Different metabolic behavior of long-chain n-3 polyunsaturated fatty acids in human platelets

Whereas numerous studies deal with the effects and metabolism of eicosapentaenoic acid (20:5(n - 3)) in platelets, very few concern docosahexaenoic acid (22:6(n - 3)), although both acids are consumed in equal amounts from most fish fat. The present paper reports the modulation of 22:6(n - 3) oxygenation as well as that of endogenous arachidonic acid (20:4(n - 6)) in 22:6(n - 3)-rich platelets. Like the oxygenation of 20:5(n - 3), the lipoxygenation of 22:6(n - 3) occurred at a low level when incubated alone, but was markedly increased in the presence of 20:4(n - 6), suggesting a similar peroxide tone dependency. 20:5(n - 3) could not replace 20:4(n - 6) in the increasing 22:6(n - 3) lipoxygenation, whereas 22:6(n - 3) shared the potentiating effect of 20:4(n - 6) on both the cyclooxygenation and the lipoxygenation of 20:5(n - 3). On the other hand, 20:5(n - 3), 22:6(n - 3) or 20:5(n - 3) + 22:6(n - 3) enrichment of platelet phospholipids inhibited the formation of cyclooxygenase but not lipoxygenase products from endogenous 20:4(n - 6) in thrombin-stimulated platelets. In doing so, 22:6(n - 3) appeared even more potent than 20:5(n - 3), although it was not liberated after acylation in phospholipids, the opposite of what was observed with 20:5(n - 3). Therefore, it seems that, in contrast to 20:5(n - 3), which may compete with endogenous 20:4(n - 6) at the cyclooxygenase level, 22:6(n - 3) would affect the latter enzyme activity in a different way. We conclude that 20:5(n - 3) and 22:6(n - 3) behave differently and might act synergistically on the inhibition of platelet functions after fish fat intake.     

The role of long-chain polyunsaturated fatty acids in infant cognitive development

Dietary long-chain polyunsaturated fatty acids (LCPUFA) in infancy are necessary for normal brain growth and development, and may play an important role in the development of infant cognition. Several randomized, controlled studies have evaluated the effects of feeding both term and preterm infants formula containing LCPUFA or no LCPUFA on a variety of measures of cognitive behaviour. Studies of the relation of LCPUFA to performance on tests of psychomotor development have produced inconsistent results, with supplemented infants demonstrating either higher scores or no differences in comparison to controls. This pattern suggests that global tests of development may be insufficiently sensitive for detecting the effects of LCPUFA on infant cognitive function. In contrast, studies assessing the influence of LCPUFA on development of specific cognitive behaviours have shown a significant advantage for supplemented infants on measures of visual attention and problem solving. These results suggest that LCPUFA may enhance more efficient information processing or attention regulation in infants. Whether there are any long-term effects of dietary LCPUFA in infancy on childhood cognition is not known.     

Beneficial effects of the n-3 long-chain polyunsaturated fatty acids in surgical patients: updating the evidence

The use of n-3 polyunsaturated fatty acids in surgical patients has risen by the fact that this may attenuate systemic and acute inflammatory responses secondary to surgical trauma through modulation of inflammatory mediators and cell membrane interactions. Moreover, the inclusion of n-3 fatty acids in clinical trials as part of the therapy in patients, who expect to undergo a surgical stress, suggests benefits on clinical progress. Therefore, the objective of this article is to review data from n-3 polyunsaturated fatty acid effects on biochemical parameters and on reduced length of hospitalization, number of infections, and mortality as main clinical outcomes in human surgical patients.     

