Non-dietary factors associated with n-3 long-chain PUFA levels in humans - a systematic literature review.

Numerous health benefits are attributed to the n-3 long-chain PUFA (n-3 LCPUFA); EPA and DHA. A systematic literature review was conducted to investigate factors, other than diet, that are associated with the n-3 LCPUFA levels. The inclusion criteria were papers written in English, carried out in adult non-pregnant humans, n-3 LCPUFA measured in blood or tissue, data from cross-sectional studies, or baseline data from intervention studies. The search revealed 5076 unique articles of which seventy were included in the qualitative synthesis. Three main groups of factors potentially associated with n-3 LCPUFA levels were identified: (1) unmodifiable factors (sex, genetics, age), (2) modifiable factors (body size, physical activity, alcohol, smoking) and (3) bioavailability factors (chemically bound form of supplements, krill oil v. fish oil, and conversion of plant-derived α-linolenic acid (ALA) to n-3 LCPUFA). Results showed that factors positively associated with n-3 LCPUFA levels were age, female sex (women younger than 50 years), wine consumption and the TAG form. Factors negatively associated with n-3 LCPUFA levels were genetics, BMI (if erythrocyte EPA and DHA levels are <5·6 %) and smoking. The evidence for girth, physical activity and krill oil v. fish oil associated with n-3 LCPUFA levels is inconclusive. There is also evidence that higher ALA consumption leads to increased levels of EPA but not DHA. In conclusion, sex, age, BMI, alcohol consumption, smoking and the form of n-3 LCPUFA are all factors that need to be taken into account in n-3 LCPUFA research.

Low-linoleic acid diet and oestrogen enhance the conversion of α-linolenic acid into DHA through modification of conversion enzymes and transcription factors.

Conversion of α-linolenic acid (ALA) into the longer chain n-3 PUFA has been suggested to be affected by the dietary intake of linoleic acid (LA), but the mechanism is not well known. Therefore, the purpose of this study was to evaluate the effect of a low-LA diet with and without oestrogen on the fatty acid conversion enzymes and transcription factors. Rats were fed a modified American Institute of Nutrition-93G diet with 0% n-3 PUFA or ALA, containing low or high amounts of LA for 12 weeks. At 8 weeks, the rats were injected with maize oil with or without 17ß-oestradiol-3-benzoate (E) at constant intervals for the remaining 3 weeks. Both the low-LA diet and E significantly increased the hepatic expressions of PPAR-α, fatty acid desaturase (FADS) 2, elongase of very long chain fatty acids 2 (ELOVL2) and ELOVL5 but decreased sterol regulatory element binding protein 1. The low-LA diet, but not E, increased the hepatic expression of FADS1, and E increased the hepatic expression of oestrogen receptor-α and ß. The low-LA diet and E had synergic effects on serum and liver levels of DHA and on the hepatic expression of PPAR-α. In conclusion, the low-LA diet and oestrogen increased the conversion of ALA into DHA by upregulating the elongases and desaturases of fatty acids through regulating the expression of transcription factors. The low-LA diet and E had a synergic effect on serum and liver levels of DHA through increasing the expression of PPAR-α.

Effect of long-term nutraceutical and dietary supplement use on cognition in the elderly: a 10-year systematic review of randomised controlled trials.

