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Keywords:

  • anti-fibrogenic gene;
  • hepatic stellate cells;
  • methionine- and choline-deficient diet;
  • p38;
  • RAS-ERK

Abstract

Background: The effect of transforming growth factor (TGF)-α on fibrosis varies between cell types and the role of TGF-α in hepatic fibrosis has not been fully elucidated.

Methods: We examined the effect of TGF-α on hepatic fibrosis using TGF-α-expressing transgenic mice fed a methionine- and choline-deficient (MCD) diet and human hepatic stellate cells (HSCs) line LX-2, rat and human primary HSCs.

Results: Although the expression levels of the tissue inhibitor of metalloproteinases-1 and α1(I) collagen mRNA were unchanged, feeding the TGF-α transgenic mice the MCD diet resulted in greater expression of the murine functional analogue of matrix metalloproteinase-1 (MMP-1), MMP-13 mRNA and protein and attenuated hepatic fibrosis compared with wild-type mice. TGF-α overexpression did not affect the extent of the steatosis, oxidative stress and hepatic inflammation in the MCD diet-fed mice. The effect of TGF-α on the fibrogenic and anti-fibrogenic gene expressions varied between cell types in vitro. TGF-α increased MMP-1 mRNA expressions that were completely blocked by gefitinib in LX-2 cells. The extracellular signal-regulated kinase (ERK) 1/2, c-Jun N-terminal kinase and p38 pathways were involved in MMP-1 mRNA expression in LX-2 cells. Although TGF-α increased the phosphorylation of p38, the p38 inhibitor activated the RAS-ERK pathway and increased TGF-α-induced MMP-1 mRNA expression, which suggested that there may be a crosstalk between the RAS-ERK and the p38 pathways in LX-2 cells.

Conclusions: The TGF-α may attenuate hepatic fibrosis in part because of upregulation of the expression of MMP-1. The balance between fibrogenic and anti-fibrogenic gene expression and between the activity of the RAS-ERK and the p38 pathways may be crucial for the fibrotic process.