Perinatal Dietary Polyunsaturated Fatty Acids in Brain Development, Role in Neurodevelopmental Disorders.

n-3 and n-6 polyunsaturated fatty acids (PUFAs) are essential fatty acids that are provided by dietary intake. Growing evidence suggests that n-3 and n-6 PUFAs are paramount for brain functions. They constitute crucial elements of cellular membranes, especially in the brain. They are the precursors of several metabolites with different effects on inflammation and neuron outgrowth. Overall, long-chain PUFAs accumulate in the offspring brain during the embryonic and post-natal periods. In this review, we discuss how they accumulate in the developing brain, considering the maternal dietary supply, the polymorphisms of genes involved in their metabolism, and the differences linked to gender. We also report the mechanisms linking their bioavailability in the developing brain, their transfer from the mother to the embryo through the placenta, and their role in brain development. In addition, data on the potential role of altered bioavailability of long-chain n-3 PUFAs in the etiologies of neurodevelopmental diseases, such as autism, attention deficit and hyperactivity disorder, and schizophrenia, are reviewed.

Digestive n-6 Lipid Oxidation, a Key Trigger of Vascular Dysfunction and Atherosclerosis in the Western Diet: Protective Effects of Apple Polyphenols.

SCOPE: A main risk factor of atherosclerosis is a Western diet (WD) rich in n-6 polyunsaturated fatty acids (PUFAs) sensitive to oxidation. Their oxidation can be initiated by heme iron of red meat leading to the formation of 4-hydroxy-2-nonenal (4-HNE), a cytotoxic aldehyde. An increased 4-HNE production is implicated in endothelial dysfunction and atherosclerosis. By contrast, a diet rich in proanthocyanidins reduces oxidative stress and arterial diseases. This study evaluates the effects of a WD on vascular integrity in ApolipoproteinE (ApoE-/- ) mice and the protective capacity of apple extract and puree rich in antioxidant proanthocyanidins. METHODS AND RESULTS: ApoE-/- mice are fed during 12 weeks with a WD with or without n-6 PUFAs. Moreover, two WD + n-6 PUFAs groups are supplemented with apple puree or phenolic extract. An increase in digestive 4-HNE production associated with a rise in plasmatic 4-HNE and oxidized LDL concentrations is reported. Oxidizable n-6 PUFAs consumption is associated with a worsened endothelial dysfunction and atherosclerosis. Interestingly, supplementations with apple polyphenol extract or puree prevented these impairments while reducing oxidative stress. CONCLUSION: n-6 lipid oxidation during digestion may be a key factor of vascular impairments. Nevertheless, an antioxidant strategy can limit 4-HNE formation during digestion and thus durably protect vascular function.

Pre-eclampsia is associated with reduced resolvin D1 and maresin 1 to leukotriene B4 ratios in the plasma.

PROBLEM: Omega-3 and omega-6 fatty acids can be endogenously converted into mediators with pro-inflammatory (eg, leukotriene B4/LTB4) or anti-inflammatory/pro-resolving activities (eg, resolvin D1/RvD1 and maresin 1/MaR1). Recent data indicate an imbalance of LTB4 and MaR1 levels in pre-eclampsia (PE), but the relative production of these mediators, including RvD1, and the role of these mediators in the disease pathogenesis remain unclear. Therefore, this study aimed to investigate the plasma levels of LTB4, RvD1, and MaR1 in pregnant women with or without PE and non-pregnant controls and their association with clinical/laboratory parameters of PE women. METHOD OF STUDY: LTB4, RvD1, and MaR1 plasma levels were measured by competitive enzyme immunoassay in 19 non-pregnant, 20 normotensive pregnant, and 21 PE women. RESULTS: Plasma concentrations of LTB4 were higher and RvD1 were lower in PE women than in normotensive pregnant women, who presented higher levels of LTB4 and similar levels of RvD1 to non-pregnant women. MaR1 levels did not differ among the groups. Pre-eclampsia women had decreased RvD1/LTB4 and MaR1/LTB4 ratios. Considering only the PE group, positive correlations were observed among all the mediators tested, between LTB4 and white blood cell count and between RvD1 and creatinine levels. However, all lipid mediators correlated negatively with body mass index before pregnancy. LTB4 also correlated negatively with maternal age. CONCLUSION: Our findings suggest that the PE state results in systemic overproduction of LTB4 in relation to RvD1 and MaR1, and that these lipid mediators may be involved with the disease pathogenesis.

Original Research: Effect of various dietary fats on fatty acid profile in duck liver: Efficient conversion of short-chain to long-chain omega-3 fatty acids.

Omega-3 fatty acids, especially long-chain omega-3 fatty acids, have been associated with potential health benefits for chronic disease prevention. Our previous studies found that dietary omega-3 fatty acids could accumulate in the meat and eggs in a duck model. This study was to reveal the effects of various dietary fats on fatty acid profile and conversion of omega-3 fatty acids in duck liver. Female Shan Partridge Ducks were randomly assigned to five dietary treatments, each consisting of 6 replicates of 30 birds. The experimental diets substituted the basal diet by 2% of flaxseed oil, rapeseed oil, beef tallow, or fish oil, respectively. In addition, a dose response study was further conducted for flaxseed and fish oil diets at 0.5%, 1%, and 2%, respectively. At the end of the five-week treatment, fatty acids were extracted from the liver samples and analyzed by GC-FID. As expected, the total omega-3 fatty acids and the ratio of total omega-3/omega-6 significantly increased in both flaxseed and fish oil groups when compared with the control diet. No significant change of total saturated fatty acids or omega-3 fatty acids was found in both rapeseed and beef tallow groups. The dose response study further indicated that 59-81% of the short-chain omega-3 ALA in flaxseed oil-fed group was efficiently converted to long-chain DHA in the duck liver, whereas 1% of dietary flaxseed oil could produce an equivalent level of DHA as 0.5% of dietary fish oil. The more omega-3 fatty acids, the less omega-6 fatty acids in the duck liver. Taken together, this study showed the fatty acid profiling in the duck liver after various dietary fat consumption, provided insight into a dose response change of omega-3 fatty acids, indicated an efficient conversion of short- to long-chain omega-3 fatty acid, and suggested alternative long-chain omega-3 fatty acid-enriched duck products for human health benefits.

Omega-3 fatty acids for breast cancer prevention and survivorship.

Women with evidence of high intake ratios of the marine omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) relative to the omega-6 arachidonic acid have been found to have a reduced risk of breast cancer compared with those with low ratios in some but not all case-control and cohort studies. If increasing EPA and DHA relative to arachidonic acid is effective in reducing breast cancer risk, likely mechanisms include reduction in proinflammatory lipid derivatives, inhibition of nuclear factor-κB-induced cytokine production, and decreased growth factor receptor signaling as a result of alteration in membrane lipid rafts. Primary prevention trials with either risk biomarkers or cancer incidence as endpoints are underway but final results of these trials are currently unavailable. EPA and DHA supplementation is also being explored in an effort to help prevent or alleviate common problems after a breast cancer diagnosis, including cardiac and cognitive dysfunction and chemotherapy-induced peripheral neuropathy. The insulin-sensitizing and anabolic properties of EPA and DHA also suggest supplementation studies to determine whether these omega-3 fatty acids might reduce chemotherapy-associated loss of muscle mass and weight gain. We will briefly review relevant omega-3 fatty acid metabolism, and early investigations in breast cancer prevention and survivorship.

[Nutrimetabolomics--the new stage of biochemistry of nutrition. The role of nutrilipidomic analysis].

In this review, in the light of current trends in the development of nutritional science and nutritional biochemistry the key directions associated with complex comprehensive study of metabolic processes in the body are discussed. We highlight the development of lipidomic researches and formation of nutrilipidomic analysis. We review the role of different lipids, including omega-3 and omega-6 PUFAs, in mechanism of protein expression, the nature of lipid-protein interactions, and the signaling function of lipids. Since PUFAs influence the increase of peroxide oxidation of lipids, this review summarizes current methodology used to estimate the oxidative stress.

