Abstract
ScopeDietary fat composition is an important modulator of vascular function. Non-esterified fatty acids (NEFA) enriched in saturated fatty acids (SFA) are thought to reduce vascular reactivity by attenuating insulin signalling via vasodilator pathways (phosphoinositide 3-kinase (PI3K)/Akt/endothelial nitric oxide synthase (eNOS)) and enhancing signalling via pro-inflammatory pathways.MethodsTo examine the effects of fatty acids on these pathways, human aortic endothelial cells were incubated with single fatty acids, and mixtures of these fatty acids to mimic typical NEFA composition and concentrations achieved in our previous human study. RNA was extracted to determine gene expression using real-time RT-PCR and cell lysates prepared to assess protein phosphorylation by Western blotting.ResultsOleic acid (OA, 100 µM) was shown to down regulate expression of the insulin receptor, PTEN and a PI3K catalytic (p110β) and regulatory (p85α) subunit compared to palmitic, linoleic and stearic acids (P < 0.04), and promote greater eNOS phosphorylation at Ser1177. Both concentration and composition of the SFA and SFA plus n-3 polyunsaturated fatty acids (PUFA) mixtures had significant effects on genes involved in the PI3K/Akt pathway. Greater up-regulation was found with 800 than 400 µM concentration (respective of concentrations in insulin resistant and normal individuals), whereas greater down-regulation was evident with SFA plus n-3 PUFA than SFA mixture alone.ConclusionOur findings provide novel insights into the modulation of the PI3K/Akt/eNOS pathway by single fatty acids and fatty acid mixtures. In particular, OA appears to promote signalling via this pathway, with further work required to determine the primary molecular site(s) of action.
Highlights
Elevated levels of non-esterified fatty acids (NEFA), characteristic of insulin resistant states such as obesity and type II diabetes, have been proposed to mediate their effects on vascular function by modulating insulin signalling pathways in the endothelium
In a study performed in rats, biopsies taken from the aorta showed evidence of NEFA-induced impairment of the phosphoinositide 3-kinase (PI3K) pathway, with a significant reduction in the phosphorylation of insulin receptor substrate-1 (IRS-1), Akt and endothelial nitric oxide synthase, together with impaired responses to the endothelial-dependent vasodilator, acetylcholine [2]
Our previous human study found the experimental elevation of NEFA after feeding a test oil containing saturated fatty acids (SFA) with long chain (LC) n-3 polyunsaturated fatty acids (PUFA) to reverse the impairment in flow-mediated dilatation observed with SFA alone [3], confirming previous suggestions that dietary fat composition may be an important modulator of vascular function
Summary
Elevated levels of non-esterified fatty acids (NEFA), characteristic of insulin resistant states such as obesity and type II diabetes, have been proposed to mediate their effects on vascular function by modulating insulin signalling pathways in the endothelium. In a study performed in rats, biopsies taken from the aorta showed evidence of NEFA-induced impairment of the phosphoinositide 3-kinase (PI3K) pathway, with a significant reduction in the phosphorylation of insulin receptor substrate-1 (IRS-1), Akt and endothelial nitric oxide synthase (eNOS), together with impaired responses to the endothelial-dependent vasodilator, acetylcholine [2]. Both studies achieved NEFA elevation using a commercially available triacylglycerol infusion, Intralipid, which is rich in n-6 polyunsaturated fatty acids (PUFA). OA has been shown to protect against insulin resistance by regulating the expression of genes in the PI3K signalling pathway [8], suggesting that a similar mechanism may operate in the endothelium
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