Nutraceuticals have generated interest as a way to mitigate the cognitive decline in older adults. The aim of this systematic review was to determine the evidence for these claims from the scientific literature in randomised, double-blinded, controlled trials (duration: ≥1 year; participants: n≥100; age(mean): ≥65 years). Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we searched four electronic databases (PubMed, Scopus, CINAHL and Web of Science) and identified twenty-five studies published between the 15·June·2006 and 14·June·2016. Interventions included B-vitamins, n-3 fatty acids, antioxidant vitamins and herbs. Of the B-vitamin studies, four found benefits to cognition with supplementation. The first of these B-vitamin studies, in individuals with mild cognitive impairment (n 266; duration=2 years), included benefit to executive function (P=0·015) and improvements in the Mini-Mental State Examination (MMSE) among participants with baseline homocysteine above 11·3 µmol/l (P<0·001). In the same sample, the second study found cognitive benefits of B-vitamins dependent on the higher baseline plasma n-3 fatty acid status. The third B-vitamin study (n 900; duration=2 years) reported improved performance in immediate (P=0·046) and delayed recall (P=0·013), whereas the fourth study (n 856; duration=2 years) reported slower rate of cognitive decline in the MMSE (P=0·05). One study investigating DHA treatment (n 402; duration=1·5 years) revealed the slower rate of cognitive change in apoE e4 non-carriers (P=0·03). As only five included studies revealed notable benefits, presently based on the specific compounds explored here, there is not compelling evidence to support the use nutraceuticals to improve cognition in the elderly. Future long-term trials of nutraceuticals should investigate interactions with lifestyle, blood biomarkers and genetic risk factors.

Associations of estimated Δ-5-desaturase and Δ-6-desaturase activities with stroke risk factors and risk of stroke: the Kuopio Ischaemic Heart Disease Risk Factor Study.

Stroke is a leading cause of morbidity and mortality. The role of PUFA in reducing the risk of stroke is uncertain. The concentrations of PUFA in the human body are determined both by dietary intake and by activities of desaturase enzymes. Desaturase enzymes have been associated with chronic diseases, but little is known about their association with stroke risk. We investigated the associations of Δ-6-desaturase (D6D) and Δ-5-desaturase (D5D) activities with stroke risk factors and risk of stroke among 1842 men from the prospective, population-based Kuopio Ischaemic Heart Disease Risk Factor Study, aged 42-60 years and free of CVD at baseline in 1984-1989. ANCOVA and Cox regression models were used for the analyses. Whole serum desaturase activities were estimated as product:precursor ratios - γ-linolenic acid:linoleic acid for D6D and arachidonic acid:dihomo-γ-linolenic acid for D5D. Higher D6D activity was associated with higher systolic and diastolic blood pressure, BMI, serum insulin and TAG concentrations and worse homoeostatic model assessment (HOMA) indices. In contrast, higher D5D activity was associated with lower systolic and diastolic blood pressure, BMI, serum insulin, LDL-cholesterol, TAG and C-reactive protein concentrations, higher HDL-cholesterol concentration, and better HOMA indices. During the mean follow-up of 21·2 years, 202 stroke cases occurred. Neither D6D activity (multivariable-adjusted extreme-quartile hazard ratios (HR) 1·18; 95 % CI 0·80, 1·74) nor D5D activity (HR 1·06; 95 % CI 0·70, 1·60) were associated with stroke risk. In conclusion, higher D5D activity was favourably associated and higher D6D activity unfavourably associated with several stroke risk factors, but not with the risk of incident stroke.

Genomics of lactation: role of nutrigenomics and nutrigenetics in the fatty acid composition of human milk.

Human milk covers the infant's nutrient requirements during the first 6 months of life. The composition of human milk progressively changes during lactation and it is influenced by maternal nutritional factors. Nowadays, it is well known that nutrients have the ability to interact with genes and modulate molecular mechanisms impacting physiological functions. This has led to a growing interest among researchers in exploring nutrition at a molecular level and to the development of two fields of study: nutrigenomics, which evaluates the influence of nutrients on gene expression, and nutrigenetics, which evaluates the heterogeneous individual response to nutrients due to genetic variation. Fatty acids are one of the nutrients most studied in relation to lactation given their biologically important roles during early postnatal life. Fatty acids modulate transcription factors involved in the regulation of lipid metabolism, which in turn causes a variation in the proportion of lipids in milk. This review focuses on understanding, on the one hand, the gene transcription mechanisms activated by maternal dietary fatty acids and, on the other hand, the interaction between dietary fatty acids and genetic variation in genes involved in lipid metabolism. Both of these mechanisms affect the fatty acid composition of human milk.

