulated autophagic flux and accelerated the degradation of liver collagen.DHI exerts anti-fibrotic effects in BDL rats, LX-2 cells and rat pHSCs by inhibiting the YAP and TEAD2 complex and stimulating autophagy. These findings indicate that DHI may be a potential therapeutic for the treatment of liver fibrosis.


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