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

Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
Nature (Impact Factor: 42.35). 07/2007; 447(7147):959-65. DOI: 10.1038/nature05844
Source: PubMed

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.


Available from: Masato Furuhashi, May 29, 2015
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The coordinated breakdown of intracellular triglyceride (TG) stores requires the exquisitely regulated interaction of lipolytic enzymes with regulatory, accessory and scaffolding proteins. Together they form a dynamic multi-protein network designated as the "lipolysome". Adipose triglyceride lipase (ATGL) catalyzes the initiating step of TG hydrolysis and requires comparative gene identification-58 (CGI-58) as potent activator of enzyme activity. Here, we identify adipocyte-type fatty acid-binding protein (A-FABP) and other members of the fatty acid-binding protein (FABP) family as interaction partners of CGI-58. Co-immuno-precipitation, microscale thermophoresis, and solid phase assays proved direct protein-protein interaction between A-FABP and CGI-58. Using nuclear magnetic resonance titration experiments and site-directed mutagenesis, we located a potential contact region on A-FABP. In functional terms, A-FABP stimulates ATGL-catalyzed TG hydrolysis in a CGI-58-dependent manner. Additionally, transcriptional transactivation assays with a luciferase reporter system revealed that FABPs enhance the ability of ATGL/CGI-58-mediated lipolysis to induce the activity of peroxisome proliferator-activated receptors. Our studies identify FABPs as crucial structural and functional components of the lipolysome. Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
    Journal of Biological Chemistry 05/2015; DOI:10.1074/jbc.M114.628958 · 4.60 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Multiple sclerosis (MS) is an autoimmune disease in which dysregulated immune cells attack myelin in the central nervous system (CNS), leading to irreversible neuronal degeneration. Our previous studies have demonstrated that epidermal fatty acid binding protein (E-FABP), widely expressed in immune cells, in particular in dendritic cells (DCs) and T lymphocytes, fuels the overactive immune responses in the mouse model of experimental autoimmune encephalomyelitis (EAE). In the present study, we conducted an intensive computational docking analysis to identify novel E-FABP inhibitors for regulation of immune cell functions and for treatment of EAE. We demonstrate that compound [2-(4-acetylphenoxy)-9,10-dimethoxy-6,7-dihydropyrimido[6,1-a]isoquinolin-4-one; designated as EI-03] bound to the lipid binding pocket of E-FABP and enhanced the expression of peroxisome proliferator-activating receptor (PPAR) γ. Further in vitro experiments showed that EI-03 regulated DC functions by inhibition of TNFα production while promoting IL-10 secretion. Moreover, EI-03 treatment counterregulated T cell balance by decreasing effector T cell differentiation (e.g. Th17, Th1) while increasing regulatory T cell development. Most importantly, mice treated with this newly identified compound exhibited reduced clinical symptoms of EAE in mouse models. Taken together, we have identified a new compound which displays a potential therapeutic benefit for treatment of MS by targeting E-FABP.
    BMC Immunology 05/2015; 16(1):28. DOI:10.1186/s12865-015-0091-2 · 2.25 Impact Factor
  • Edited by Karina Martinez-Mayorga, José Luis Medina-Franco, 01/2014; Springer., ISBN: 978-3-319-10225-2