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 and Gökhan S. Hotamisligil ()
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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
Genichi Atsumi: Harvard School of Public Health, Boston, Massachusetts 02115, USA
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

Nature, 2007, vol. 447, issue 7147, 959-965

Abstract: 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.

Date: 2007
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DOI: 10.1038/nature05844

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