Protection against in vivo liver ischemia-reperfusion injury by n-3 long-chain polyunsaturated fatty acids in the rat

Abstract

N-3 polyunsaturated fatty acids (n-3 PUFA) affect inflammatory processes. This study evaluated the effects of dietary supplementation with fish oil on hepatic ischemia-reperfusion (IR) injury in the rat. Parameters of liver injury (serum transaminases and histology) and oxidative stress (serum 8-isoprostanes and hepatic GSH and GSSG), were correlated with NF-κB DNA binding and FA composition and inflammatory cytokine release. N-3 PUFA supplementation significantly increased liver n-3 PUFA content and decreased n-6/n-3 PUFA ratios. IR significantly modified liver histology and enhanced serum transaminases, 8-isoprotanes and inflammatory cytokines, with net reduction in liver GSH levels and net increment in those of GSSG. Early increase (3 h) and late reduction (20 h) in NF-κB activity was induced. All IR-induced changes were normalized by n-3 PUFA supplementation. In conclusion, prevention of liver IR-injury was achieved by n-3 PUFA supplementation, with suppression of oxidative stress and recovery of pro-inflammatory cytokine homeostasis and NF-κB functionality lost during IR.     

n-3 polyunsaturated fatty acids and the cardiovascular system

n-3 Polyunsaturated fatty acids, mainly those contained in fish oils, are candidates for inclusion in secondary prevention programmes for coronary heart disease, based on the results of recent randomized trials in humans. Marine n-3 polyunsaturated fatty acids retard coronary atherosclerosis and appear to prevent fatal arrhythmias; and they decrease mortality subsequent to myocardial infarction.     

Adaptive thermogenesis by dietary n-3 polyunsaturated fatty acids: Emerging evidence and mechanisms

Brown/beige fat plays a crucial role in maintaining energy homeostasis through non-shivering thermogenesis in response to cold temperature and excess nutrition (adaptive thermogenesis). Although numerous molecular and genetic regulators have been identified, relatively little information is available regarding thermogenic dietary molecules. Recently, a growing body of evidence suggests that high consumption of n-3 polyunsaturated fatty acids (PUFA) or activation of GPR120, a membrane receptor of n-3 PUFA, stimulate adaptive thermogenesis. In this review, we summarize the emerging evidence that n-3 PUFA promote brown/beige fat formation and highlight the potential mechanisms whereby n-3 PUFA require GPR120 as a signaling platform or act independently. Human clinical trials are revisited in the context of energy expenditure. Additionally, we explore some future perspective that n-3 PUFA intake might be a useful strategy to boost or sustain metabolic activities of brown/beige fat at different lifecycle stages of pregnancy and senescence. Given that a high ratio of n-6/n-3 PUFA intake is associated with the development of obesity and type 2 diabetes, understanding the impact of n-6/n-3 ratio on energy expenditure and adaptive thermogenesis will inform the implementation of a novel nutritional strategy for preventing obesity.     

Intravenous infusion of n-3 polyunsaturated fatty acids.

Dietary supplementation with n-3 polyunsaturated fatty acids (PUFA) is regarded as beneficial for the prevention and treatment of atherosclerosis and thrombosis and chronic inflammatory diseases like rheumatoid arthritis and psoriasis. It may be possible to treat some acute diseases like acute myocardial infarction or acute rejection of grafted organs if it is possible to make n-3 PUFA take effect quickly (in hours instead of days). Three sets of experiments were done. In Experiment 1, emulsion of trieicosapentaenoyl-glycerol (EPA-TG) and tridocosahexaenoyl-glycerol was infused through rabbit ear veins, and the leukotriene B4/B5 production from polymorphonuclear leukocytes was measured at different time points by high-performance liquid chromatography. In Experiment 2, delayed type hypersensitivity (DTH) of mice was measured with sheep red blood cells as an antigen. Pure n-3 PUFA emulsions or a control solution were infused through tail veins just before the second challenge of the antigen. DTH was measured 24 hr after the second challenge. In Experiment 3, human natural killer cell activity was measured using K562 target cells before and after the infusion of pure EPA-TG emulsion to an antecubital vein. Leukotriene B4 production by rabbit polymorphonuclear leukocytes was depressed by 40% by EPA-TG infusion. DTH was suppressed almost completely by n-3 PUFA infusion. Natural killer cell activity was suppressed almost completely by EPA-TG infusion in 8 hr. DTH, natural killer cell activity, and leukotriene B4 production are probably related to acute rejection of grafted organs.(ABSTRACT TRUNCATED AT 250 WORDS)     

The metabolic role of n-3 polyunsaturated fatty acids: relationship to human disease.