Differential response to an algae supplement high in DHA mediated by maternal periconceptional diet: intergenerational effects of n-6 fatty acids.

Algae high in docosahexaenoic acid (DHA) may provide a source of long-chain omega-3 polyunsaturated fatty acids (LCn-3PUFA) for inclusion in the diet of lambs to improve the LCn-3PUFA status of meat. The effect of background LCn-3PUFA status on the metabolism of high DHA algae is, however, unknown. The aim of the current study was to determine whether the response to a high in DHA algae supplement fed to lambs for six weeks prior to slaughter was mediated by a maternal periconceptional diet. Forty Poll Dorset × Border Leicester × Merino weaner lambs were allocated to receive either a ration based on oat grain, lupin grain, and chopped lucerne (control) or the control ration with DHA-Gold™ algae included at 1.92 % DM (Algae) based on whether the dams of lambs had previously been fed a diet high in n-3 or n-6 around conception. LCn-3PUFA concentration was determined in plasma and red blood cells (RBC) prior to and following feeding. The concentrations of EPA and DHA in the plasma and RBC of lambs receiving the control ration were significantly (p < 0.001) lower when lambs received the ration for 14 days compared with pre-feeding concentrations. The concentrations of EPA and DHA were also significantly (p < 0.001) higher when lambs consumed the Algae ration compared with the control ration for 42 days. The increase in EPA and DHA was, however, significantly (p < 0.05) lower if lamb dams had previously been fed a diet high in n-6 at conception. Assessing the previous nutrition and n-3 status of lambs may allow producers to more accurately predict the likely response to supplements high in LCn-3PUFA, particularly, DHA.

Dietary omega-6 fatty acid lowering increases bioavailability of omega-3 polyunsaturated fatty acids in human plasma lipid pools.

BACKGROUND: Dietary linoleic acid (LA, 18:2n-6) lowering in rats reduces n-6 polyunsaturated fatty acid (PUFA) plasma concentrations and increases n-3 PUFA (eicosapentaenoic (EPA) and docosahexaenoic acid (DHA)) concentrations. OBJECTIVE: To evaluate the extent to which 12 weeks of dietary n-6 PUFA lowering, with or without increased dietary n-3 PUFAs, alters unesterified and esterified plasma n-6 and n-3 PUFA concentrations in subjects with chronic headache. DESIGN: Secondary analysis of a randomized trial. Subjects with chronic headache were randomized for 12 weeks to (1) average n-3, low n-6 (L6) diet; or (2) high n-3, low n-6 LA (H3-L6) diet. Esterified and unesterified plasma fatty acids were quantified at baseline (0 weeks) and after 12 weeks on a diet. RESULTS: Compared to baseline, the L6 diet reduced esterified plasma LA and increased esterified n-3 PUFA concentrations (nmol/ml), but did not significantly change plasma arachidonic acid (AA, 20:4n-6) concentration. In addition, unesterified EPA concentration was increased significantly among unesterified fatty acids. The H3-L6 diet decreased esterified LA and AA concentrations, and produced more marked increases in esterified and unesterified n-3 PUFA concentrations. CONCLUSION: Dietary n-6 PUFA lowering for 12 weeks significantly reduces LA and increases n-3 PUFA concentrations in plasma, without altering plasma AA concentration. A concurrent increase in dietary n-3 PUFAs for 12 weeks further increases n-3 PUFA plasma concentrations and reduces AA.

Altered colonic mucosal availability of n-3 and n-6 polyunsaturated fatty acids in ulcerative colitis and the relationship to disease activity.

