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Keywords: non-esterified fatty acid (NEFA)
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Articles
Journal:
Clinical Science
Clin Sci (Lond) (2013) 125 (5): 247–255.
Published: 10 May 2013
...-esterified fatty acid (NEFA) oxidative stress • NEFAs play an important role in the development and progression of endothelial dysfunction and, therefore, they may contribute to cardiovascular events. Dihydropyridine calcium channel blockers (DHP CCBs) may ameliorate such adverse effects of NEFAs...
Abstract
Circulating NEFAs (non-esterified fatty acids) from adipose tissue lipolysis lead to endothelial dysfunction and insulin resistance in patients with the metabolic syndrome or Type 2 diabetes mellitus. The aim of the present study was to test the hypothesis that DHP (dihydropyridine) CCBs (calcium channel blockers) prevent NEFA-induced endothelial and haemorheological dysfunction independently of their antihypertensive properties. Using a double-blind cross-over study design, nifedipine, amlodipine, diltiazem or placebo were administered to eight healthy subjects for 2 days before each study day. On the study days, the following were assessed before and after the infusion of lipid and heparin to raise serum NEFAs: endothelial function, by measuring FBF (forearm blood flow) responses to ACh (acetylcholine); leucocyte activation, by ex vivo measurement of plasma MPO (myeloperoxidase) levels, adherent leucocyte numbers and whole blood transit time through microchannels; and oxidative stress, by determining plasma levels of d-ROMs (derivatives of reactive oxygen metabolites). Effects of the CCBs on NF-κB (nuclear factor κB) p65 phospholylation stimulated by NEFAs were assessed in cultured monocytic cells in vitro . Elevated NEFAs reduced the responses to ACh and significantly increased whole blood transit time, adherent leucocyte numbers and d-ROMs. Nifedipine and amlodipine, but not diltiazem, prevented NEFA-induced endothelial dysfunction, leucocyte activation and enhancement of oxidative stress without affecting BP (blood pressure), whereas all these drugs prevented NEFA-induced p65 activation in vitro . These results suggest that DHP CCBs, independent of their antihypertensive properties in humans, prevent NEFA-induced endothelial and haemorheological dysfunction through inhibition of NEFA-induced leucocyte activation, although the sensitivity to drugs of leucocyte Ca 2+ channels may differ among cells.
Articles
Eleanor Jarvie, Sylvie Hauguel-de-Mouzon, Scott M. Nelson, Naveed Sattar, Patrick M. Catalano, Dilys J. Freeman
Journal:
Clinical Science
Clin Sci (Lond) (2010) 119 (3): 123–129.
Published: 28 April 2010
..., distribution and reproduction in any medium, provided the original work is properly cited. body fat lipotoxicity metabolic programming non-esterified fatty acid (NEFA) obesity pregnancy The 70–100% increase in maternal obesity over the last decade has had ramifications for all aspects of...
Abstract
Increasing maternal obesity is a challenge that has an impact on all aspects of female reproduction. Lean and obese pregnant women gain similar fat mass, but lean women store fat in the lower-body compartment and obese women in central compartments. In the non-pregnant, central storage of fat is associated with adipocyte hypertrophy and represents a failure to adequately store excess fatty acids, resulting in metabolic dysregulation and ectopic fat accumulation (lipotoxicity). Obese pregnancy is associated with exaggerated metabolic adaptation, endothelial dysfunction and increased risk of adverse pregnancy outcome. We hypothesize that the preferential storage of fat in central rather than ‘safer’ lower-body depots in obese pregnancy leads to lipotoxicity. The combination of excess fatty acids and oxidative stress leads to the production of oxidized lipids, which can be cytotoxic and influence gene expression by acting as ligands for nuclear receptors. Lipid excess and oxidative stress provoke endothelial dysfunction. Oxidized lipids can inhibit trophoblast invasion and influence placental development, lipid metabolism and transport and can also affect fetal developmental pathways. As lipotoxicity has the capability of influencing both maternal endothelial function and placental function, it may link maternal obesity and placentally related adverse pregnancy outcomes such as miscarriage and pre-eclampsia. The combination of excess/altered lipid nutrient supply, suboptimal in utero metabolic environment and alterations in placental gene expression, inflammation and metabolism may also induce obesity in the offspring.
