Gene expression during chemically induced liver fibrosis: Effect of halofuginone on TGF-β signaling

Y. Gnainsky, Z. Kushnirsky, G. Bilu, Y. Hagai, O. Genina, H. Volpin, R. Bruck, G. Spira, A. Nagler, N. Kawada, K. Yoshizato, D. P. Reinhardt, T. A. Libermann, M. Pines

Research output: Contribution to journalArticlepeer-review

Abstract

Hepatic fibrosis is associated with the activation of stellate cells (HSCs), the major source of extracellular matrix (ECM) proteins. Transforming growth factor-β (TGF-β), signaling via Smad3, is the most profibrogenic cytokine and the major promoter of ECM synthesis. Halofuginone, an inhibitor of liver fibrosis, inhibits TGF-β-dependent Smad3 phosphorylation in human HSCs in culture. We have used transcriptional profiling to evaluate the effect of halofuginone on gene expression during the progression of thioacetamide (TAA)-induced liver fibrosis in the rat and have focused on genes that are associated with TGF-β. TAA treatment causes alterations in the expression of 7% of liver genes. Halofuginone treatment prevents the changes in the expression of 41% of these genes and results in the inhibition of HSC activation and collagen synthesis. During the early stages of the disease, halofuginone affects genes involved in alcohol, lipid, protein, and phosphate metabolism and cell adhesion and, at later stages, in the cell cycle (cell development, differentiation, cell proliferation, and apoptosis). The activation of TGF-β-dependent genes, such as tartrate-resistant acid phosphatase, its putative substrate osteopontin, stellate cell activation-association protein, and fibrillin-1, during chemically induced fibrosis is prevented by halofuginone. This study thus highlights the role of TGF-β signaling in liver fibrosis and especially its potential for pharmacological intervention. Halofuginone, which has demonstrated efficacy and tolerance in animals and humans, could become an effective and novel therapy for liver fibrosis.

Original languageEnglish
Pages (from-to)153-166
Number of pages14
JournalCell and Tissue Research
Volume328
Issue number1
DOIs
StatePublished - Apr 2007

Keywords

  • Acid phosphatase
  • Collagen
  • Cytoglobin/STAP
  • Fibrillin
  • Fibrosis
  • Liver
  • Osteopontin
  • Rat (Wistar, male)

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