Leptin augments inflammatory and profibrogenic responses in the murine liver induced by hepatotoxic chemicals

Authors

  • Kenichi Ikejima,

    1. Department of Gastroenterology, Central Laboratory for Medical Science, Juntendo University School of Medicine, Tokyo, Japan.
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  • Hajime Honda,

    1. Department of Gastroenterology, Central Laboratory for Medical Science, Juntendo University School of Medicine, Tokyo, Japan.
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  • Mutsuko Yoshikawa,

    1. Department of Gastroenterology, Central Laboratory for Medical Science, Juntendo University School of Medicine, Tokyo, Japan.
    2. Division of Biochemistry, Central Laboratory for Medical Science, Juntendo University School of Medicine, Tokyo, Japan.
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  • Miyoko Hirose,

    1. Department of Gastroenterology, Central Laboratory for Medical Science, Juntendo University School of Medicine, Tokyo, Japan.
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  • Tsuneo Kitamura,

    1. Department of Gastroenterology, Central Laboratory for Medical Science, Juntendo University School of Medicine, Tokyo, Japan.
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  • Yoshiyuki Takei,

    1. Department of Gastroenterology, Central Laboratory for Medical Science, Juntendo University School of Medicine, Tokyo, Japan.
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  • Nobuhiro Sato

    Corresponding author
    1. Department of Gastroenterology, Central Laboratory for Medical Science, Juntendo University School of Medicine, Tokyo, Japan.
    2. Division of Biochemistry, Central Laboratory for Medical Science, Juntendo University School of Medicine, Tokyo, Japan.
    • Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1, Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan. fax: (81) 3-3813-8862
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Abstract

Lines of evidence suggested a possible link between leptin and hepatic fibrosis; however, whether leptin modulates the fibrogenesis in the liver remains unclear. The purpose of this study, therefore, was to evaluate the effect of leptin on inflammatory and profibrogenic responses in the liver caused by hepatotoxic chemicals. Male C57Bl/6 mice were given carbon tetrachloride (CCl4) (0.1 μL/g body wieght [BW], intraperitoneally [IP]) and/or recombinant murine leptin (1 μg/g BW, IP) simultaneously, and sacrificed up to 72 hours later. Further, some mice were given thioacetamide (TAA; 200 μg/g BW, IP) and leptin 3 times per week for 4 weeks to evaluate the effect of leptin on chronic fibrogenic responses. A simultaneous injection of leptin enhanced acute CCl4-induced necroinflammatory and subsequent fibrotic changes in the hepatic lobules. The steady-state messenger RNA (mRNA) levels of α1(I) procollagen and heat shock protein 47 (HSP47) in the liver were potentiated when leptin was injected together with CCl4. Expression of α smooth muscle actin (α-SMA) in the liver after CCl4 treatment was also augmented markedly in combination with leptin. Further, leptin increased transforming growth factor β1 (TGF-β1) mRNA in the liver 24 hours after acute CCl4 about 4-fold higher than CCl4 alone. Moreover, leptin enhanced hepatic fibrosis and induction of α1(I) procollagen mRNA caused by chronic TAA administration. Collectively, these findings indicated that leptin augments both inflammatory and profibrogenic responses in the liver caused by hepatotoxic chemicals. It is postulated that the increase in systemic leptin levels enhances up-regulation of TGF-β1, leading to activation of stellate cells, thereby augmenting the fibrogenic response in the liver.

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