title: Treatment of diabetes and atherosclerosis by inhibiting fatty-acid-binding protein aP2.
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.
authors.affiliation: Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
authors.forename: Masato
authors.initials: M
authors.lastname: Furuhashi
authors.forename: Gürol
authors.initials: G
authors.lastname: Tuncman
authors.forename: Cem Z
authors.initials: CZ
authors.lastname: Görgün
authors.forename: Liza
authors.initials: L
authors.lastname: Makowski
authors.forename: Genichi
authors.initials: G
authors.lastname: Atsumi
authors.forename: Eric
authors.initials: E
authors.lastname: Vaillancourt
authors.forename: Keita
authors.initials: K
authors.lastname: Kono
authors.forename: Vladimir R
authors.initials: VR
authors.lastname: Babaev
authors.forename: Sergio
authors.initials: S
authors.lastname: Fazio
authors.forename: MacRae F
authors.initials: MF
authors.lastname: Linton
authors.forename: Richard
authors.initials: R
authors.lastname: Sulsky
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Robl
authors.forename: Rex A
authors.initials: RA
authors.lastname: Parker
authors.forename: Gökhan S
authors.initials: GS
authors.lastname: Hotamisligil
mesh_terms: D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000273:Adipose Tissue / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D001713:Biphenyl Compounds / Q000378:metabolism; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism; D003920:Diabetes Mellitus / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D050556:Fatty Acid-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008954:Models, Biological; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000378:metabolism
chemical_list: C559288:2-(2'-(5-ethyl-3,4-diphenyl-1H-pyrazol-1-yl)biphenyl-3-yloxy)acetic acid; D001057:Apolipoproteins E; D001713:Biphenyl Compounds; C493411:Fabp4 protein, mouse; D050556:Fatty Acid-Binding Proteins; D011720:Pyrazoles; D002784:Cholesterol