Fatty acid-binding protein 4 impairs the insulin-dependent nitric oxide pathway in vascular endothelial cells.
BACKGROUND
Recent studies have shown that fatty acid-binding protein 4 (FABP4) plasma levels are associated with impaired endothelial function in type 2 diabetes (T2D). In this work, we analysed the effect of FABP4 on the insulin-mediated nitric oxide (NO) production by endothelial cells in vitro.


METHODS
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).


RESULTS
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.


CONCLUSIONS
These findings provide a mechanistic linkage between FABP4 and impaired endothelial function in diabetes, which leads to an increased cardiovascular risk.
Research Unit on Lipids and Atherosclerosis, Universitat Rovira i Virgili, IISPV, Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Reus, Spain.
Gemma
G
Aragonès
Paula
P
Saavedra
Mercedes
M
Heras
Anna
A
Cabré
Josefa
J
Girona
Lluís
L
Masana
D002478:Cells, Cultured; D004789:Enzyme Activation; D050556:Fatty Acid-Binding Proteins / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors
C493410:FABP4 protein, human; D050556:Fatty Acid-Binding Proteins; C526292:IRS1 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D012333:RNA, Messenger; D009569:Nitric Oxide; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt