Erythrocyte polyunsaturated fatty acid composition is associated with depression and FADS genotype in Caucasians

Background: Polyunsaturated fatty acids (PUFAs) play an important role in the pathophysiology of major depressive disorder (MDD), related, in part, to their role in inflammatory systems. The enzymes δ-5 and δ-6 desaturase are the rate-limiting steps in the metabolism of PUFAs and are encoded in the genes fatty acid desaturase (FADS) 1 and 2, respectively. Single nucleotide polymorphisms (SNPs) and haplotypes within the FADS gene cluster have been shown to influence PUFA composition.

Aim: The objective of this study was to determine whether key omega-3 (n-3) and omega-6 (n-6) fatty acids may be associated with depression, and to explore the role of FADS genotype in PUFA variation.

Methods: Four erythrocyte long chain (LC) fatty acids (linoleic acid [LA], α-linolenic acid [ALA], arachidonic acid [AA] and Eicosapentaenoic acid [EPA]), as well as six SNPs (rs174537, rs174547, rs174570, rs174575, rs498793 and rs3834458) within the FADS gene cluster were measured in a sample of 207 participants (154 with MDD versus 53 non-depressed controls).

Results: The precursor LC-PUFAs LA and ALA appeared to be negatively associated with depression (P?P?0.01, respectively), while AA:LA (surrogate measure of desaturase activity) was positively associated with depression (P?0.01). No significant differences were noted in erythrocyte EPA, AA or AA:EPA between groups. Minor alleles of each SNP (excluding rs498793) were associated with variation in desaturase activity and LA. Both rs174537 and rs174547 were associated with ALA. No genotype was associated with EPA or AA. Minor alleles of rs174537 and rs174547 were significantly associated with lower odds of MDD (although significance was lost after correction for multiple comparisons).

Conclusion: Precursor LC-PUFAs, LA and ALA, appear to be associated with MDD and potentially modulated by genetic variation in the FADS gene cluster. These results provide support for the consideration of PUFA composition, diet and FADS genetic variation in the pathophysiology of MDD.     

Genetic variants of the FADS gene cluster are associated with erythrocyte membrane LC PUFA levels in patients with mild cognitive impairment

Background

Long-chain (> 20 C-atoms) polyunsaturated fatty acids (LC PUFAs) of both the omega-6 (n-6) and omega-3 (n-3) series are important for the functional integrity of brain and thereby cognition, memory and mood. Clinical studies observed associations between altered LC PUFA levels and neurodegenerative diseases such as Alzheimer´s disease and its prodromal stage, mild cognitive impairment (MCI).

Methods

The present study examined the LC PUFA status of MCI patients with specific view on the relative LC n-3 PUFA levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in erythrocyte membranes (omega-3 index). 12 single nucleotide polymorphisms (SNPs) of the FADS1, FADS2, and FADS3 gene clusters were genotyped in 111 MCI patients and evaluated associations with PUFA levels in erythrocyte membranes (primary outcome). In addition, the associations between FADS SNPs and LC PUFA levels with serum lipid levels as well as depressive symptoms were examined (secondary outcomes).

Results

Minor allele carrier of rs174546, rs174548 (FADS1), rs3834458, rs1535, rs174574, rs174575, rs174576, and rs174578 (FADS2) showed significant higher n-6 and n-3 precursor PUFA levels (linoleic acid, and alpha-linolenic acid, respectively) and lower arachidonic acid (AA) levels in erythrocyte membranes compared to the major allele carriers. Differences in EPA and DHA levels were not significant. Minor allele carriers of rs174574, rs174576 and rs174578 (FADS2) and rs174455 (FADS3) exhibited significant higher triglyceride levels, whereas minor allele carriers for rs174449 and rs174455 (FADS3) exhibited significant higher total- and LDL-cholesterol levels compared to the more common variant. The mean omega-3 index of the study cohort was 6.19 ± 1.55 %. In more than 85 % of the patients, the omega-3 index was below 8 % and in 23 % below 5 %. Moreover, it was shown that a low DHA status and omega-3 index was associated with depressive symptoms (Beck’s depression-inventory).

Discussion and conclusion

These findings indicate an association between several FADS genotypes for higher n-6 and n-3 precursor PUFA and lower AA levels in erythrocyte membranes in minor compared to major allele carriers. To what extent FADS genotypes and a lower conversion of LA and ALA to biologically important LC PUFAs such as AA, EPA and DHA contributes to cognitive decline should be investigated in further trials. Nevertheless, the omega-3 index in this cohort of MCI patients can be classified as insufficient.

