AICAR, an AMPK Activator, Has Protective Effects on Alcohol-Induced Fatty Liver in Rats

Authors

  • Kengo Tomita,

    1. Department of Internal Medicine (KT, NK, HK, SK, YH, TK, HN, HI, TH), Keio University School of Medicine, Tokyo, Japan; the Department of Molecular Life Science (GT, SA), School of Medicine, Tokai University, Kanagawa, Japan; the Department of Immunology (TA), Juntendo University School of Medicine, Tokyo, Japan.
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  • Gen Tamiya,

    1. Department of Internal Medicine (KT, NK, HK, SK, YH, TK, HN, HI, TH), Keio University School of Medicine, Tokyo, Japan; the Department of Molecular Life Science (GT, SA), School of Medicine, Tokai University, Kanagawa, Japan; the Department of Immunology (TA), Juntendo University School of Medicine, Tokyo, Japan.
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  • Satoshi Ando,

    1. Department of Internal Medicine (KT, NK, HK, SK, YH, TK, HN, HI, TH), Keio University School of Medicine, Tokyo, Japan; the Department of Molecular Life Science (GT, SA), School of Medicine, Tokai University, Kanagawa, Japan; the Department of Immunology (TA), Juntendo University School of Medicine, Tokyo, Japan.
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  • Naoto Kitamura,

    1. Department of Internal Medicine (KT, NK, HK, SK, YH, TK, HN, HI, TH), Keio University School of Medicine, Tokyo, Japan; the Department of Molecular Life Science (GT, SA), School of Medicine, Tokai University, Kanagawa, Japan; the Department of Immunology (TA), Juntendo University School of Medicine, Tokyo, Japan.
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  • Haruna Koizumi,

    1. Department of Internal Medicine (KT, NK, HK, SK, YH, TK, HN, HI, TH), Keio University School of Medicine, Tokyo, Japan; the Department of Molecular Life Science (GT, SA), School of Medicine, Tokai University, Kanagawa, Japan; the Department of Immunology (TA), Juntendo University School of Medicine, Tokyo, Japan.
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  • Shinzo Kato,

    1. Department of Internal Medicine (KT, NK, HK, SK, YH, TK, HN, HI, TH), Keio University School of Medicine, Tokyo, Japan; the Department of Molecular Life Science (GT, SA), School of Medicine, Tokai University, Kanagawa, Japan; the Department of Immunology (TA), Juntendo University School of Medicine, Tokyo, Japan.
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  • Yoshinori Horie,

    1. Department of Internal Medicine (KT, NK, HK, SK, YH, TK, HN, HI, TH), Keio University School of Medicine, Tokyo, Japan; the Department of Molecular Life Science (GT, SA), School of Medicine, Tokai University, Kanagawa, Japan; the Department of Immunology (TA), Juntendo University School of Medicine, Tokyo, Japan.
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  • Takehiko Kaneko,

    1. Department of Internal Medicine (KT, NK, HK, SK, YH, TK, HN, HI, TH), Keio University School of Medicine, Tokyo, Japan; the Department of Molecular Life Science (GT, SA), School of Medicine, Tokai University, Kanagawa, Japan; the Department of Immunology (TA), Juntendo University School of Medicine, Tokyo, Japan.
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  • Toshifumi Azuma,

    1. Department of Internal Medicine (KT, NK, HK, SK, YH, TK, HN, HI, TH), Keio University School of Medicine, Tokyo, Japan; the Department of Molecular Life Science (GT, SA), School of Medicine, Tokai University, Kanagawa, Japan; the Department of Immunology (TA), Juntendo University School of Medicine, Tokyo, Japan.
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  • Hiroshi Nagata,

    1. Department of Internal Medicine (KT, NK, HK, SK, YH, TK, HN, HI, TH), Keio University School of Medicine, Tokyo, Japan; the Department of Molecular Life Science (GT, SA), School of Medicine, Tokai University, Kanagawa, Japan; the Department of Immunology (TA), Juntendo University School of Medicine, Tokyo, Japan.
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  • Hiromasa Ishii,

    1. Department of Internal Medicine (KT, NK, HK, SK, YH, TK, HN, HI, TH), Keio University School of Medicine, Tokyo, Japan; the Department of Molecular Life Science (GT, SA), School of Medicine, Tokai University, Kanagawa, Japan; the Department of Immunology (TA), Juntendo University School of Medicine, Tokyo, Japan.
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  • Toshifumi Hibi

    Corresponding author
    1. Department of Internal Medicine (KT, NK, HK, SK, YH, TK, HN, HI, TH), Keio University School of Medicine, Tokyo, Japan; the Department of Molecular Life Science (GT, SA), School of Medicine, Tokai University, Kanagawa, Japan; the Department of Immunology (TA), Juntendo University School of Medicine, Tokyo, Japan.
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  • Supported by a grant from Keio University, School of Medicine, Nateglinide Memorial Toyoshima Research and Education Fund, and the 21st Century Center-Of-Excellence (COE) Program from Ministry of Education, Culture, Sports, Science and Technology.

Reprint requests: Toshifumi Hibi, MD, Department of Internal Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan; Fax: +81-3-3357-6156; E-mail: thibi@sc.itc.keio.ac.jp

Abstract

Abstract: Background: Previous work with metformin has shown that this antidiabetic agent improves nonalcoholic fatty liver in ob/ob mice. AMP-activated protein kinase (AMPK) is one of the major cellular regulators of lipid and glucose metabolism, and reportedly mediates the beneficial metabolic effects of metformin. In this study, we examined the effects of 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR), an AMPK activator, on an experimental model of ethanol-induced hepatic steatosis.

Methods: Rats were randomly divided into three groups: (A) rats fed ethanol-containing liquid diet for six weeks; (B) rats pair-fed ethanol-containing liquid diet for six weeks, during the last three weeks of which they were subcutaneously injected with 0.5 mg AICAR/g body weight per day; (C) rats pair-fed isocaloric liquid diet without ethanol for six weeks. At the end of the six-week period, the animals were sacrificed. Serum and liver specimens were analyzed using biochemical and histologic methods, as well as real-time PCR.

Results: Chronic ethanol feeding resulted in fatty liver both histologically and biochemically, whereas AICAR administration attenuated the degree of change in the liver. AICAR also decreased the hepatic sterol regulatory factor binding protein-1c (SREBP-1c) and reduced fatty acid synthase (FAS) expression; these changes led to reduced triglyceride synthesis in rat livers. Furthermore, detection of 4-hydroxy-2-nonenal (4-HNE)-protein adducts showed that the AICAR treatment also decreased the products of lipid peroxidation.

Conclusion: In this preclinical rat model, AICAR, an AMPK activator, appears to protect the liver from fatty changes associated with chronic alcohol use. As such, AICAR may have a role in the treatment and prevention of alcohol-induced fatty liver.

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