1. An increasing body of evidence suggests that certain types of fat have beneficial effects on human health. 2. Fish oils in particular have been shown to exert positive effects on atherosclerosis, heart disease and carcinogenesis. 3. These positive effects are thought to be mediated through eicosanoids derived from polyunsaturated fatty acids of the n-3 family which are present in large quantities in fish oils.     

Docosahexaenoic acid synthesis from n-3 polyunsaturated fatty acids in differentiated rat brain astrocytes

DHA, the main n-3 PUFA in the brain, is synthesized from n-3 PUFA precursors by astrocytes. To assess the potential of this process to supply DHA for the brain, we investigated whether the synthesis in astrocytes is dependent on DHA availability. Rat brain astrocytes differentiated with dibutyryl cAMP and incubated in media containing 10% fetal bovine serum synthesized DHA from alpha-linolenic acid ([1-(14)C]18:3n-3), docosapentaenoic acid ([3-(14)C]22:5n-3), tetracosapentaenoic acid ([3-(14)C]24:5n-3), and tetracosahexaenoic acid ([3-(14)C]24:6n-3). When DHA was added to media containing a 5 microM concentration of these (14)C-labeled n-3 PUFA, radiolabeled DHA synthesis was reduced but not completely suppressed even when the DHA concentration was increased to 15 microM. Radiolabeled DHA synthesis also was reduced but not completely suppressed when the astrocytes were treated with 30 microM DHA for 24 h before incubation with 5 microM [1-(14)C]18:3n-3.These findings indicate that although the DHA synthesis in astrocytes is dependent on DHA availability, some synthesis continues even when the cells have access to substantial amounts of DHA. This suggests that DHA synthesis from n-3 PUFA precursors is a constitutive process in the brain and, therefore, is likely to have an essential function.     

Studies on the metabolic fate of n-3 polyunsaturated fatty acids

Several different processes involved in the metabolic fate of docosahexaenoic acid (DHA, C22:6n-3) and its precursor in the biosynthesis route, C24:6n-3, were studied. In cultured skin fibroblasts, the oxidation rate of [1-14C] 24:6n-3 was 2.7 times higher than for [1-14C]22:6n-3, whereas [1-14C]22:6n-3 was incorporated 7 times faster into different lipid classes than was [1-14C]24:6n-3. When determining the peroxisomal acyl-CoA oxidase activity, similar specific activities for C22:6(n-3)-CoA and C24:6(n-3)-CoA were found in mouse kidney peroxisomes. Thioesterase activity was measured for both substrates in mouse kidney peroxisomes as well as mitochondria, and C22:6(n-3)-CoA was hydrolyzed 1.7 times faster than C24:6(n-3)-CoA. These results imply that the preferred metabolic fate of C24:6(n-3)-CoA, after its synthesis in the endoplasmic reticulum (ER), is to move to the peroxisome, where it is beta-oxidized, producing C22:6(n-3)-CoA. This DHA-CoA then preferentially moves back, probably as free fatty acid, to the ER, where it is incorporated into membrane lipids.     

Recent studies on interactions between n-3 and n-6 polyunsaturated fatty acids in brain and other tissues

Recent literature provides a basis for understanding the behavioral, functional, and structural consequences of nutritional deprivation or disease-related abnormalities of n-3 polyunsaturated fatty acids. The literature suggests that these effects are mediated through competition between n-3 and n-6 polyunsaturated fatty acids at certain enzymatic steps, particularly those involving polyunsaturated fatty acid elongation and desaturation. One critical enzymatic site is a delta6-desaturase. On the other hand, an in-vivo method in rats, applied following chronic n-3 nutritional deprivation or chronic administration of lithium, indicates that the cycles of de-esterification/re-esterification of docosahexaenoic acid (22:6n-3) and arachidonic acid (20:4n-6) within brain phospholipids operate independently of each other, and thus that the enzymes regulating each of these cycles are not likely sites of n-3/n-6 competition.     