BACKGROUND AND AIMS: The polyunsaturated fatty acids (PUFA) arachidonic acid (AA, n-6) and eicosapentaenoic acid (EPA, n-3) are precursors of eicosanoids and other lipid mediators which have critical roles in inflammation. The mediators formed from the different PUFA have different potencies. We hypothesised that metabolic changes associated with colonic mucosal inflammation would modify the bioavailability of the eicosanoid precursors AA and EPA. METHODS: Colonic mucosa biopsies were obtained from patients with ulcerative colitis and from matched controls. Inflammation was graded endoscopically and histologically. Esterified and non-esterified fatty acids were determined within the biopsies using gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry, respectively. RESULTS: Biopsy samples were collected from 69 UC patients (54 providing both inflamed and non-inflamed mucosa) and 69 controls. Inflamed mucosa had higher AA (p<0.001) and lower EPA (p<0.010) contents and a higher AA:EPA ratio (p<0.001). Inflamed mucosa also had higher docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA) and lower linoleic acid (LA) and α-linolenic acid (α-LNA) contents (all p<0.001), compared to non-inflamed and controls. There were significant correlations between severity of inflammation and contents of AA, DPA and DHA (positive correlations) and of LA, α-LNA and EPA (negative correlations). CONCLUSIONS: Higher AA, AA:EPA ratio, DPA and DHA and lower LA, α-LNA and EPA are seen in inflamed mucosa in UC and correlate with severity of inflammation. This suggests an alteration in fatty acid metabolism in the inflamed gut mucosa, which may offer novel targets for intervention and should be considered if nutritional strategies are used.

Lipid content in hepatic and gonadal adipose tissue parallel aortic cholesterol accumulation in mice fed diets with different omega-6 PUFA to EPA plus DHA ratios.

BACKGROUND & AIMS: Diets with low omega (ω)-6 polyunsaturated fatty acids (PUFA) to eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA) ratios have been shown to decrease aortic cholesterol accumulation and have been suggested to promote weight loss. The involvement of the liver and gonadal adipose tissue (GAT) in mediating these effects is not well understood. LDL receptor null mice were used to assess the effect of an atherogenic diet with different ω-6:EPA+DHA ratios on weight gain, hepatic and GAT lipid accumulation, and their relationship to atherosclerosis. METHODS: Four groups of mice were fed a high saturated fat and cholesterol diet (HSF ω-6) alone, or with ω-6 PUFA to EPA+DHA ratios up to 1:1 for 32 weeks. Liver and GAT were collected for lipid and gene expression analysis. RESULTS: The fatty acid profile of liver and GAT reflected the diets. All diets resulted in similar weight gains. Compared to HSF ω-6 diet, the 1:1 ratio diet resulted in lower hepatic total cholesterol (TC) content. Aortic TC was positively correlated with hepatic and GAT TC and triglyceride. These differences were accompanied by significantly lower expression of CD36, ATP-transporter cassette A1, scavenger receptor B class 1, 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), acetyl-CoA carboxylase alpha, acyl-CoA synthetase long-chain family member 5, and stearoyl-coenzyme A desaturase 1 (SCD1) in GAT, and HMGCR, SCD1 and cytochrome P450 7A1 in liver. CONCLUSIONS: Dietary ω-6:EPA+DHA ratios did not affect body weight, but lower ω-6:EPA+DHA ratio diets decreased liver lipid accumulation, which possibly contributed to the lower aortic cholesterol accumulation.

A double-blind, placebo-controlled study investigating the effects of omega-3 supplementation in children aged 8-10 years from a mainstream school population.

Despite the increased interest in the effects of omega-3 supplementation on children's learning and behaviour, there are a lack of controlled studies of this kind that have utilised a typically developing population. This study investigated the effects of omega-3 supplementation in 450 children aged 8-10 years old from a mainstream school population, using a randomised, double-blind, placebo-controlled design. Participants were supplemented with either active supplements (containing docosahexaenoic acid, DHA and eicosapentaenoic acid, EPA) or a placebo for 16 weeks. Cheek cell fatty acid levels were recorded pre- and post-supplementation and a range of cognitive tests and parent and teacher questionnaires were used as outcome measures. After supplementation, changes in the relationship between omega-6 and omega-3 were significant in the active group. Despite the wide range of cognitive and behavioural outcome measures employed, only three significant differences between groups were found after 16 weeks, one of which was in favour of the placebo condition. Exploring the associations between changes in fatty acid levels and changes in test and questionnaire scores also produced equivocal results. These findings are discussed in relation to previous findings with clinical populations and future implications for research.

