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

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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.

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Authors and Affiliations

  1. Institute of Animal Sciences, The Volcani Center, P.O. Box 6, Bet Dagan, 50250, Israel

    Y. Gnainsky, G. Bilu, Y. Hagai, O. Genina & M. Pines

  2. The Genomics and Bioinformatics Center Agricultural Research Organization, The Volcani Center, Bet Dagan, Israel

    Z. Kushnirsky & H. Volpin

  3. Department of Gastroenterology, E. Wolfson Medical Center, Holon and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

    R. Bruck

  4. Department of Anatomy and Cell Biology, The Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel

    G. Spira

  5. Division of Hematology, Sheba Medical Center, Tel Hashomer, Israel

    A. Nagler

  6. Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan

    N. Kawada

  7. Developmental Biology Laboratory, CLUSTER project, and 21st Century COE Program, Department of Biological Science, Graduate School of Science, Hiroshima University, Hiroshima, Japan

    K. Yoshizato

  8. Department of Anatomy and Cell Biology, Faculties of Medicine and Dentistry, McGill University, Montreal, Quebec, Canada

    D. P. Reinhardt

  9. BIDMC Genomics Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA

    T. A. Libermann

Authors
  1. Y. Gnainsky
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  2. Z. Kushnirsky
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  3. G. Bilu
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  4. Y. Hagai
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  5. O. Genina
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  6. H. Volpin
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  7. R. Bruck
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  8. G. Spira
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  9. A. Nagler
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  10. N. Kawada
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  11. K. Yoshizato
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  12. D. P. Reinhardt
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  13. T. A. Libermann
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  14. M. Pines
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Corresponding author

Correspondence to M. Pines.

Additional information

This study was supported by the Israel Science Foundation (ISF; 537/01), Canadian Institutes of Health Research (MOP-68836), and NIH grants U01 DK58739 and R21 CA108303 and is a contribution from the Agricultural Research Organization, The Volcani Center, Bet Dagan, Israel (no. 481/05).

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Gnainsky, Y., Kushnirsky, Z., Bilu, G. et al. Gene expression during chemically induced liver fibrosis: effect of halofuginone on TGF-β signaling. Cell Tissue Res 328, 153–166 (2007). https://doi.org/10.1007/s00441-006-0330-1

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  • DOI: https://doi.org/10.1007/s00441-006-0330-1

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