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Treatment of diabetes and atherosclerosis by inhibiting fatty-acid-binding protein aP2

Author

Listed:
  • Masato Furuhashi

    (Harvard School of Public Health, Boston, Massachusetts 02115, USA)

  • Gürol Tuncman

    (Harvard School of Public Health, Boston, Massachusetts 02115, USA)

  • Cem Z. Görgün

    (Harvard School of Public Health, Boston, Massachusetts 02115, USA)

  • Liza Makowski

    (Harvard School of Public Health, Boston, Massachusetts 02115, USA
    Present address: Department of Medicine, Division of Endocrinology, Metabolism, and Nutrition, Duke University Medical Center, Durham, North Carolina 27704, USA)

  • Genichi Atsumi

    (Harvard School of Public Health, Boston, Massachusetts 02115, USA
    Present address: Clinical Molecular Biology, Teikyo University, Kanagawa 199-0195, Japan.)

  • Eric Vaillancourt

    (Harvard School of Public Health, Boston, Massachusetts 02115, USA)

  • Keita Kono

    (Harvard School of Public Health, Boston, Massachusetts 02115, USA)

  • Vladimir R. Babaev

    (Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA)

  • Sergio Fazio

    (Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA)

  • MacRae F. Linton

    (Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA)

  • Richard Sulsky

    (Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543, USA)

  • Jeffrey A. Robl

    (Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543, USA)

  • Rex A. Parker

    (Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543, USA)

  • Gökhan S. Hotamisligil

    (Harvard School of Public Health, Boston, Massachusetts 02115, USA)

Abstract

Adipocyte fatty-acid-binding protein, aP2 (FABP4) is expressed in adipocytes and macrophages, and integrates inflammatory and metabolic responses. Studies in aP2-deficient mice have shown that this lipid chaperone has a significant role in several aspects of metabolic syndrome, including type 2 diabetes and atherosclerosis. Here we demonstrate that an orally active small-molecule inhibitor of aP2 is an effective therapeutic agent against severe atherosclerosis and type 2 diabetes in mouse models. In macrophage and adipocyte cell lines with or without aP2, we also show the target specificity of this chemical intervention and its mechanisms of action on metabolic and inflammatory pathways. Our findings demonstrate that targeting aP2 with small-molecule inhibitors is possible and can lead to a new class of powerful therapeutic agents to prevent and treat metabolic diseases such as type 2 diabetes and atherosclerosis.

Suggested Citation

  • Masato Furuhashi & Gürol Tuncman & Cem Z. Görgün & Liza Makowski & Genichi Atsumi & Eric Vaillancourt & Keita Kono & Vladimir R. Babaev & Sergio Fazio & MacRae F. Linton & Richard Sulsky & Jeffrey A. , 2007. "Treatment of diabetes and atherosclerosis by inhibiting fatty-acid-binding protein aP2," Nature, Nature, vol. 447(7147), pages 959-965, June.
    • Handle: RePEc:nat:nature:v:447:y:2007:i:7147:d:10.1038_nature05844
    DOI: 10.1038/nature05844
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