title: The anti-hepatic fibrosis effects of dihydrotanshinone I are mediated by disrupting the yes-associated protein and transcriptional enhancer factor D2 complex and stimulating autophagy.
abstract: Dihydrotanshinone I (DHI), a lipophilic component of traditional Chinese medicine Salvia miltiorrhiza Bunge, has various therapeutic effects. We investigated the anti-fibrotic effect of DHI and its underlying mechanisms in vitro and in vivo.
  
  
  
  Rats subjected to bile duct ligation (BDL) were treated with DHI (25 mg·kg-1·day-1, i.p.) for 14 days. 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, yes-associated protein (YAP) downstream genes and autophagy markers were examined using western blot and real-time PCR analyses. Similar analyses were done in rat primary hepatic stellate cells (pHSCs). Autophagy flux was assessed by immunofluorescence.
  
  
  
  In BDL rats, DHI administration attenuated liver necrosis, bile duct proliferation and collagen accumulation and reduced the expression of genes associated with fibrogenesis, including Tgfb1, Mmp-2, Acta2 and Col1a1. DHI (1, 5, 10 μmol·L-1) 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, connective tissue growth factor, 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.
authors.affiliation: Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Maoxu
authors.initials: M
authors.lastname: Ge
authors.affiliation: Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.affiliation: Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Yixuan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Naren
authors.initials: N
authors.lastname: Li
authors.affiliation: Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Shuangshuang
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Wuli
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Hebei Key Laboratory for Chronic Diseases, School of Basic Medical Sciences, North China University of Science and Technology, Tangshan, China.
authors.forename: Yongzhan
authors.initials: Y
authors.lastname: Zhen
authors.affiliation: Department of Anatomy and Physiology, Kansas State University College of Veterinary Medicine, Manhattan, KS, 66506, USA.
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Yu
authors.affiliation: Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Hongwei
authors.initials: H
authors.lastname: He
authors.affiliation: Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Rong-Guang
authors.initials: RG
authors.lastname: Shao
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects*; D001652:Bile Ducts / Q000473:pathology / Q000601:surgery; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005663:Furans; D055166:Hepatic Stellate Cells / Q000187:drug effects*; D006801:Humans; D008026:Ligation; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D015394:Molecular Structure; D010616:Phenanthrenes / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011809:Quinones; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000091102:YAP-Signaling Proteins
chemical_list: D051017:Apoptosis Regulatory Proteins; D005663:Furans; D010616:Phenanthrenes; D011809:Quinones; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C509425:Yap1 protein, rat; C000713095:dihydrotanshinone I