     

Investigation of Maternal Diet and FADS1 Polymorphism Associated with Long-Chain Polyunsaturated Fatty Acid Compositions in Human Milk

Increasing the amount of long-chain polyunsaturated fatty acids (LCPUFA) in human milk is an important strategy for infant growth and development. We investigated the associations of LCPUFA compositions in human milk with maternal diet (especially fish and shellfish intake), with fatty acid Δ5 desaturase gene (FADS1) polymorphisms, and with gene-diet interactions. The present study was performed as part of an adjunct study of the Japan Environment and Children’s Study. The participants were 304 lactating females, who provided human milk 6–7 months after delivery. Fatty acids in human milk were analyzed by gas chromatography, and dietary surveys were conducted using a brief self-administered diet history questionnaire. We also analyzed a single nucleotide polymorphism of FADS1 (rs174547, T/C). There was a significant difference in arachidonic acid (ARA) composition in human milk among the genotype groups, and the values were decreasing in the order of TT > TC > CC. The concentrations of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were also different between TT and CC genotype, indicating a tendency for decreasing values in the same order. The composition of ARA showed significant gene–dietary interactions in multiple regression analysis, and the positive correlation between fish and shellfish intake and ARA composition in human milk was significant only in the CC genotype. Moreover, the factor most strongly associated with EPA and DHA composition in human milk was fish and shellfish intake. Therefore, it was suggested that increasing fish and shellfish intake in mothers may increase EPA and DHA composition in human milk, while increasing fish and shellfish intake in CC genotype mothers may lead to increased ARA composition in human milk.     

Decreasing linoleic acid with constant alpha-linolenic acid in dietary fats increases (n-3) eicosapentaenoic acid in plasma phospholipids in healthy men

High linoleic acid (LA) intakes have been suggested to reduce alpha-linolenic acid [ALA, 18:3(n-3)] metabolism to eicosapentaenoic acid [EPA, 20:5(n-3)] and docosahexaenoic acid [DHA, 22:6(n-3)], and favor high arachidonic acid [ARA, 20:4(n-6)]. We used a randomized cross-over study with men (n = 22) to compare the effect of replacing vegetable oils high in LA with oils low in LA in foods, while maintaining constant ALA, for 4 wk each, on plasma (n-3) fatty acids. Nonvegetable sources of fat, except fish and seafoods, were unrestricted. We determined plasma phospholipid fatty acids at wk 0, 2, 4, 6, and 8, and triglycerides, cholesterol, serum CRP, and IL-6, and platelet aggregation at wk 0, 4, and 8. LA and ALA intakes were 3.8 +/- 0.12% and 1.0 +/- 0.05%, and 10.5 +/- 0.53% and 1.1 +/- 0.06% energy with LA:ALA ratios of 4:0 and 10:1 during the low and high LA diets, respectively. The plasma phospholipid LA was higher and EPA was lower during the high than during the low LA diet period (P < 0.001), but DHA declined over the 8-wk period (r = -0.425, P < 0.001). The plasma phospholipid ARA:EPA ratios were (mean +/- SEM) 20.7 +/- 1.52 and 12.9 +/- 1.01 after 4 wk consuming the high or low LA diets, respectively (P < 0.001); LA was inversely associated with EPA (r = -0.729, P < 0.001) but positively associated with ARA:EPA (r = 0.432, P < 0.001). LA intake did not influence ALA, ARA, DPA, DHA, or total, LDL or HDL cholesterol, CRP or IL-6, or platelet aggregation. In conclusion, high LA intakes decrease plasma phospholipid EPA and increase the ARA:EPA ratio, but do not favor higher ARA.     

FADS1 and FADS2 Gene Polymorphisms Modulate the Relationship of Omega-3 and Omega-6 Fatty Acid Plasma Concentrations in Gestational Weight Gain: A NISAMI Cohort Study

The polymorphisms of fatty acid desaturase genes FADS1 and FADS2 have been associated with an increase in weight gain. We investigated FADS1 and FADS2 gene polymorphisms and the relation between ω-3 and ω-6 fatty acid plasma concentrations and gestational weight gain. A prospective cohort study of 199 pregnant women was followed in Santo Antônio de Jesus, Brazil. Plasma levels of polyunsaturated fatty acids (PUFAs) were measured at baseline and gestational weight gain during the first, second, and third trimesters. Fatty acid recognition was carried out with the aid of gas chromatography. Single nucleotide polymorphisms (SNPs) were genotyped using real-time PCR. Statistical analyses included Structural Equation Modelling. A direct effect of FADS1 and FADS2 gene polymorphisms on gestational weight was observed; however, only the SNP rs174575 (FADS2) showed a significant positive direct effect on weight over the course of the pregnancy (0.106; p = 0.016). In terms of the influence of SNPs on plasma levels of PUFAs, it was found that SNP rs174561 (FADS1) and SNP rs174575 (FADS2) showed direct adverse effects on plasma concentrations of ω-3 (eicosapentaenoic acid and alpha-linoleic acid), and only SNP rs174575 had positive direct effects on plasma levels of ARA and the ARA/LA (arachidonic acid/linoleic acid) ratio, ω-6 products, while the SNP rs3834458 (FADS2) had an adverse effect on plasma concentrations of EPA, leading to its increase. Pregnant women who were heterozygous and homozygous for the minor allele of the SNP rs3834458 (FADS2), on the other hand, showed larger concentrations of series ω-3 substrates, which indicates a protective factor for women’s health.     

