Treatment of diabetes and atherosclerosis by inhibiting fatty-acid-binding protein aP2.
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.
Furuhashi
Masato
M
Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
Tuncman
Gürol
G
Görgün
Cem Z
CZ
Makowski
Liza
L
Atsumi
Genichi
G
Vaillancourt
Eric
E
Kono
Keita
K
Babaev
Vladimir R
VR
Fazio
Sergio
S
Linton
MacRae F
MF
Sulsky
Richard
R
Robl
Jeffrey A
JA
Parker
Rex A
RA
Hotamisligil
Gökhan S
GS
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
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