A study of associations between early DHA status and fatty acid desaturase (FADS) SNP and developmental outcomes in children of obese mothers.

DHA from diet or endogenous synthesis has been proposed to affect infant development, however, results are inconclusive. In this study, we aim to verify previously observed fatty acid desaturase gene cluster (FADS) SNP-specific associations with erythrocyte DHA status in 9-month-old children and sex-specific association with developmental outcomes. The study was performed in 166 children (55 % boys) of obese mothers. Erythrocyte fatty acid composition was analysed in blood-samples obtained at 9 months of age, and developmental outcomes assessed by the Ages and Stages Questionnaire at 3 years. Erythrocyte DHA level ranged from 4·4 to 9·9 % of fatty acids, but did not show any association with FADS SNP or other potential determinants. Regression analysis showed associations between erythrocyte DHA and scores for personal-social skills (ß 1·8 (95 % CI 0·3, 3·3), P=0·019) and problem solving (ß 3·4 (95 % CI 1·2, 5·6), P=0·003). A tendency was observed for an association in opposite direction between minor alleles (G-variant) of rs1535 and rs174575 and personal-social skills (P=0·062 and 0·068, respectively), which became significant when the SNP were combined based on their previously observed effect on erythrocyte DHA at 9 months of age (ß 2·6 (95 % CI 0·01, 5·1), P=0·011). Sex-SNP interaction was indicated for rs174575 genotype on fine motor scores (P=0·016), due to higher scores among minor allele carrying girls (P=0·043), whereas no effect was seen among boys. In conclusion, DHA-increasing FADS SNP and erythrocyte DHA status were consistently associated with improved personal-social skills in this small cohort of children of obese mothers irrespective of sex, but the sample was too small to verify potential sex-specific effects.

Maternal fatty acid desaturase genotype correlates with infant immune responses at 6 months.

Breast milk long-chain PUFA (LCPUFA) have been associated with changes in early life immune responses and may modulate T-cell function in infancy. We studied the effect of maternal fatty acid desaturase (FADS) genotype and breast milk LCPUFA levels on infants' blood T-cell profiles and ex vivo-produced cytokines after anti-CD3/CD28 stimulation of peripheral blood mononuclear cells in 6-month-old infants from the Copenhagen Prospective Study of Asthma in Childhood birth cohort. LCPUFA concentrations of breast milk were assessed at 4 weeks of age, and FADS SNP were determined in both mothers and infants (n 109). In general, breast milk arachidonic acid (AA) levels were inversely correlated with the production of IL-10 (r -0.25; P=0.004), IL-17 (r -0.24; P=0.005), IL-5 (r -0.21; P=0.014) and IL-13 (r -0.17; P=0.047), whereas EPA was positively correlated with the counts of blood regulatory T-cells and cytotoxic T-cells and decreased T-helper cell counts. The minor FADS alleles were associated with lower breast milk AA and EPA, and infants of mothers carrying the minor allele of FADS SNP rs174556 had higher production of IL-10 (r -0.23; P=0.018), IL-17 (r -0.25; P=0.009) and IL-5 (r -0.21; P=0.038) from ex vivo-activated immune cells. We observed no association between T-cell distribution and maternal or infant FADS gene variants. We conclude that increased maternal LCPUFA synthesis and breast milk AA are associated with decreased levels of IL-5, IL-13 (type-2 related), IL-17 (type-17 related) and IL-10 (regulatory immune responses), but not with interferon-γ and TNF-α, which could be due to an effect of the maternal FADS variants on the offspring immune response transferred via breast milk LCPUFA.

Long-chain n-3 PUFA in vegetarian women: a metabolic perspective.

