Lipid-induced oxidative stress causes steatohepatitis in mice fed an atherogenic diet

Authors

  • Naoto Matsuzawa,

    1. Department of Disease Control and Homeostasis, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan
    2. Department of Pharmacy and Health Science, Graduate School of Natural Science and Technology, Kanazawa University, Kanazawa, Japan
    Search for more papers by this author
  • Toshinari Takamura,

    Corresponding author
    1. Department of Disease Control and Homeostasis, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan
    • Department of Disease Control and Homeostasis, Graduate School of Medical Science, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa 920-8641, Japan===

    Search for more papers by this author
    • fax: (81) 76-234-4250

  • Seiichiro Kurita,

    1. Department of Disease Control and Homeostasis, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan
    Search for more papers by this author
  • Hirofumi Misu,

    1. Department of Disease Control and Homeostasis, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan
    Search for more papers by this author
  • Tsuguhito Ota,

    1. Department of Disease Control and Homeostasis, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan
    Search for more papers by this author
  • Hitoshi Ando,

    1. Department of Disease Control and Homeostasis, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan
    Search for more papers by this author
  • Masayoshi Yokoyama,

    1. Department of Disease Control and Homeostasis, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan
    Search for more papers by this author
  • Masao Honda,

    1. Department of Disease Control and Homeostasis, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan
    Search for more papers by this author
  • Yoh Zen,

    1. Department of Human Pathology, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan
    Search for more papers by this author
  • Yasuni Nakanuma,

    1. Department of Human Pathology, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan
    Search for more papers by this author
  • Ken-ichi Miyamoto,

    1. Department of Pharmacy and Health Science, Graduate School of Natural Science and Technology, Kanazawa University, Kanazawa, Japan
    Search for more papers by this author
  • Shuichi Kaneko

    1. Department of Disease Control and Homeostasis, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan
    Search for more papers by this author

  • Potential conflict of interest: Nothing to report.

Abstract

Recently, nonalcoholic steatohepatitis (NASH) was found to be correlated with cardiovascular disease events independently of the metabolic syndrome. The aim of this study was to investigate whether an atherogenic (Ath) diet induces the pathology of steatohepatitis necessary for the diagnosis of human NASH and how cholesterol and triglyceride alter the hepatic gene expression profiles responsible for oxidative stress. We investigated the liver pathology and plasma and hepatic lipids of mice fed the Ath diet. The hepatic gene expression profile was examined with microarrays and real-time polymerase chain reactions. The Ath diet induced dyslipidemia, lipid peroxidation, and stellate cell activation in the liver and finally caused precirrhotic steatohepatitis after 24 weeks. Cellular ballooning, a necessary histological feature defining human NASH, was observed in contrast to existing animal models. The addition of a high-fat component to the Ath diet caused hepatic insulin resistance and further accelerated the pathology of steatohepatitis. A global gene expression analysis revealed that the Ath diet up-regulated the hepatic expression levels of genes for fatty acid synthesis, oxidative stress, inflammation, and fibrogenesis, which were further accelerated by the addition of a high-fat component. Conversely, the high-fat component down-regulated the hepatic gene expression of antioxidant enzymes and might have increased oxidative stress. Conclusion: The Ath diet induces oxidative stress and steatohepatitis with cellular ballooning. The high-fat component induces insulin resistance, down-regulates genes for antioxidant enzymes, and further aggravates the steatohepatitis. This model suggests the critical role of lipids in causing oxidative stress and insulin resistance leading to steatohepatitis. (HEPATOLOGY 2007.)

Ancillary