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.

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Available from: Masato Furuhashi, Aug 03, 2015
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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.
    European Journal of Medicinal Chemistry 01/2015; 90. DOI:10.1016/j.ejmech.2014.11.020 · 3.43 Impact Factor
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    • "It has been shown that the serum levels of A-FABP are associated with non-alcoholic fatty liver disease (NAFLD) in T2DM (Koh et al. 2009) and with abnormalities in glucose metabolism and development of T2DM in Chinese cohort (Tso et al. 2007). Levels of A-FABP are associated with severity of CAD, and its inhibition can be helpful in treatment of atherosclerosis and T2DM (Bao et al. 2011; Furuhashi et al. 2007; Tuncman et al. 2006). Although there are many studies regarding the serum levels of A-FABP and its association with T2DM, none of the studies report hepatic levels of A-FABP or expression of its gene. "
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    ABSTRACT: Dietary omega-3 fatty acids have been demonstrated to have positive physiological effects on lipid metabolism, cardiovascular system and insulin resistance. Type-2 diabetes (T2DM) is known for perturbations in fatty acid metabolism leading to dyslipidemia. Our objective was to investigate beneficial effects of dietary flaxseed oil and fish oil in streptozotocin-nicotinamide induced diabetic rats. Thirty-six adult, male, Wistar rats were divided into six groups: three diabetic and three non-diabetic. Diabetes was induced by an injection of nicotinamide (110 mg/kg) and STZ (65 mg/kg). The animals received either control, flaxseed oil or fish oil (10 % w/w) enriched diets for 35 days. Both diets lowered serum triglycerides and very low-density lipoprotein cholesterol levels and elevated serum high-density lipoprotein cholesterol levels in diabetic rats, while serum total cholesterol and LDL-C levels remained unaffected. Both the diets increased omega-3 levels in plasma and RBCs of diabetic rats. Flaxseed oil diet significantly up-regulated the key transcription factor peroxisome proliferator-activated receptor-α (PPAR-α ) and down-regulated sterol regulatory element-binding protein-1 (SREBP-1) in diabetic rats, which would have increased β-oxidation of fatty acids and concomitantly reduced lipogenesis respectively, thereby reducing TG levels. Fish oil diet, on the contrary lowered serum TG levels without altering PPAR-α while it showed a non-significant reduction in SREBP-1 expression in diabetic rats. Another key finding of the study is the activation of D5 and D6 desaturases in diabetic rats by flaxseed oil diet or fish oil diets, which may have resulted in an improved omega-3 status and comparable effects shown by both diets. The reduced expression of Liver-fatty acid binding protein in diabetic rats was restored by fish oil alone, while both diets showed equal effects on adipocyte fatty acid-binding protein expression. We also observed down-regulation of atherogenic cytokines tumor necrosis factor-α and interleukin-6 by both the diets. In conclusion, dietary flaxseed oil and fish oil have therapeutic potential in preventing lipid abnormalities in T2DM.
    Genes & Nutrition 12/2012; 8(3). DOI:10.1007/s12263-012-0326-2 · 3.42 Impact Factor
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    • "Adipocyte Induction by fatty acids, PPARγ agonists, dexamethazone, and insulin [23] [24] [25] [26] [27] Lipolysis (interaction with HSL) [28] [29] [30] Regulation of insulin secretion during lipolysis [29] Fatty acid sensor (interaction with JAK2) [31] Regulation of lipid metabolism and differentiation (interaction with PTEN) [32] Protection from insulin resistance and diabetes in deficient mice Insulin resistance, diabetes [14] [15] [18] [19] [21] Protection from insulin resistance and diabetes by a FABP4 inhibitor Insulin resistance, diabetes [33] Macrophage Induction by PMA, LPS, PPARγ agonists, ox-LDL, and AGE/RAGE [11, 34–38] Reduction by atorvastatin and metformin [39] [40] Activation of IKK-NF-κB pathway [41] Activation of JNK-AP-1 pathway [42] Inhibition of PPARγ-LXRα-ABCA1 pathway [41] FOXO1-mediated transcription [40] Association with ER stress [22] Protection from insulin resistance and diabetes in double-deficient mice * Insulin resistance, diabetes [21] Protection from atherosclerosis in deficient mice Atherosclerosis [11] [16] [20] Protection from insulin resistance and atherosclerosis by a FABP4 inhibitor Insulin resistance, atherosclerosis [33] Dendritic cell Activation of IKK-NF-κB pathway [12] T-cell priming [12] Endothelial cell Expression in capillary and small vein but not in artery [43] Regulation by VEGF-A/VEGFR2 and bFGF [43] Induction in regenerated endothelial cells after balloon denudation of artery [44] Induction by intermittent hypoxia [45] FOXO1-mediated transcription inhibited by angiopoietin-1 [46] Expression in aortic endothelium of old ApoE-deficient mice [47] Improvement of dysfunction in aortic endothelium by a FABP4 inhibitor Endothelial dysfunction [47] Association with oxidative stress and activation of NF-κB and P53 pathways Cellular senescence [48] [49] Bronchial epithelial cell Induction by Th2 cytokines IL-4 and IL-13 [13] Suppression by Th1 cytokine interferon γ [13] Noninduction by PPARγ agonists [13] Protection from asthma in deficient mice Asthma [13] Lung Detection in lung lavage cells obtained from patients Bronchopulmonary dysplasia [50] Detection in lung lavage cells obtained from patients Sarcoidosis [51] Ovary Expression in granulosa cells inside atretic antral follicles [52] Association with FABP4 gene polymorphisms Polycystic ovary syndrome [53] International Journal of Inflammation "
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    ABSTRACT: Over the past decade, a large body of evidence has emerged demonstrating an integration of metabolic and immune response pathways. It is now clear that obesity and associated disorders such as insulin resistance and type 2 diabetes are associated with a metabolically driven, low-grade, chronic inflammatory state, referred to as "metaflammation." Several inflammatory cytokines as well as lipids and metabolic stress pathways can activate metaflammation, which targets metabolically critical organs and tissues including adipocytes and macrophages to adversely affect systemic homeostasis. On the other hand, inside the cell, fatty acid-binding proteins (FABPs), a family of lipid chaperones, as well as endoplasmic reticulum (ER) stress, and reactive oxygen species derived from mitochondria play significant roles in promotion of metabolically triggered inflammation. Here, we discuss the molecular and cellular basis of the roles of FABPs, especially FABP4 and FABP5, in metaflammation and related diseases including obesity, diabetes, and atherosclerosis.
    10/2011; 2011:642612. DOI:10.4061/2011/642612
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