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Mice lacking liver-specific β-catenin develop steatohepatitis and fibrosis after iron overload

  • Morgan E. Preziosi
    Affiliations
    Department of Pathology (Division of Experimental Pathology), University of Pittsburgh, Pennsylvania, United States

    Pittsburgh Liver Research Center, University of Pittsburgh, Pennsylvania, United States
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  • Sucha Singh
    Affiliations
    Department of Pathology (Division of Experimental Pathology), University of Pittsburgh, Pennsylvania, United States

    Pittsburgh Liver Research Center, University of Pittsburgh, Pennsylvania, United States
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  • Erika V. Valore
    Affiliations
    Department of Medicine University of California at Los Angeles, Los Angeles, CA, United States

    Department of Pathology and Laboratory Medicine, University of California at Los Angeles, Los Angeles, CA, United States
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  • Grace Jung
    Affiliations
    Department of Medicine University of California at Los Angeles, Los Angeles, CA, United States

    Department of Pathology and Laboratory Medicine, University of California at Los Angeles, Los Angeles, CA, United States
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  • Branimir Popovic
    Affiliations
    Department of Pathology (Division of Experimental Pathology), University of Pittsburgh, Pennsylvania, United States
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  • Minakshi Poddar
    Affiliations
    Department of Pathology (Division of Experimental Pathology), University of Pittsburgh, Pennsylvania, United States

    Pittsburgh Liver Research Center, University of Pittsburgh, Pennsylvania, United States
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  • Shanmugam Nagarajan
    Affiliations
    Department of Pathology (Division of Experimental Pathology), University of Pittsburgh, Pennsylvania, United States

    Pittsburgh Liver Research Center, University of Pittsburgh, Pennsylvania, United States
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  • Tomas Ganz
    Affiliations
    Department of Medicine University of California at Los Angeles, Los Angeles, CA, United States

    Department of Pathology and Laboratory Medicine, University of California at Los Angeles, Los Angeles, CA, United States
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  • Satdarshan P. Monga
    Correspondence
    Corresponding author. Address: Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, 200 Lothrop Street S-422 BST, Pittsburgh, PA 15261, United States. Tel.: +1 (412) 648 9966; fax: +1 (412) 648 1916.
    Affiliations
    Department of Pathology (Division of Experimental Pathology), University of Pittsburgh, Pennsylvania, United States

    Pittsburgh Liver Research Center, University of Pittsburgh, Pennsylvania, United States

    Department of Medicine (Division of Gastroenterology, Hepatology and Nutrition), University of Pittsburgh, Pennsylvania, United States
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Published:March 21, 2017DOI:https://doi.org/10.1016/j.jhep.2017.03.012

      Background & Aims

      Iron overload disorders such as hereditary hemochromatosis and iron loading anemias are a common cause of morbidity from liver diseases and increase risk of hepatic fibrosis and hepatocellular carcinoma (HCC). Treatment options for iron-induced damage are limited, partly because there is lack of animal models of human disease. Therefore, we investigated the effect of iron overload in liver-specific β-catenin knockout mice (KO), which are susceptible to injury, fibrosis and tumorigenesis following chemical carcinogen exposure.

      Methods

      Iron overload diet was administered to KO and littermate control (CON) mice for various times. To ameliorate an oxidant-mediated component of tissue injury, N-Acetyl-L-(+)-cysteine (NAC) was added to drinking water of mice on iron overload diet.

      Results

      KO on iron diet (KO +Fe) exhibited remarkable inflammation, followed by steatosis, oxidative stress, fibrosis, regenerating nodules and occurrence of occasional HCC. Increased injury in KO +Fe was associated with activated protein kinase B (AKT), ERK, and NF-κB, along with reappearance of β-catenin and target gene Cyp2e1, which promoted lipid peroxidation and hepatic damage. Addition of NAC to drinking water protected KO +Fe from hepatic steatosis, injury and fibrosis, and prevented activation of AKT, ERK, NF-κB and reappearance of β-catenin.

      Conclusions

      The absence of hepatic β-catenin predisposes mice to hepatic injury and fibrosis following iron overload, which was reminiscent of hemochromatosis and associated with enhanced steatohepatitis and fibrosis. Disease progression was notably alleviated by antioxidant therapy, which supports its chemopreventive role in the management of chronic iron overload disorders.

      Lay summary

      Lack of animal models for iron overload disorders makes it hard to study the disease process for improving therapies. Feeding high iron diet to mice that lack the β-catenin gene in liver cells led to increased inflammation followed by fat accumulation, cell death and wound healing that mimicked human disease. Administration of an antioxidant prevented hepatic injury in this model.

      Graphical abstract

      Keywords

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