In vivo hepatic endoplasmic reticulum stress in patients with chronic hepatitis C

Authors

  • Tarik Asselah,

    Corresponding author
    1. INSERM U773, Centre de Recherche CRB3, Paris, 75018, France
    2. Université Denis Diderot-Paris 7, Site Bichat, 75018, France
    3. Service d'Hépatologie, Hôpital Beaujon, Clichy, 92118, France
    • Service d'Hépatologie, Hôpital Beaujon, Clichy, 92118, France.
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  • Ivan Bièche,

    1. INSERM, U745, Université René Descartes, Paris 75006, France
    2. Service de Génétique Moléculaire, Hôpital Beaujon, Clichy, France
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  • Abdellah Mansouri,

    1. INSERM U773, Centre de Recherche CRB3, Paris, 75018, France
    2. Université Denis Diderot-Paris 7, Site Bichat, 75018, France
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  • Ingrid Laurendeau,

    1. INSERM, U745, Université René Descartes, Paris 75006, France
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  • Dominique Cazals-Hatem,

    1. Service d'Anatomie Pathologie, Hôpital Beaujon, Clichy, France
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  • Gérard Feldmann,

    1. INSERM U773, Centre de Recherche CRB3, Paris, 75018, France
    2. Université Denis Diderot-Paris 7, Site Bichat, 75018, France
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  • Pierre Bedossa,

    1. INSERM U773, Centre de Recherche CRB3, Paris, 75018, France
    2. Université Denis Diderot-Paris 7, Site Bichat, 75018, France
    3. Service d'Anatomie Pathologie, Hôpital Beaujon, Clichy, France
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  • Valérie Paradis,

    1. INSERM U773, Centre de Recherche CRB3, Paris, 75018, France
    2. Université Denis Diderot-Paris 7, Site Bichat, 75018, France
    3. Service d'Anatomie Pathologie, Hôpital Beaujon, Clichy, France
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  • Michelle Martinot-Peignoux,

    1. INSERM U773, Centre de Recherche CRB3, Paris, 75018, France
    2. Université Denis Diderot-Paris 7, Site Bichat, 75018, France
    3. Service d'Hépatologie, Hôpital Beaujon, Clichy, 92118, France
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  • Didier Lebrec,

    1. INSERM U773, Centre de Recherche CRB3, Paris, 75018, France
    2. Université Denis Diderot-Paris 7, Site Bichat, 75018, France
    3. Service d'Hépatologie, Hôpital Beaujon, Clichy, 92118, France
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  • Cécile Guichard,

    1. INSERM U773, Centre de Recherche CRB3, Paris, 75018, France
    2. Université Denis Diderot-Paris 7, Site Bichat, 75018, France
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  • Eric Ogier-Denis,

    1. INSERM U773, Centre de Recherche CRB3, Paris, 75018, France
    2. Université Denis Diderot-Paris 7, Site Bichat, 75018, France
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  • Michel Vidaud,

    1. INSERM, U745, Université René Descartes, Paris 75006, France
    2. Service de Génétique Moléculaire, Hôpital Beaujon, Clichy, France
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  • Zéra Tellier,

    1. Laboratoire Français du Fractionnement et des Biotechnologies, Courtaboeuf, France
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  • Vassili Soumelis,

    1. INSERM U653, Institut Curie, 75245 Paris, France
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  • Patrick Marcellin,

    1. INSERM U773, Centre de Recherche CRB3, Paris, 75018, France
    2. Université Denis Diderot-Paris 7, Site Bichat, 75018, France
    3. Service d'Hépatologie, Hôpital Beaujon, Clichy, 92118, France
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  • Richard Moreau

    1. INSERM U773, Centre de Recherche CRB3, Paris, 75018, France
    2. Université Denis Diderot-Paris 7, Site Bichat, 75018, France
    3. Service d'Hépatologie, Hôpital Beaujon, Clichy, 92118, France
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  • No conflicts of interest were declared.

Abstract

In hepatocytes, the accumulation of unfolded proteins in the endoplasmic reticulum (ER) causes ER stress and the unfolded protein response (UPR), mediated by the ER-resident stress sensors ATF-6, IRE1, and PERK. UPR-responsive genes are involved in the fate of ER-stressed cells. Cells carrying hepatitis C virus (HCV) subgenomic replicons exhibit in vitro ER stress and suggest that HCV inhibits the UPR. Since in vivo ER homeostasis is unknown in livers with chronic HCV infection, we investigated ER stress and the UPR in liver samples from untreated patients with chronic hepatitis C (CHC), in comparison with normal livers. Electron microscopy, western blotting, and real-time RT-PCR were used in liver biopsy specimens. Electron microscopy identified features showing ER stress in hepatocyte samples from patients with CHC; however, ‘ER-stressed’ hepatocytes were found in clusters (3-5 cells) that were scattered in the liver parenchyma. Western blot analysis confirmed the existence of hepatic ER stress by showing activation of the three ER stress sensors ATF-6, IRE1, and PERK in CHC. Real-time RT-PCR showed no significant induction of UPR-responsive genes in CHC. In contrast, genes involved in the control of diffuse processes such as liver proliferation, inflammation, and apoptosis were significantly induced in CHC. In conclusion, livers from patients with untreated CHC exhibit in vivo hepatocyte ER stress and activation of the three UPR sensors without apparent induction of UPR-responsive genes. This lack of gene induction may be explained by the inhibiting action of HCV per se (as suggested by in vitro studies) and/or by our finding of the localized nature of hepatocyte ER stress. Copyright © 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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