Highly unsaturated (n-3) fatty acids, but not alpha-linolenic, conjugated linoleic or gamma-linolenic acids, reduce tumorigenesis in Apc(Min/+) mice

We showed previously that dietary eicosapentaenoic acid [EPA, 20:5(n-3)] is antitumorigenic in the APC:(Min/+) mouse, a genetic model of intestinal tumorigenesis. Only a few studies have evaluated the effects of dietary fatty acids, including EPA and docosahexaenoic acid [DHA, 22:6(n-3)], in this animal model and none have evaluated the previously touted antitumorigenicity of alpha-linolenic acid [ALA, 18:3(n-3)], conjugated linoleic acid [CLA, 77% 18:2(n-7)], or gamma-linolenic acid [GLA, 18:3(n-6)]. Stearidonic acid [SDA, 18:4(n-3)], the Delta6-desaturase product of ALA, which is readily metabolized to EPA, has not been evaluated previously for antitumorigenic efficacy. This study was undertaken to evaluate the antitumorigenicity of these dietary fatty acids (ALA, SDA, EPA, DHA, CLA and GLA) compared with oleic acid [OA, 18:1(n-9)] at a level of 3 g/100 g in the diets of APC:(Min/+) mice and to determine whether any alterations in tumorigenesis correspond to alterations in prostaglandin biosynthesis. Tumor multiplicity was significantly lower by approximately 50% in mice fed SDA or EPA compared with controls, whereas less pronounced effects were observed in mice fed DHA (P: = 0.15). ALA, CLA and GLA were ineffective at the dose tested. Although lower tumor numbers coincided with significantly lower prostaglandin levels in SDA- and EPA-fed mice, ALA and DHA supplementation resulted in equally low prostaglandin levels, despite proving less efficacious with regard to tumor number. Prostaglandin levels did not differ significantly in the CLA and GLA groups compared with controls. These results suggest that SDA and EPA attenuate tumorigenesis in this model and that this effect may be related in part to alterations in prostaglandin biosynthesis.     

Using a fingertip whole blood sample for rapid fatty acid measurement: method validation and correlation with erythrocyte polar lipid compositions in UK subjects

It is well accepted that n-3 long-chain PUFA intake is positively associated with a range of health benefits. However, while benefits have been clearly shown, especially for CVD, the mechanisms for prevention/benefit are less understood. Analysis of plasma and erythrocyte phospholipids (PL) have been used to measure the status of the highly unsaturated fatty acids (HUFA), especially EPA (20 : 5n-3) and DHA (22 : 6n-3), although the time and complexity of the process places limitations on the sample numbers analysed. An assay has been developed using whole blood, collected by finger prick, and stored on absorbant paper, subjected to direct methylation and fatty acids quantified by automated GC. Tests on fatty acid stability show that blood samples are stable when stored at - 20°C for 1 month although some loss of HUFA was seen at 4°C. A total of fifty-one patients, including twenty-seven who consumed no fatty acid supplements, provided a blood sample for analysis. Concentrations of all major fatty acids were measured in erythrocyte PL and whole blood. The major HUFA, including EPA, DHA and arachidonic acid (ARA; 20 : 4n-6), as well as the ARA:EPA ratio and the percentage n-3 HUFA/total HUFA all showed good correlations, between erythrocyte PL and whole blood. Values of r2 ranged from 0.48 for ARA to 0.95 for the percentage of n-3 HUFA/total HUFA. This assay provides a non-invasive, rapid and reliable method of HUFA quantification with the percentage of n-3 HUFA value providing a potential blood biomarker for large-scale nutritional trials.     

脂肪酸去饱和酶基因多态性对儿童脂肪酸构成和认知记忆的影响

目的探讨脂肪酸去饱和酶（FADS）多态性对学龄儿童红细胞膜多不饱和脂肪酸(PUFAs)构成和认知记忆的影响。方法对参与补充DHA随机对照试验的8～12岁的南雄市坪田镇小学生进行基线问卷调查收集一般情况、膳食资料、体格测量并采集空腹血。采用数字广度测试和威斯康星卡片分类测试评估认知记忆功能。测定红细胞膜脂肪酸构成,提取血凝块DNA进行FADS4个位点的多态性分析。结果共调查106名三至五年级在校小学生,男生62人,女生44人,平均年龄为（9.17±1.03）岁。不同红细胞膜DHA的含量构成的调查对象认知记忆功能差异无统计学意义（均P＞0.05）。FADS的4个位点相互间符合H-W平衡（0.409～0.970）。FADS rs174561基因型不同C18∶2、C18∶3（n-6）、C20∶5、总n-3、AA/LA、EPA/ALA的比例差异有统计学意义（P＜0.01或P＜0.05）。混合线性模型分析结果发现,完成分类数、概念化水平数、概念化水平mm+Mm基因型者高于MM基因型者（均P＜0.05）,mm+Mm基因型者总错误数和总错误率低于MM基因型者（均P＜0.05）。结论FADS多态性可影响学龄儿童体内PUFAs构成和认知记忆功能。     