Articles
Journal:
Clinical Science
Clin Sci (Lond) (2010) 118 (5): 351–358.
Published: 23 November 2009
... Journal compilation © 2010 Biochemical Society 2010 fatty acid intrauterine growth restriction (IUGR) long-chain polyunsaturated fatty acid (LCPUFA) non-esterified fatty acid (NEFA) pregnancy retinol The human fetus is dependent on adequate placental transport of fatty acids from the...
Abstract
IUGR (intrauterine growth restriction) increases the incidence of perinatal complications and, although several placental transport functions have been shown to be altered in pregnancies complicated by IUGR, the mechanism behind it is not well understood. The aim of the present study was to investigate factors in maternal and cord blood plasma from normal and IUGR-complicated pregnancies associated with the body weight of newborns. At the time of Caesarean section, 24 women with IUGR pregnancies were compared with a group of 30 normal controls with AGA (appropriate gestational age) fetuses who were studied at Caesarean section, which took place 5 weeks later than IUGR pregnancies, and also to a group of 25 non-delivered gestational age-matched control pregnant women (AGA-35wk). Maternal plasma retinol, γ- and α-tocopherol, NEFAs (non-esterified fatty acids), and palmitic, palmitoleic, γ-linolenic and arachidonic acids were higher in women with IUGR pregnancies than in AGA-35wk controls, whereas stearic and α-linolenic acids were lower. Smaller differences were found when comparing these variables for IUGR and AGA women. However, umbilical vein plasma γ-tocopherol, cholesterol, triacylglycerols and NEFAs were higher in the IUGR group than in the AGA group, whereas arachidonic acid was lower. Maternal plasma retinol and NEFAs were the only variables negatively correlated with birthweight when multiple linear regressions were analysed. In conclusion, the increased levels of circulating retinol and NEFAs in maternal plasma are negatively associated with birth and placental weights, which may reflect an impaired placental transfer in IUGR pregnancies. As retinoids are involved in the control of gene transcription, it is proposed that a decrease in placental transfer of retinol could underlie the metabolic dysfunction of IUGR pregnancies.
Articles
An M. Van Berendoncks, Paul Beckers, Vicky Y. Hoymans, Nadine Possemiers, Floris L. Wuyts, Christiaan J. Vrints, Viviane M. Conraads
Journal:
Clinical Science
Clin Sci (Lond) (2010) 118 (4): 281–289.
Published: 16 November 2009
... ). 8 4 2009 31 7 2009 6 8 2009 6 8 2009 © The Authors Journal compilation © 2010 Biochemical Society 2010 adiponectin chronic heart failure exercise training non-esterified fatty acid (NEFA) N-terminal pro-brain natriuretic peptide (NT-proBNP) CHF (chronic heart...
Abstract
High adiponectin concentrations have emerged as an independent risk factor of outcome in patients with CHF (chronic heart failure); however, modification of adiponectin in CHF patients has not been assessed to date. The aim of the present study was to investigate the effect of exercise training on adiponectin levels in CHF patients. A total of 80 patients with CHF due to systolic dysfunction were included. The effect of 4 months exercise training was studied in 46 patients, whereas the remaining 34 untrained CHF patients served as a sedentary control group. Circulating adiponectin concentrations, exercise capacity, anthropometric data and NT-proBNP (N-terminal pro-brain natriuretic peptide) levels were assessed. Adiponectin levels were significantly higher in CHF patients compared with healthy subjects [9.3 (7.1–16.1) and 4.9 (3.9–8.6) mg/l respectively; P =0.015]. Stratification of CHF patients according to tertiles of NT-proBNP revealed an increase in adiponectin with disease severity ( P <0.0001). Exercise training reduced circulating adiponectin levels in CHF patients [10.7 (7.2–17.6) mg/l before training to 9.4 (5.9–14.8) mg/l after training; P =0.013], whereas no changes were observed in the sedentary CHF group [9.0 (7.0–13.5) mg/l before training and 10.1 (6.0–15.7) mg/l after a similar time interval]. A significant time×group interaction ( P =0.008) was observed for the mean change in adiponectin between the trained and untrained CHF patients. Adiponectin concentrations were positively associated with NT-proBNP and HDL (high-density lipoprotein)-cholesterol and negatively correlated with BMI (body mass index), triacylglycerols and exercise capacity. In conclusion, circulating adiponectin concentrations are higher in CHF patients compared with healthy subjects and increase with disease severity. Exercise training for 4 months lowers circulating adiponectin levels.
