Furuhashi, M. et al. Treatment of diabetes and atherosclerosis by inhibiting fatty-acid-binding protein aP2. Nature 447, 959-965

Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
Nature (Impact Factor: 41.46). 07/2007; 447(7147):959-65. DOI: 10.1038/nature05844
Source: PubMed


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.

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Available from: Masato Furuhashi
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    • "The biological relevance of FABP4 is underscored by the findings that FABP4 knockout (FABP4 − / − ) mice exhibit marked protection against insulin resistance, atherosclerosis, fatty liver disease, and asthma [5,10–14]. Consistent with these studies, a small-molecule inhibitor of FABP4 (BMS309403) has been found to be an effective therapeutic agent for the treatment of atherosclerosis and type 2 diabetes mellitus (T2DM) in mouse models [15]. FABP4 is secreted from adipocytes via a non-classical, calcium-dependent mechanism [16] that is regulated by lipolytic pathways [17]. "
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    ABSTRACT: Fatty acid-binding protein 4 (FABP4) is an adipose tissue-secreted adipokine that is involved in the regulation of energetic metabolism and inflammation. Increased levels of circulating FABP4 have been detected in individuals with cardiovascular risk factors. Recent studies have demonstrated that FABP4 has a direct effect on peripheral tissues, specifically promoting vascular dysfunction; however, its mechanism of action is unknown. The objective of this work was to assess the specific interactions between exogenous FABP4 and the plasma membranes of endothelial cells. Immunofluorescence assays showed that exogenous FABP4 localized along the plasma membranes of human umbilical vein endothelial cells (HUVECs), interacting specifically with plasma membrane proteins. Anti-FABP4 immunoblotting revealed two covalent protein complexes containing FABP4 and its putative receptor; these complexes were approximately 108 kDa and 77 kDa in size. Proteomics and mass spectrometry experiments revealed that cytokeratin 1 (CK1) was the FABP4-binding protein. An anti-CK1 immunoblot confirmed the presence of CK1. FABP4-CK1 complexes were also detected in HAECs, HCASMCs, HepG2 cells and THP-1 cells. Pharmacological FABP4 inhibition by BMS309403 results in a slight decrease in the formation of these complexes, indicating that fatty acids may play a role in FABP4 functionality. In addition, we demonstrated that exogenous FABP4 crosses the plasma membrane to enter the cytoplasm and nucleus in HUVECs. These findings indicate that exogenous FABP4 interacts with plasma membrane proteins, specifically CK1. These data contribute to our current knowledge regarding the mechanism of action of circulating FABP4.
    Full-text · Article · Sep 2015 · Biochimica et Biophysica Acta
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    • "Indeed, several series of smallmolecule inhibitors of FABP4 have been reported over the last decade [10e17]. For example, BMS309403, a highly active inhibitor of FABP4, demonstrated to be effective to improve glucose metabolism , enhance insulin sensitivity in both dietary and genetic mouse models of obesity and diabetes, and ameliorate the symptom of atherosclerosis [18]. The above studies indicated the potential application of FABP4 inhibitors in the treatment of diabetes and atherosclerosis. "
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    ABSTRACT: Fatty acid binding protein 4 (FABP4) is a potential drug target for diabetes and atherosclerosis. For discovering new chemical entities as FABP4 inhibitors, structure-based virtual screening (VS) was performed, bioassay demonstrated that 16 of 251 tested compounds are FABP4 inhibitors, among which compound m1 are more active than endogenous ligand linoleic acid (LA). Based on the structure of m1, new derivatives were designed and prepared, leading to the discovery of two more potent inhibitors, compounds 9 and 10. To further explore the binding mechanisms of these new inhibitors, we determined the X-ray structures of the complexes of FABP4-9 and FABP4-10, which revealed similar binding conformations of the two compounds. Residue Ser53 and Arg126 formed direct hydrogen bonding with the ligands. We also found that 10 could significantly reduce the levels of lipolysis on mouse 3T3-L1 adipocytes. Taken together, in silico, in vitro and crystallographic data provide useful hints for future development of novel inhibitors against FABP4.
    Full-text · Article · Jan 2015 · European Journal of Medicinal Chemistry
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    • "Emerging evidence indicates that FABP4 acts at the integration between metabolic and inflammatory pathways and plays an important role in the development of insulin resistance and atherosclerosis [4-6]. It has also been demonstrated in experimental models that chemical inhibition of FABP4 could be a therapeutic strategy against insulin resistance, diabetes mellitus, fatty liver disease and atherosclerosis [7]. "
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    ABSTRACT: Background Fatty acid-binding protein 4 (FABP4) is expressed in both adipocytes and macrophages. Recent studies have shown secretion of FABP4 from adipocytes and association of elevated serum FABP4 level with obesity, insulin resistance, hypertension, and atherosclerosis. However, little is known about role of FABP4 in cardiac function.Methods From the database of the Tanno-Sobetsu Study, data for 190 subjects (male/female: 82/108) who were not treated with any medication and underwent echocardiography in 2011 or 2012 were retrieved for analyses of relationships between serum FABP4 concentration, metabolic markers and parameters of echocardiography.ResultsSerum FABP4 level was positively correlated with age, body mass index (BMI), blood pressure (BP), LDL cholesterol, HOMA-R and mean left ventricular (LV) wall thickness (LVWT, males: r¿=¿0.315, females: r¿=¿0.401, p¿<¿0.01) and was negatively correlated with HDL cholesterol, estimated glomerular filtration rate (eGFR) and peak myocardial velocity during early diastole (e¿; males: r¿=¿¿0.434, females: r¿=¿¿0.353, p¿<¿0.01), an index of LV diastolic function. However, no significant correlation was found between FABP4 level and LV end-diastolic dimension, LV ejection fraction or LV mass index. There were significant correlations of e¿ with age, BMI, BP, eGFR, brain natriuretic peptide (BNP), FABP4, metabolic markers and LVWT. Multivariate regression analysis adjusted by HOMA-R, BMI, eGFR, BNP or LVWT in addition to age, gender and BP revealed that serum FABP4 concentration was independently correlated with e¿.Conclusions Elevation of circulating FABP4 may contribute to LV diastolic dysfunction in a general population.
    Full-text · Article · Aug 2014 · Cardiovascular Diabetology
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