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31 August 2009

Ceramide mediates inhibition of the AKT/eNOS signaling pathway by palmitate in human vascular endothelial cells

Xie Xiao-YunA, Chen Zhuo-XiongE, Lei Min-XiangA, He XingxuanB, Edward H. SchuchmanC, liu FengF, Xu Han-SongG, Lin An-HuaD

Med Sci Monit 2009; 15(9): BR254-261 :: ID: 878172

Abstract

Background
In metabolic syndrome, down-regulation of the insulin signaling leads to insulin-regulated metabolism and cardiovascular dyfunctions. Free fatty acids (FFAs) in the circulation are increased in this disorder and inhibit insulin signaling. Lipid oversupply contributes to the development of insulin resistance, likely by promoting the accumulation of lipid metabolites capable of inhibiting signal transduction.
Material and Method
This study was designed to examine the effects of FFAs and their metabolites on the insulin signaling pathway that leads to the activation of endothelial nitric oxide synthase (eNOS) and increase in nitric oxide (NO) production in endothelial cells.
Results
Here we demonstrate that exposing human umbilical vein endothelial cells (HUVECs) to palmitate inhibits activation of Akt/eNOS signal pathway by insulin, and subsequently insulin-stimulated NO generation. Palmitate concomitantly induced the accumulation of ceramide, a product of acyl-CoA that has been shown to accumulate in insulin-resistant tissues and to inhibit insulin signaling. Preventing de novo ceramide synthesis abolished the antagonistic effect of palmitate toward the Akt/ eNOS pathway. Moreover, inducing ceramide buildup augmented the inhibitory effect of palmitate.
Conclusions
Taken together, we have demonstrated that palmitic acid induces accumulation of ceramide, which appears to mediate palmitic acid's inhibitory effects on the Akt/eNOS pathway, leading to a significant decrease in NO generation. Therefore, ceramide is a necessary and sufficient intermediate mediating the inhibition of the AKT/eNOS signaling pathway by palmitate in endothelial cells.

Keywords: Signal Transduction - physiology, Proto-Oncogene Proteins c-akt - metabolism, Palmitates - metabolism, Nitric Oxide Synthase Type III - metabolism, Nitric Oxide - metabolism, Insulin Resistance, Metabolic Syndrome X - physiopathology, Insulin - metabolism, Immunosuppressive Agents - metabolism, Fumonisins - metabolism, Fatty Acids, Nonesterified - metabolism, Fatty Acids, Monounsaturated - metabolism, Enzyme Inhibitors - metabolism, Endothelial Cells - metabolism, Ceramides - metabolism

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Medical Science Monitor eISSN: 1643-3750
Medical Science Monitor eISSN: 1643-3750