Articles
Journal:
Clinical Science
Clin Sci (Lond) (2008) 114 (3): 183–193.
Published: 08 January 2008
... 20 6 2007 20 7 2007 © The Authors Journal compilation © 2008 Biochemical Society 2008 AMP-dependent kinase (AMPK) fatty acid oxidation hypothalamus lipid metabolic syndrome non-esterified fatty acid (NEFA) obesity White adipose tissue, the body's major energy store...
Abstract
The MS (metabolic syndrome) is a cluster of clinical and biochemical abnormalities characterized by central obesity, dyslipidaemia [hypertriglyceridaemia and decreased HDL-C (high-density lipoprotein cholesterol)], glucose intolerance and hypertension. Insulin resistance, hyperleptinaemia and low plasma levels of adiponectin are also widely related to features of the MS. This review focuses on lipid metabolism alterations associated with the MS, paying special attention to changes in plasma lipids and cellular fatty acid oxidation. Lipid metabolism alterations in liver and peripheral tissues are addressed, with particular reference to adipose and muscle tissues, and the mechanisms by which some adipokines, namely leptin and adiponectin, mediate the regulation of fatty acid oxidation in those tissues. Activation of the AMPK (AMP-dependent kinase) pathway, together with a subsequent increase in fatty acid oxidation, appear to constitute the main mechanism of action of these hormones in the regulation of lipid metabolism. Decreased activation of AMPK appears to have a role in the development of features of the MS. In addition, alteration of AMPK signalling in the hypothalamus, which may function as a sensor of nutrient availability, integrating multiple nutritional and hormonal signals, may have a key role in the appearance of the MS.
Articles
Niels P. Riksen, Marlies Bosselaar, Stephan J.L. Bakker, Robert J. Heine, Gerard A. Rongen, Cees J. Tack, Paul Smits
Journal:
Clinical Science
Clin Sci (Lond) (2007) 113 (1): 33–40.
Published: 01 June 2007
... 2007 © The Authors Journal compilation © 2007 Biochemical Society 2007 adenosine non-esterified fatty acid (NEFA) arterial compliance blood flow autonomic nervous system The metabolic syndrome is characterized by (central) obesity, insulin resistance, glucose intolerance...
Abstract
Plasma NEFA (non-esterified fatty acid) concentrations are elevated in patients with obesity. In the present study we first aimed to provide an integral haemodynamic profile of elevated plasma NEFAs by the simultaneous assessment of blood pressure, pulse wave velocity, FBF (forearm blood flow) and sympathetic nervous system activity during acute elevation of NEFAs. Secondly, we hypothesized that NEFA-induced vasodilation is mediated by adenosine receptor stimulation. In a randomized cross-over trial in healthy subjects, Intralipid® was infused for 2 h to elevate plasma NEFAs. Glycerol was administered as the Control infusion. We assessed blood pressure, pulse wave velocity, FBF (using venous occlusion plethysmography) and sympathetic nervous system activity by measurement of noradrenaline and adrenaline. During the last 15 min of Intralipid®/Control infusion, the adenosine receptor antagonist caffeine (90 μg·min −1 ·dl −1 ) was administered into the brachial artery of the non-dominant arm. Compared with Control infusion, Intralipid® increased pulse wave velocity, SBP (systolic blood pressure) and pulse pressure, as well as FBF (from 1.8±0.2 to 2.7±0.6 and from 2.3±0.2 to 2.7±0.6 ml·min −1 ·dl −1 for Intralipid® compared with Control infusion; P <0.05, n =9). Although in a positive control study caffeine attenuated adenosine-induced forearm vasodilation ( P <0.01, n =6), caffeine had no effect on Intralipid®-induced vasodilation ( P =0.5). In conclusion, elevation of plasma NEFA levels increased pulse wave velocity, SBP and pulse pressure. FBF was also increased, either by baroreflex-mediated inhibition of the sympathetic nervous system or by a direct vasodilating effect of NEFAs. As the adenosine receptor antagonist caffeine could not antagonize the vasodilator response, this response is not mediated by adenosine receptor stimulation.