Childrens' learning and behaviour and the association with cheek cell polyunsaturated fatty acid levels.

Increasing interest in the role of omega-3 fatty acids in relation to neurodevelopmental disorders (e.g. ADHD, dyslexia, autism) has occurred as a consequence of some international studies highlighting this link. In particular, some studies have shown that children with ADHD may have lower concentrations of polyunsaturated fatty acids (PUFAs), particularly omega-3, in their red blood cells and plasma, and that supplementation with omega-3 fatty acids may alleviate behavioural symptoms in this population. However, in order to compare levels it seems appropriate to establish fatty acid levels in a mainstream school aged population and if levels relate to learning and behaviour. To date no study has established this. For this study, cheek cell samples from 411 typically developing school children were collected and analysed for PUFA content, in order to establish the range in this population. In addition, measures of general classroom attention and behaviour were assessed in these children by teachers and parents. Cognitive performance tests were also administered in order to explore whether an association between behaviour and/or cognitive performance and PUFA levels exists. Relationships between PUFA levels and socio-economic status were also explored. Measures of reading, spelling and intelligence did not show any association with PUFA levels, but some associations were noted with the level of omega-3 fatty acids and teacher and parental reports of behaviour, with some evidence that higher omega-3 levels were associated with decreased levels of inattention, hyperactivity, emotional and conduct difficulties and increased levels of prosocial behaviour. These findings are discussed in relation to previous findings from omega-3 supplementation studies with children.

The omega-6/omega-3 ratio and cardiovascular disease risk: uses and abuses.

The cardioprotective effects of omega-3 fatty acids (n-3 FAs) are well known, but the role that the n-6 FAs play in coronary heart disease is unclear. These two classes of essential FAs compete for a number of enzyme systems, and their metabolites can powerfully influence (often in different directions) inflammatory responses, vascular reactivity, and platelet aggregation. Accordingly, the n-6/n-3 FA ratio may be of value in interpreting biomarker data and in making nutritional recommendations. Although initially appealing, there are few human experimental and clinical trial data to support this view. This paper reviews a variety of studies that, in the aggregate, suggest that the ratio is, both on theoretical and evidential grounds, of little value. Metrics that include the n-3 FAs alone, especially eicosapentaenoic and docosahexaenoic acids, appear to hold the greatest promise.

Interplay between different polyunsaturated fatty acids and risk of coronary heart disease in men.

BACKGROUND: Consumption of polyunsaturated fatty acids (PUFAs) may reduce coronary heart disease (CHD) risk, but n-6 PUFAs may compete with n-3 PUFA metabolism and attenuate benefits. Additionally, seafood-based, long-chain n-3 PUFAs may modify the effects of plant-based, intermediate-chain n-3 PUFAs. However, the interactions of these PUFAs in relation to CHD risk are not well established. METHODS AND RESULTS: Among 45,722 men free of known cardiovascular disease in 1986, usual dietary intake was assessed at baseline and every 4 years by using validated food-frequency questionnaires. CHD incidence was prospectively ascertained. Over 14 years of follow-up, participants experienced 218 sudden deaths, 1521 nonfatal myocardial infarctions (MIs), and 2306 total CHD events (combined sudden death, other CHD deaths, and nonfatal MI). In multivariate-adjusted analyses, both long-chain and intermediate-chain n-3 PUFA intakes were associated with lower CHD risk, without modification by n-6 PUFA intake. For example, men with > or = median long-chain n-3 PUFA intake (> or =250 mg/d) had a reduced risk of sudden death whether n-6 PUFA intake was below (<11.2 g/d; hazard ratio [HR]=0.52; 95% confidence interval [CI]=0.34 to 0.79) or above (> or =11.2 g/d; HR=0.60; 95% CI=0.39 to 0.93) the median compared with men with a < median intake of both. In similar analyses, > or = median intake of intermediate-chain n-3 PUFAs (> or =1080 mg/d) was associated with a reduced total CHD risk whether n-6 PUFA intake was lower (HR=0.88; 95% CI=0.78 to 0.99) or higher (HR=0.89; 95% CI=0.79 to 0.99) compared with a < median intake of both. Intermediate-chain n-3 PUFAs were particularly associated with CHD risk when long-chain n-3 PUFA intake was very low (<100 mg/d); among these men, each 1 g/d of intermediate-chain n-3 PUFA intake was associated with an approximately 50% lower risk of nonfatal MI (HR=0.42; 95% CI=0.23 to 0.75) and total CHD (HR=0.53; 95% CI=0.34 to 0.83). CONCLUSIONS: n-3 PUFAs from both seafood and plant sources may reduce CHD risk, with little apparent influence from background n-6 PUFA intake. Plant-based n-3 PUFAs may particularly reduce CHD risk when seafood-based n-3 PUFA intake is low, which has implications for populations with low consumption or availability of fatty fish.

