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Fatty acid-binding protein 4 impairs the insulin-dependent nitric oxide pathway in vascular endothelial cells

DOI: 10.1186/1475-2840-11-72

Keywords: Diabetes, Endothelium, Fatty acid-binding protein 4 (FABP4), Endothelial dysfunction, Insulin, Insulin-signalling pathway, Endothelial nitric oxide synthase (eNOS), Nitric oxide (NO)

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Abstract:

In human umbilical vascular endothelial cells (HUVECs), we measured the effects of FABP4 on the insulin-mediated endothelial nitric oxide synthase (eNOS) expression and activation and on NO production. We also explored the impact of exogenous FABP4 on the insulin-signalling pathway (insulin receptor substrate 1 (IRS1) and Akt).We found that eNOS expression and activation and NO production are significantly inhibited by exogenous FABP4 in HUVECs. FABP4 induced an alteration of the insulin-mediated eNOS pathway by inhibiting IRS1 and Akt activation. These results suggest that FABP4 induces endothelial dysfunction by inhibiting the activation of the insulin-signalling pathway resulting in decreased eNOS activation and NO production.These findings provide a mechanistic linkage between FABP4 and impaired endothelial function in diabetes, which leads to an increased cardiovascular risk.The adipose fatty acid-binding protein (FABP), also known as FABP4 and aP2, is one of the best characterised intracellular lipid transport proteins [1]. It belongs to the superfamily of low-molecular-weight intracellular lipid-binding proteins and plays a central regulatory role in energy metabolism and inflammation [2,3]. FABP4 is highly expressed in mature adipocytes and accounts for approximately 6?% of their soluble protein. FABP4 is also found circulating in the plasma. In the last several years, much effort has been focused on uncovering the role of FABP4. However, neither the secretory pathways nor the functions of circulating FABP4 are known. We and other authors have shown that FABP4 levels are increased in obesity, metabolic syndrome (MS), type 2 diabetes (T2D), and familial combined hyperlipidaemia or lipodystrophy syndromes, and these levels are also closely correlated with adverse lipid profiles and insulin resistance [4-10]. In these studies, serum FABP4 predicted the development of MS and atherosclerosis [11,12].A recent study showed that although serum levels of both adipocy

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