Vegetarian diets have been associated with health benefits, but paradoxically are low in EPA and DHA which are important for development, particularly of the central nervous system, and for health. Humans have limited capacity for synthesis of EPA and DHA from α-linolenic acid, although this is greater in women than men. Oily fish and, to a lesser extent, dairy foods and meat are the primary sources of EPA and DHA in the diet. Exclusion of these foods from the diet by vegetarians is associated consistently with lower EPA and DHA status in vegetarian women compared with omnivores. The purpose of the present review was to assess the impact of low EPA and DHA status in vegetarian pregnancies on the development and health of children. EPA and DHA status was lower in breast milk and in infants of vegetarian mothers than those born to omnivore mothers, which suggests that in the absence of pre-formed dietary EPA and DHA, synthesis from α-linolenic acid is an important process in determining maternal EPA and DHA status in pregnancy. However, there have been no studies that have investigated the effect of low maternal DHA status in vegetarians on cognitive function in children. It is important to address this gap in knowledge in order to be confident that vegetarian and vegan diets during pregnancy are safe in the context of child development.

The impact of fatty acid desaturase genotype on fatty acid status and cardiovascular health in adults.

The aim of this review was to determine the impact of the fatty acid desaturase (FADS) genotype on plasma and tissue concentrations of the long-chain (LC) n-3 PUFA, including EPA and DHA, which are associated with the risk of several diet-related chronic diseases, including CVD. In addition to dietary intakes, which are low for many individuals, tissue EPA and DHA are also influenced by the rate of bioconversion from α-linolenic acid (αLNA). Δ-5 and Δ-6 desaturase enzymes, encoded for by FADS1 and FADS2 genes, are key desaturation enzymes involved in the bioconversion of essential fatty acids (αLNA and linoleic acid (LA)) to longer chained PUFA. In general, carriers of FADS minor alleles tend to have higher habitual plasma and tissue levels of LA and αLNA, and lower levels of arachidonic acid, EPA and also to a lesser extent DHA. In conclusion, available research findings suggest that FADS minor alleles are also associated with reduced inflammation and CVD risk, and that dietary total fat and fatty acid intake have the potential to modify relationships between FADS gene variants and circulating fatty acid levels. However to date, neither the size-effects of FADS variants on fatty acid status, nor the functional SNP in FADS1 and 2 have been identified. Such information could contribute to the refinement and targeting of EPA and DHA recommendations, whereby additional LC n-3 PUFA intakes could be recommended for those carrying FADS minor alleles.

Plasma phospholipid EPA and DHA are divergently associated with overall mortality in newly diagnosed diabetic patients: results from a follow-up of the Nord-Trøndelag Health (HUNT) Study, Norway.

Data concerning the long-term effects of n-3 and n-6 PUFA on disease control and development of complications in diabetic patients are inconsistent. The relationship between plasma phospholipid PUFA and total mortality in type 2 diabetes is unknown. The present study aims to investigate the association between plasma phospholipid fatty acid relative concentrations expressed as weight percentage and total mortality in patients with type 2 diabetes. Mortality rates were evaluated at 5, 10, 15 and 20 years in patients with newly diagnosed diabetes (n 323) and matched non-diabetic controls (n 200) recruited from the Nord-Trøndelag Health (HUNT) Study, Norway. Kaplan-Meier survival curves were constructed and Cox regression analysis was used to calculate hazard ratios (HR) adjusted for biochemical and clinical covariates. After 10 years of follow-up, EPA in the diabetic population was negatively associated with total mortality, with an HR at the fifth quintile of 0·47 (95 % CI 0·25, 0·90) compared with the first quintile. In contrast, DHA was positively associated with total mortality, with an HR at the fifth quintile of 2·87 (95 % CI 1·45, 5·66). Neither EPA nor DHA was associated with total mortality in matched non-diabetic controls. In conclusion, plasma phospholipid relative concentrations of EPA were negatively associated, while those of DHA were positively associated with total mortality in diabetics. This difference in associations suggests a differential effect of EPA and DHA in patients with type 2 diabetes.