Brief episode of STZ-induced hyperglycemia produces cardiac abnormalities in rats fed a diet rich in n-6 PUFA.

Diabetic patients are particularly susceptible to cardiomyopathy independent of vascular disease, and recent evidence implicates cell death as a contributing factor. Given its protective role against apoptosis, we hypothesized that dietary n-6 polyunsaturated fatty acid (PUFA) may well decrease the incidence of this mode of cardiac cell death after diabetes. Male Wistar rats were first fed a diet rich in n-6 PUFA [20% (wt/wt) sunflower oil] for 4 wk followed by streptozotocin (STZ, 55 mg/kg) to induce diabetes. After a brief period of hyperglycemia (4 days), hearts were excised for functional, morphological, and biochemical analysis. In diabetic rats, n-6 PUFA decreased caspase-3 activity, crucial for myocardial apoptosis. However, cardiac necrosis, an alternative mode of cell death, increased. In these hearts, a rise in linoleic acid and depleted cardiac glutathione could explain this "switch" to necrotic cell death. Additionally, mitochondrial abnormalities, impaired substrate utilization, and enhanced triglyceride accumulation could have also contributed to a decline in cardiac function in these animals. Our study provides evidence that, in contrast to other models of diabetic cardiomyopathy that exhibit cardiac dysfunction only after chronic hyperglycemia, n-6 PUFA feeding coupled with only 4 days of diabetes precipitated metabolic and contractile abnormalities in the heart. Thus, although promoted as being beneficial, excess n-6 PUFA, with its predisposition to induce obesity, insulin resistance, and ultimately diabetes, could accelerate myocardial abnormalities in diabetic patients.

New lipids in enteral feeding.

PURPOSE OF REVIEW: Lipid sources for enteral nutrition continue to be an exciting area of investigation. It is timely to review recent developments which have largely contributed to thrust enteral feeding into a new era. RECENT FINDINGS: Although much more research needs to be done, there is a better understanding of the competitive relationships between n-6/n-3 fatty acids in conditions of metabolic and immune stress as well as in autoimmune and degenerative diseases. Although structured lipids are more completely absorbed and cleared, other more important clinical benefits need to be documented before they can be considered cost-effective. Immune enhancing formulas are the subject of controversy and some have been shown to be more effective than others. Enteral formulations with short-chain fatty acids are promising but more experimental work on the normal, and the sick colon is needed. Finally, there are a few isolated studies suggesting that enteral feeding with liposomes and with lipolytic products may have advantages when the digestive phase needs to be circumvented. The era of nutrigenomics, in which the effect of specific lipids on genes and proteins is being explored, is with us. We can look forward to nutrigenetics when the effect of genetic variation on the interaction between diet and disease will guide our practice. SUMMARY: Clinicians already have access to lipid sources and formulations which allow them to individualize enteral feeding programs. More clinical and technological research needs to be carried out, however, before products can be tailored to produce optimal effects in specific conditions.