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.Lipids and lipid signals are critical in the integration of metabolic and inflammatory response systems and consequently play significant parts in the pathogenesis of a cluster of chronic metabolic diseases, including type 2 diabetes, fatty liver disease and atherosclerosis 1 . However, how lipids couple to target signalling pathways or metabolic processes and how their intracellular trafficking is regulated are poorly understood. Cytoplasmic fatty-acid-binding proteins (FABPs) are a family of 14-15-kDa proteins that

A-FABP and Oxidative Stress Underlie the Impairment of Endothelium-Dependent Relaxations to Serotonin and the Intima-Medial Thickening in the Porcine Coronary Artery with Regenerated Endothelium

“…The present results thus confirm that the function of the vascular smooth muscle cells is not significantly affected by the endothelial regeneration process. 30,31 Incubation for 30 min with apocynin [10 −4 M; antioxidant and inhibitor of NADPH oxidase 35,36 ] or BMS309403 [3 × 10 −6 M; A-FABP inhibitor 23,37 ] had no significant effect on the responses, in terms of EC 50 or maximal response, of porcine coronary arteries with either native or regenerated endothelium ( Figure 2; Table 1) to serotonin, bradykinin, detaNONOate, and isoproterenol. Therefore, any effect (shown below) observed with these inhibitors after chronic treatment cannot be attributed to acute pharmacological actions per se of these agents.…”

Lipid signalling in disease

“…Targeting the hormone-sensitive lipase (HSL), which liberates free fatty acids for cellular uptake, is an option that has been realized with the use of orlistat. Similarly, smallmolecule inhibitors of FABP4 have produced promising results in preventing metabolic syndrome in high-fat diet animal models, and raises hopes that this strategy might advance further 50,[52][53][54] . Cellular stress that is caused by an excess of fatty acids can be alleviated using orally active chemical chaperones that act to stabilize protein conformation and improve the protein folding capacity of the ER.…”

Mechanisms by which diabetes increases cardiovascular disease

“…aP2 deficiency also reduces atherosclerotic lesions in Apoe −/− mice [58]. Recently, pharmacological inhibition of aP2 has been demonstrated to reduce atherosclerosis in Apoe −/− mice, probably due to inhibition of foam cell formation, production of inflammatory chemokines and cytokines [59]. Atorvastatin, a β-HMG CoA reductase inhibitor, has been demonstrated to suppress aP2 in vitro [60].…”