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

Furuhashi M, Tuncman G, Görgün CZ, Makowski L, Atsumi G, Vaillancourt E, Kono K, Babaev VR, Fazio S, Linton MF, Sulsky R, Robl JA, Parker RA, Hotamisligil GS
Nature. 2007 447 (7147): 959-65

PMID: 17554340 · PMCID: PMC4076119 · DOI:10.1038/nature05844

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.

MeSH Terms (20)

Adipocytes Adipose Tissue Animals Apolipoproteins E Atherosclerosis Biphenyl Compounds Cell Line Cholesterol Diabetes Mellitus Fatty Acid-Binding Proteins Humans Inflammation Liver Macrophages Mice Mice, Inbred C57BL Mice, Mutant Strains Models, Biological Obesity Pyrazoles

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