The DOI matches its Crossref record; 8 of the 8 references it cites were found in a registry or an index.
Free Fatty Acid Impairment of Nitric Oxide Production in Endothelial Cells Is Mediated by IKKβ
Abstract
Objective— Free fatty acids (FFA) are commonly elevated in diabetes and obesity and have been shown to impair nitric oxide (NO) production by endothelial cells. However, the signaling pathways responsible for FFA impairment of NO production in endothelial cells have not been characterized. Insulin receptor substrate-1 (IRS-1) regulation is critical for activation of endothelial nitric oxide synthase (eNOS) in response to stimulation by insulin or fluid shear stress. Methods and Results— We demonstrate that insulin-mediated tyrosine phosphorylation of IRS-1 and serine phosphorylation of Akt, eNOS, and NO production are significantly inhibited by treatment of bovine aortic endothelial cells with 100 μmol/L FFA composed of palmitic acid for 3 hours before stimulation with 100 nM insulin. This FFA preparation also increases, in a dose-dependent manner, IKKβ activity, which regulates activation of NF- κB, a transcriptional factor associated with inflammation. Similarly, elevation of other common FFA such as oleic and linoleic acid also induce IKKβ activation and inhibit insulin-mediated eNOS activation. Overexpression of a kinase inactive form of IKKβ blocks the ability of FFA to inhibit insulin-dependent NO production, whereas overexpression of wild-type IKKβ recapitulates the effect of FFA on insulin-dependent NO production. Conclusions— Elevated levels of common FFA found in human serum activate IKKβ in endothelial cells leading to reduced NO production, and thus may serve to link pathways involved in inflammation and endothelial dysfunction.
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Cites
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Yu, C., Chen, Y., Cline, G. W., Zhang, D., Zong, H., Wang, Y., Bergeron, R., Kim, J. K., Cushman, S. W., Cooney, G. J., et al. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m200958200 · Cited by 1,561
Effect of a single high-fat meal on endothelial function in healthy subjects
Vogel, R. A., Corretti, M. C., & Plotnick, G. D. (1997) · The American Journal of Cardiology · doi:10.1016/s0002-9149(96)00760-6 · Cited by 798
Elevated circulating free fatty acid levels impair endothelium-dependent vasodilation
Steinberg, H. O., Tarshoby, M., Monestel, R., Hook, G., Cronin, J., Johnson, A., Bayazeed, B., & Baron, A. D. (1997) · Journal of Clinical Investigation · doi:10.1172/jci119636 · Cited by 761
Zeng, G., Nystrom, F. H., Ravichandran, L. V., Cong, L.-N., Kirby, M., Mostowski, H., & Quon, M. J. (2000) · Circulation · doi:10.1161/01.cir.101.13.1539 · Cited by 745
Prevention of fat-induced insulin resistance by salicylate
Kim, J. K., Kim, Y.-J., Fillmore, J. J., Chen, Y., Moore, I., Lee, J., Yuan, M., Li, Z. W., Karin, M., Perret, P., et al. (2001) · Journal of Clinical Investigation · doi:10.1172/jci11559 · Cited by 737
Mechanism by which high-dose aspirin improves glucose metabolism in type 2 diabetes
Hundal, R. S., Petersen, K. F., Mayerson, A. B., Randhawa, P. S., Inzucchi, S., Shoelson, S. E., & Shulman, G. I. (2002) · Journal of Clinical Investigation · doi:10.1172/jci0214955 · Cited by 557
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Cited by
Kim, J.-A., Montagnani, M., Koh, K. K., & Quon, M. J. (2006) · Circulation · doi:10.1161/circulationaha.105.563213 · Cited by 1,652
Inflammation and insulin resistance
de Luca, C., & Olefsky, J. M. (2008) · FEBS Letters · doi:10.1016/j.febslet.2007.11.057 · Cited by 1,161
Role of Mitochondrial Dysfunction in Insulin Resistance
Kim, J.-A., Wei, Y., & Sowers, J. R. (2008) · Circulation Research · doi:10.1161/circresaha.107.165472 · Cited by 1,103
Toll-Like Receptor-4 Mediates Vascular Inflammation and Insulin Resistance in Diet-Induced Obesity
Kim, F., Pham, M., Luttrell, I., Bannerman, D. D., Tupper, J., Thaler, J., Hawn, T. R., Raines, E. W., & Schwartz, M. W. (2007) · Circulation Research · doi:10.1161/circresaha.106.142851 · Cited by 584
Self-citationPosey, K. A., Clegg, D. J., Printz, R. L., Byun, J., Morton, G. J., Vivekanandan-Giri, A., Pennathur, S., Baskin, D. G., Heinecke, J. W., Woods, S. C., et al. (2009) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.90377.2008 · Cited by 586
Metadata
- Authors
- Kim, F., Tysseling, K. A., Rice, J., Pham, M., Haji, L., Gallis, B. M., Baas, A. S., Paramsothy, P., Giachelli, C. M., Corson, M. A., & Raines, E. W.
- Venue
- Arteriosclerosis, Thrombosis, and Vascular Biology
- Published
- 2005-05
- Volume
- 25
- Issue
- 5
- Pages
- 989-994
- ISSN
- 1079-5642 (ISSN-L)
- 1524-4636
- OpenAlex
- W2164680983
- Cited by
- 307
- References
- 8
- FWCI
- 10.95
- Type
- journal article
- Language
- en
- Open access
- closed
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- CoChat. (2026). Citation check: Free Fatty Acid Impairment of Nitric Oxide Production in Endothelial Cells Is Mediated by IKKβ. https://app.cochat.ai/papers/10.1161/01.atv.0000160549.60980.a8
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- Kim, F., Tysseling, K. A., Rice, J., Pham, M., Haji, L., Gallis, B. M., Baas, A. S., Paramsothy, P., Giachelli, C. M., Corson, M. A., & Raines, E. W. (2005). Free Fatty Acid Impairment of Nitric Oxide Production in Endothelial Cells Is Mediated by IKKβ. Arteriosclerosis, Thrombosis, and Vascular Biology. https://doi.org/10.1161/01.atv.0000160549.60980.a8
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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