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


METHODS
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.
Xiao-Yun
Xie
X
Department of Endocrinology, Xiangya Hospital of Central South University, Hunan Province, Changsha, China.
Zhuo-Xiong
Chen
C
Min-Xiang
Lei
L
Xingxuan
He
H
Schuchman
Edward H
EH
Feng
Liu
L
Han-Song
Xu
X
An-Hua
Lin
L
D000818:Animals; D002478:Cells, Cultured; D002518:Ceramides / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000378:metabolism; D005229:Fatty Acids, Monounsaturated / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D037341:Fumonisins / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D024821:Metabolic Syndrome / Q000378:metabolism / Q000503:physiopathology; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D010168:Palmitates / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
D002518:Ceramides; D004791:Enzyme Inhibitors; D005229:Fatty Acids, Monounsaturated; D005230:Fatty Acids, Nonesterified; D037341:Fumonisins; D007166:Immunosuppressive Agents; D007328:Insulin; D010168:Palmitates; D009569:Nitric Oxide; C056933:fumonisin B1; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt; C001996:thermozymocidin