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HCV proteins increase expression of heme oxygenase-1 (HO-1) and decrease expression of Bach1 in human hepatoma cells

  • Tahereh Ghaziani
    Affiliations
    Department of Medicine, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030-1111, USA

    The Liver-Biliary-Pancreatic Center, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030-1111, USA
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  • Ying Shan
    Affiliations
    Department of Medicine, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030-1111, USA

    The Liver-Biliary-Pancreatic Center, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030-1111, USA
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  • Richard W. Lambrecht
    Affiliations
    Department of Pharmacology, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030-1111, USA

    The Liver-Biliary-Pancreatic Center, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030-1111, USA
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  • Susan E. Donohue
    Affiliations
    Department of Medicine, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030-1111, USA

    The Liver-Biliary-Pancreatic Center, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030-1111, USA
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  • Thomas Pietschmann
    Affiliations
    Department of Molecular Virology, University of Heidelberg, Heidelberg, Germany
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  • Ralf Bartenschlager
    Affiliations
    Department of Molecular Virology, University of Heidelberg, Heidelberg, Germany
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  • Herbert L. Bonkovsky
    Correspondence
    Corresponding author. Address: Departments of Medicine, Molecular, Microbial, and Structural Biology, The Liver-Biliary-Pancreatic Center, University of Connecticut Health Center, MC-1111, 263 Farmington Avenue, Farmington, CT 06030-1111, USA. Tel.: +1 860 679 3759; fax: +1 860 679 1931.
    Affiliations
    Department of Medicine, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030-1111, USA

    Department of Molecular, Microbial and Structural Biology, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030-1111, USA

    The Liver-Biliary-Pancreatic Center, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030-1111, USA
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Published:February 03, 2006DOI:https://doi.org/10.1016/j.jhep.2005.12.020

      Background/Aims

      Hepatitis C infection induces hepatic oxidative stress. Heme oxygenase (HO), the rate-controlling enzyme of heme catabolism, plays a key role as a protector against oxidative, and other stresses. Other recent work has implicated Bach1, a heme binding protein that represses gene expression, in the regulation of HO-1 gene expression.

      Methods

      We investigated the effects of HCV polyprotein expression on expression of HO-1 and Bach1 genes in human hepatoma cells (Huh-7 cells).

      Results

      HO-1 was up-regulated in the cell line expressing HCV proteins from core up to the aminoterminal domain of NS3. Addition of increasing concentrations of N-acetylcysteine (NAC) led to down-regulation of HO-1 in cells expressing HCV proteins. In contrast, Bach1 was significantly down-regulated in these cells. Sodium arsenite, a strong inducer of oxidative stress and HO-1, reduced Bach1 expression in wild type Huh-7 cells, and NAC partially abrogated this decrease.

      Conclusions

      Huh-7 cells expressing HCV proteins show significant up-regulation of the HO-1 gene, and reciprocal down-regulation of the Bach1 gene. Exogenous oxidative stressors and anti-oxidants can modulate expression of these genes. These and other results suggest a key role of down-regulation of Bach1 and up-regulation of HO-1 in diminishing cytotoxic effects of HCV proteins in human hepatocytes.

      Keywords

      Abbreviations::

      AP (activator protein), ARE (anti-oxidant response element), HCV (hepatitis C virus), HO (heme oxygenase), Nrf2 (NF-E2-related factor 2), NS (nonstructural), ROS (reactive oxygen species), RT-PCR (reverse transcription-polymerase chain reaction)
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