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

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. Robl, Rex A. Parker, Gökhan S. Hotamisligil

    Research output: Contribution to journalArticle

    473 Scopus citations

    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.

    Original languageEnglish (US)
    Pages (from-to)959-965
    Number of pages7
    JournalNature
    Volume447
    Issue number7147
    DOIs
    StatePublished - Jun 21 2007

    ASJC Scopus subject areas

    • General

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    Furuhashi, M., Tuncman, G., Görgün, C. Z., Makowski, L., Atsumi, G., Vaillancourt, E., Kono, K., Babaev, V. R., Fazio, S., Linton, M. F., Sulsky, R., Robl, J. A., Parker, R. A., & Hotamisligil, G. S. (2007). Treatment of diabetes and atherosclerosis by inhibiting fatty-acid-binding protein aP2. Nature, 447(7147), 959-965. https://doi.org/10.1038/nature05844