Gypenosides Ameliorate Carbon Tetrachloride-Induced Liver Fibrosis by Inhibiting the Differentiation of Hepatic Progenitor Cells into Myofibroblasts

Am J Chin Med. 2017;45(5):1061-1074. doi: 10.1142/S0192415X17500574. Epub 2017 Jun 28.


Gypenosides (GPs), the predominant components of Gynostemma pentaphyllum, exert antifibrotic effects; however, the mechanisms underlying their ability to ameliorate liver fibrosis are unclear. Liver fibrosis was induced in C57BL/6 mice via subcutaneous injection of 10% carbon tetrachloride (CCl[Formula: see text] three times a week for two weeks. Then, CCl4 was administered in conjunction with intragastric GPs for another three weeks. For in vitro analyses, WB-F344, hepatatic progenitor cells (HPCs) were treated with transforming growth factor beta 1 (TGF-[Formula: see text]1) with or without GPs for 48[Formula: see text]h. The results showed that alanine aminotransferase (ALT) and aspartate transaminase (AST) activity, deposition of collagen, hydroxyproline content, and expression of alpha-smooth muscle actin ([Formula: see text]-SMA) and collagen type I (Col I) were significantly decreased after treatment with GPs ([Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text]). In the 5M CCl4 group, the expression of HPC markers, Sox9 and cytokeratin 19 (CK19), was significantly increased compared with the normal or GPs-treated group ([Formula: see text], [Formula: see text]). Immunostaining showed that the number of Sox9 and [Formula: see text]-SMA double-positive cells was higher in the 5M CCl4 group than in the normal group, but the addition of GPs caused this cell number to decrease. In WB-F344 cells, the expression of [Formula: see text]-SMA and Col I was significantly increased after treatment with TGF-[Formula: see text], whereas in the GPs treatment group, expression was markedly decreased ([Formula: see text]). The levels of TGF-[Formula: see text] and TGF-[Formula: see text]R1 were markedly reduced after GPs treatment both in vivo and in vitro. In conclusion, GPs ameliorated CCl4-induced liver fibrosis via the inhibition of TGF-[Formula: see text] signaling, consequently inhibiting the differentiation of HPCs into myofibroblasts.

Keywords: Gypenosides; Hepatic Progenitor Cells; Liver Fibrosis; TGF- Signaling.

MeSH terms

  • Actins / metabolism
  • Alanine Transaminase / metabolism
  • Animals
  • Aspartate Aminotransferases / metabolism
  • Carbon Tetrachloride / adverse effects*
  • Cell Differentiation / drug effects*
  • Cells, Cultured
  • Collagen Type I / metabolism
  • Depression, Chemical
  • Gynostemma / chemistry*
  • Keratin-19 / metabolism
  • Liver / cytology*
  • Liver Cirrhosis / chemically induced
  • Liver Cirrhosis / drug therapy*
  • Liver Cirrhosis / pathology*
  • Male
  • Mice, Inbred C57BL
  • Myofibroblasts / pathology*
  • Phytotherapy*
  • Plant Extracts / isolation & purification
  • Plant Extracts / pharmacology
  • Plant Extracts / therapeutic use
  • SOX9 Transcription Factor / metabolism
  • Stem Cells / cytology*
  • Stem Cells / metabolism
  • Transforming Growth Factor beta1 / pharmacology


  • Actins
  • Collagen Type I
  • Keratin-19
  • Plant Extracts
  • SOX9 Transcription Factor
  • Sox9 protein, mouse
  • Transforming Growth Factor beta1
  • alpha-smooth muscle actin, mouse
  • gypenoside
  • Carbon Tetrachloride
  • Aspartate Aminotransferases
  • Alanine Transaminase