Acute effects of elevated NEFA on vascular function: a comparison of SFA and MUFA

There is emerging evidence to show that high levels of NEFA contribute to endothelial dysfunction and impaired insulin sensitivity. However, the impact of NEFA composition remains unclear. A total of ten healthy men consumed test drinks containing 50 g of palm stearin (rich in SFA) or high-oleic sunflower oil (rich in MUFA) on separate occasions; a third day included no fat as a control. The fats were emulsified into chocolate drinks and given as a bolus (approximately 10 g fat) at baseline followed by smaller amounts (approximately 3 g fat) every 30 min throughout the 6 h study day. An intravenous heparin infusion was initiated 2 h after the bolus, which resulted in a three- to fourfold increase in circulating NEFA level from baseline. Mean arterial stiffness as measured by digital volume pulse was higher during the consumption of SFA (P,0·001) but not MUFA (P¼0·089) compared with the control. Overall insulin and gastric inhibitory peptide response was greater during the consumption of both fats compared with the control (P,0·001); there was a second insulin peak in response to MUFA unlike SFA. Consumption of SFA resulted in higher levels of soluble intercellular adhesion molecule-1 (sI-CAM) at 330 min than that of MUFA or control (P#0·048). There was no effect of the test drinks on glucose, total nitrite, plasminogen activator inhibitor-1 or endothelin-1 concentrations. The present study indicates a potential negative impact of elevated NEFA derived from the consumption of SFA on arterial stiffness and sI-CAM levels. More studies are needed to fully investigate the impact of NEFA composition on risk factors for CVD

Differential effects of single fatty acids and fatty acid mixtures on the phosphoinositide 3-kinase/Akt/eNOS pathway in endothelial cells

Scope: Dietary 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. Methods: To 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. Results: Oleic 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 with 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. Conclusion: Our 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

Acute effects of elevated NEFA on vascular function: a comparison of SFA and MUFA

Abstract There is emerging evidence to show that high levels of NEFA contribute to endothelial dysfunction and impaired insulin sensitivity. However, the impact of NEFA composition remains unclear. A total of ten healthy men consumed test drinks containing 50 g of palm stearin (rich in SFA) or high-oleic sunflower oil (rich in MUFA) on separate occasions; a third day included no fat as a control. The fats were emulsified into chocolate drinks and given as a bolus (approximately 10 g fat) at baseline followed by smaller amounts (approximately 3 g fat) every 30 min throughout the 6 h study day. An intravenous heparin infusion was initiated 2 h after the bolus, which resulted in a three-to fourfold increase in circulating NEFA level from baseline. Mean arterial stiffness as measured by digital volume pulse was higher during the consumption of SFA (P, 0·001) but not MUFA (P¼0·089) compared with the control. Overall insulin and gastric inhibitory peptide response was greater during the consumption of both fats compared with the control (P, 0·001); there was a second insulin peak in response to MUFA unlike SFA. Consumption of SFA resulted in higher levels of soluble intercellular adhesion molecule-1 (sI-CAM) at 330 min than that of MUFA or control (P# 0·048). There was no effect of the test drinks on glucose, total nitrite, plasminogen activator inhibitor-1 or endothelin-1 concentrations. The present study indicates a potential negative impact of elevated NEFA derived from the consumption of SFA on arterial stiffness and sI-CAM levels. More studies are needed to fully investigate the impact of NEFA composition on risk factors for CVD

Effect of non-esterified fatty acid composition on vascular function : acute postprandial and in vitro insulin signalling studies

Background Elevated levels of circulating non-esterified fatty acids (NEFA) are often observed during type 11 diabetes and have been proposed as a contributory factor for atherosclerosis. Experimental elevation of NEFA in healthy subjects impairs vascular function, but the impact of NEFA fatty acid composition is unclear. In vitro studies implicate a role for fatty acid-induced defects in insulin signalling, but these may be limited by unphysiological experimental exposures. Aim To examine the effect of varying NEFA concentration and fatty acid composition on vascular function, and explore the potential role of the endothelial insulin signalling pathway. Methods Two acute human studies elevated NEFA in healthy volunteers using oral fat loads of differing fatty acid composition together with a heparin infusion over 330 or 390min. Vascular function was assessed using flow-mediated dilatation (FMD), laser Doppler iontophoresis (LDI) or digital volume pulse (DVP). Regular venous blood samples were taken to assess lipid and insulin metabolism, as well as markers of endothelial function. In a subset of subjects, the notion that an infusion of insulin could restore vascular function was explored, this also served as a measure of whole-body insulin sensitivity (51). Extensive method development was undertaken to determine the impact of fatty acid incubations (single and mixtures) on proteins involved in the insulin signalling pathway in human aortic endothelial cells (HAEC). Results In the pilot study (10 males), an elevation of NEFA enriched in saturated fatty acids (5FA) versus mono unsaturated fatty acids (MUFA) was associated with an increase in a marker of arterial stiffness (DVPs,) and endothelial inflammation (sICAM). In the main study (30 males, 29 females), an elevation of 5FA-rich NEFA impaired FMD but a moderate substitution of 5FA for long-chain n-3 polyunsaturated fatty acids (LC n-3 PUFA) reversed the impact, leading to a mean difference of 2.06 ± 0.29 % (P<0.001); LDI measures increased after both fat regimes (P~0.026) and there was no change in DVP indices. In the subset analysis, insulin infusion was not associated with an increase in FMD, although there was some indication that responses differed by gender. 51 was greater during the LC n-S PUFA regime compared with 5FA alone in males only (P=0.041). Preliminary in vitro work indicated that the MUFA, oleic acid increased the phosphorylation status of the enzyme which produces nitric oxide, a key vasodilator, however further method optimisation may be required. Conclusion These studies have shown that NEFA concentration and fatty acid composition can acutely modulate vascular function, and broadly support current advice to limit 5FA and increase LC n-3 PUFA consumption for prevention of heart disease. The large number of subjects included in the main study allowed us to show that both gender and genotype modulate the endothelial response to NEFA. A variety of mechanisms are likely to contribute to these findings and require further investigation in in vitro models which best replicate the physiological environment.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