Articles
Journal:
Clinical Science
Clin Sci (Lond) (2007) 112 (1): 27–42.
Published: 01 December 2006
... secretion and β-cell integrity. Correspondence: Dr Philip Newsholme (email philip.newsholme@ucd.ie ). 11 5 2006 26 6 2006 3 7 2006 The Biochemical Society 2007 acetyl-CoA apoptosis fatty acid toxicity glucose metabolism insulin secretion non-esterified fatty acid...
Abstract
Both stimulatory and detrimental effects of NEFAs (non-esterified fatty acids) on pancreatic β-cells have been recognized. Acute exposure of the pancreatic β-cell to high glucose concentrations and/or saturated NEFAs results in a substantial increase in insulin release, whereas chronic exposure results in desensitization and suppression of secretion, followed by induction of apoptosis. Some unsaturated NEFAs also promote insulin release acutely, but they are less toxic to β-cells during chronic exposure and can even exert positive protective effects. Therefore changes in the levels of NEFAs are likely to be important for the regulation of β-cell function and viability under physiological conditions. In addition, the switching between endogenous fatty acid synthesis or oxidation in the β-cell, together with alterations in neutral lipid accumulation, may have critical implications for β-cell function and integrity. Long-chain acyl-CoA (formed from either endogenously synthesized or exogenous fatty acids) controls several aspects of β-cell function, including activation of specific isoenzymes of PKC (protein kinase C), modulation of ion channels, protein acylation, ceramide formation and/or NO-mediated apoptosis, and transcription factor activity. In this review, we describe the effects of exogenous and endogenous fatty acids on β-cell metabolism and gene and protein expression, and have explored the outcomes with respect to insulin secretion and β-cell integrity.
Articles
Journal:
Clinical Science
Clin Sci (Lond) (2004) 106 (4): 421–432.
Published: 01 April 2004
... The Biochemical Society 2004 atherosclerosis atherosclerotic-prone mice apolipoprotein B mRNA editing enzyme (Apobec1) low-density lipoprotein (LDL) receptor non-esterified fatty acid (NEFA) platelet-activating factor acetylhydrolase (PAF-AH) Clinical Science (2004) 106, 421 432 (Printed...
Abstract
Animal models provide vital tools to explicate the pathogenesis of atherosclerosis. Accordingly, we established two atherosclerosis-prone mice models: (i) mice lacking the LDL (low-density lipoprotein) receptor (LDLR) and the ability to edit apo (apolipoprotein) B mRNA (Apobec1; designated LDb : LDLR -/- Apobec1 -/- ), and (ii) mice with the LDb background, who also overexpressed human apoB100 (designated LTp : LDLR -/- Apobec1 -/- ERhB +/+ ). Both LDb and LTp mice had markedly elevated levels of LDL and increased levels of NEFAs (non-esterified fatty acids) compared with C57BL / 6 wild-type mice. However, fasting glucose and insulin levels in both animals were not different than those in C57BL / 6 wild-type mice. It has been suggested that PAF-AH (platelet-activating factor acetylhydrolase) increases susceptibility to vascular disease. Both LDb and LTp mice had significantly higher PAF-AH mRNA levels compared with C57BL / 6 wild-type mice. PAF-AH gene expression was also significantly influenced by age and sex. Interestingly, PAF-AH mRNA levels were significantly higher in both LTp male and female mice than in the LDb mice. This increased PAF-AH gene expression was associated with elevated plasma PAF-AH enzyme activities ( LTp > LDb > C57BL / 6 ). Moreover, a greater proportion of PAF-AH activity was associated with the apoB-containing lipoproteins: 29% in LTp and 13% in LDb mice compared with C57BL / 6 wild-type animals (6.7%). This may explain why LTp mice developed more atherosclerotic lesions than LDb mice by 8 months of age. In summary, increased plasma NEFAs, PAF-AH mRNA and enzyme activities are associated with accelerated atherogenesis in these animal models.