The effect of n-3 long-chain polyunsaturated fatty acids and lipoic acid on the heart in the ovariectomized rat model of menopause

Menopause occurs as consequence of ovarian senescence that leads to a drop of oestrogen hormone. The decreased oestrogen levels combined with the impairment of the redox system may contribute to the increased risk of postmenopausal cardiovascular disease. Supplementation with antioxidants may be an alternative to reduce cardiovascular risk. The study evaluated the effect of dietary supplementation with docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and α-lipoic acid (LA) for a period of 16 weeks on oxidative stress biomarkers in the hearts of ovariectomized 3-month-old rats. Ovariectomy did not increase the level of the damage markers malondialdehyde and carbonyl, and both were decreased by LA supplementation. Ovariectomy increased the levels of the endogenous antioxidants glutathione, vitamin C and H₂O₂ consumption, after restoration by DHA, EPA, and LA supplementation. Vitamin E, glutathione peroxidase, glutathione-S-transferase, and superoxide dismutase are not altered by ovariectomy. Lipid and protein damage are not increased after ovariectomy and a portion of the endogenous antioxidants concomitantly increased, suggesting that hearts may be protected by these antioxidants. DHA, EPA, and LA restored these endogenous antioxidants, showing that all evaluated supplements are effective in modulating the antioxidant redox system in the heart. LA showed additional effect on redox markers, decreasing lipid and protein damage markers.     

The effects of n-3 and n-6 polyunsaturated fatty acids on plasma lipids and fatty acids of treated phenylketonuric children

Dietary-treated phenylketonuric patients (PKUs) display low levels of long-chain polyunsaturated fatty acids (PUFA) in plasma lipids. In a 6-month clinical trial we observed a decrease of triglycerides and an increase of n-3 long-chain PUFA in plasma of PKUs supplemented with fish oil, while no major differences in respect to the baseline values were found in a group supplemented with blackcurrant oil. A more complete source of long-chain PUFA of both the n-6 and n-3 series should be investigated for dietary supplementation of PKU patients.     

The effect of dietary n-3 long-chain polyunsaturated fatty acids on femur mineral density and biomarkers of bone metabolism in healthy, diabetic and dietary-restricted growing rats

INTRODUCTION: Dietary fish oil promotes bone formation in healthy states, but its effect during insulin deficiency or nutrient restriction is unclear. METHODS: Eighty weanling male rats were randomized to receive an injection of streptozotocin to induce insulin deficiency (diabetes) or saline (control) and a diet containing soy oil or corn + fish oil for 35 days. Half of the saline-injected rats were randomized to 20% dietary restriction. Measurements were growth, biomarkers of bone metabolism and femur bone mass. RESULTS: Density of femur was elevated in the corn + fish group and reduced in the diabetes group. Plasma osteocalcin and bone prostaglandin E2 (PGE2) were reduced by the corn + fish diet. N-telopeptide, IGF-1, bone PGE2 and urinary Ca were highest and calcitriol lowest in the diabetes group. CONCLUSIONS: These data suggest that the benefit of a diet high in n-3 long-chain polyunsaturated fatty acid is most advantageous to long bone density in healthy states.     

High feeding intensity increases the severity of fatty liver in the American mink (Neovison vison) with potential ameliorating role for long-chain n-3 polyunsaturated fatty acids

Background

Rapid body fat mobilization, obesity, and an inadequate supply of n-3 polyunsaturated fatty acids (PUFA) have been suggested to play roles in the etiology of fatty liver in the American mink (Neovison vison). This study examined the effects of feeding intensity and dietary fat source on fatty liver induced by fasting. In a multi-factorial design, 3 different fat sources (herring oil, rich in n-3 PUFA, soya oil, rich in n-6 PUFA, and canola oil, rich in n-9 monounsaturated fatty acids) were fed to mink at a low and high feeding intensity for 10 weeks, followed by an overnight or a 5-day fasting treatment to induce fatty liver.

Results

Fasting led to the development of fatty liver with increased severity in the mink fed at the high feeding intensity. The herring oil diet, high in long-chain n-3 PUFA, was found to decrease the severity of fatty liver in the mink at the high feeding intensity.

Conclusion

Preventing excessive weight gain and increasing dietary intake of n-3 long-chain PUFA may help prevent excessive lipid accumulation during prolonged periods of fasting or inappetence by promoting hepatic fatty acid oxidation.