DHA-rich fish oil reverses the detrimental effects of saturated fatty acids on postprandial vascular reactivity

Background: Experimental elevation of nonesterified fatty acids (NEFAs) impairs endothelial function, but the effect of NEFA composition is unknown. Objective: The objective was to test the effect of acute elevation of NEFAs enriched with either saturated fatty acids (SFAs) or SFAs with long-chain (LC) n−3 (omega-3) PUFAs on vascular function measured via flow-mediated dilatation (FMD), laser Doppler iontophoresis (LDI), and digital volume pulse (DVP). Design: In 59 subjects (30 men and 29 women), repeated oral fat feeding of either palm stearin (SFA) or palm stearin with DHA-rich fish oil (SFA + LC n−3 PUFA) was performed on 2 separate occasions with continuous heparin infusion to elevate NEFAs for a duration of 60 to 240 min. Vascular function was measured at baseline and at the end of NEFA elevation; venous blood was collected for measurement of lipids and circulating markers of endothelial function. Results: NEFA elevation during consumption of the SFA-rich drinks was associated with a marked impairment of FMD, whereas consumption of SFAs + LC n−3 PUFAs improved FMD response, with a mean (±SEM) difference of 2.06 ± 0.29% (P < 0.001). Positive correlations were found with percentage weight of LC n−3 PUFAs in circulating NEFAs and change in FMD response [Spearman's rho (rs) = 0.460, P < 0.001]. LDI measures increased during both treatments (P ≤ 0.026), and there was no change in DVP indexes. Conclusions: The composition of NEFAs can acutely affect FMD. The beneficial effect of LC n−3 PUFAs on postprandial vascular function warrants further investigation but may be mediated by nitric oxide–independent mechanisms. This trial is registered at clinicaltrials.gov as NCT01351324

Minimum recovery time between reactive hyperemia stimulus in the repeated measurement of brachial flow-mediated dilatation.

The ability to undertake repeat measurements of flow-mediated dilatation (FMD) within a short time of a previous measurement would be useful to improve accuracy or to repeat a failed initial procedure. Although standard methods report that a minimum of 10 min is required between measurements, there is no published data to support this. Thirty healthy volunteers had five FMD measurements performed within a 2-h period, separated by various time intervals (5, 15 and 30 min). In 19 volunteers, FMD was also performed as soon as the vessel had returned to its baseline diameter. There was no significant difference between any of the FMD measurements or parameters across the visits indicating that repeat measurements may be taken after a minimum of 5 min or as soon as the vessel has returned to its baseline diameter, which in some subjects may be less than 5 min

Effect of multiple micronutrient supplementation during pregnancy on inflammatory markers in Nepalese women.

BACKGROUND: Multiple micronutrient supplementation of Nepalese women during pregnancy is associated with a significant increase in birth weight. OBJECTIVE: We tested the hypothesis that improved birth weight in infants of mothers supplemented with micronutrients is associated with a decrease in inflammatory responses and an increase in the production of T helper 1 cells and T helper 2 cells. DESIGN: The study was embedded in a randomized controlled trial of 15 micronutrients, compared with iron-folate supplementation (control), given during pregnancy with the aim of increasing birth weight. Blood samples were collected at 32 wk of gestation, 12-20 wk after supplementation began, for the measurement of inflammatory markers. Breast-milk samples were collected 1 mo after delivery for the measurement of the ratio of milk sodium to potassium (milk Na:K). In an opportunistically selected subgroup of 70 women, mitogen-stimulated cytokine production was measured ex vivo in whole blood. RESULTS: Blood eosinophils; plasma concentrations of the acute phase reactants C-reactive protein, alpha(1)-acid glycoprotein (AGP), neopterin, and ferritin; milk Na:K; and the production of interleukin (IL) 10, IL-4, interferon gamma, and tumor necrosis factor alpha in whole blood did not differ significantly between the supplemented and control groups. Plasma C-reactive protein and AGP were higher in women who had a preterm delivery, and AGP was higher in women who delivered a low-birth-weight term infant than in women who delivered a normal-birth-weight term infant. CONCLUSIONS: The results indicate an association between systemic inflammation in late pregnancy and compromised delivery outcome in Nepalese women but do not support the hypothesis that multiple micronutrient supplementation changes cytokine production or inflammatory markers