Supplementing lactating women with flaxseed oil does not increase docosahexaenoic acid in their milk

BACKGROUND: Flaxseed oil is a rich source of 18:3n-3 (alpha-linolenic acid, or ALA), which is ultimately converted to 22:6n-3 (docosahexaenoic acid, or DHA), a fatty acid important for the development of the infant brain and retina. OBJECTIVE: The objective of this study was to determine the effect of flaxseed oil supplementation on the breast-milk, plasma, and erythrocyte contents of DHA and other n-3 fatty acids in lactating women. DESIGN: Seven women took 20 g flaxseed oil (10.7 g ALA) daily for 4 wk. Breast-milk and blood samples were collected weekly before, during, and after supplementation and were analyzed for fatty acid composition. RESULTS: Breast milk, plasma, and erythrocyte ALA increased significantly over time (P < 0.001) and after 2 and 4 wk of supplementation (P < 0.05). Over time, 20:5n-3 (eicosapentaenoic acid, or EPA) increased significantly in breast milk (P = 0.004) and in plasma (P < 0.001). In addition, plasma EPA increased significantly (P < 0.05) after 2 and 4 wk of supplementation. There were significant increases over time in breast-milk 22:5n-3 (docosapentaenoic acid, or DPA) (P < 0.02), plasma DPA (P < 0.001), and erythrocyte DPA (P < 0.01). No significant changes were observed in breast-milk, plasma, or erythrocyte DHA contents after flaxseed oil supplementation. CONCLUSIONS: Dietary flaxseed oil increased the breast-milk, plasma, and erythrocyte contents of the n-3 fatty acids ALA, EPA, and DPA but had no effect on breast-milk, plasma, or erythrocyte DHA contents.     

Persistent changes in the fatty acid composition of erythrocyte membranes after moderate intake of n-3 polyunsaturated fatty acids: study design implications.

To examine the incorporation of n-3 polyunsaturated fatty acids (PUFAs) into erythrocyte membranes during and after moderate n-3 PUFA intake, 12 healthy men were fed three diets for 6-wk periods in a 3 x 3 crossover design, supplying different amounts of eicosapentaenoic acid (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3): a control diet, a fish diet (0.15 g EPA/d, 0.41 g DHA/d), and a fish + oil diet (5 g fish oil/d; 0.99 g EPA/d and 0.99 g DHA/d). A 6-wk washout period was allowed between diets. Between 6 and 12 wk after the fish + oil diet, erythrocyte EPA and DHA were still declining and it was only after 18 wk that erythrocyte EPA had returned to baseline whereas DHA had not. Investigators examining variables that are influenced by altered membrane fatty acid composition should be aware of these prolonged effects when designing studies. Protracted washout periods (greater than 18 wk) make the classic crossover design prohibitive and a parallel design becomes essential.     

Differences in arachidonic acid levels and fatty acid desaturase (FADS) gene variants in African Americans and European Americans with diabetes or the metabolic syndrome

Over the past 50 years, increases in dietary n-6 PUFA, such as linoleic acid, have been hypothesised to cause or exacerbate chronic inflammatory diseases. The present study examines an individual's innate capacity to synthesise n-6 long-chain PUFA (LC-PUFA) with respect to the fatty acid desaturase (FADS) locus in Americans of African and European descent with diabetes or the metabolic syndrome. Compared with European Americans (EAm), African Americans (AfAm) exhibited markedly higher serum levels of arachidonic acid (AA) (EAm 7·9 (sd 2·1), AfAm 9·8 (sd 1·9) % of total fatty acids; P < 2·29 × 10??) and the AA:n-6-precursor fatty acid ratio, which estimates FADS1 activity (EAm 5·4 (sd 2·2), AfAm 6·9 (sd 2·2); P = 1·44 × 10??). In all, seven SNP mapping to the FADS locus revealed strong association with AA, EPA and dihomo-γ-linolenic acid (DGLA) in the EAm. Importantly, EAm homozygous for the minor allele (T) had significantly lower AA levels (TT 6·3 (sd 1·0); GG 8·5 (sd 2·1); P = 3·0 × 10??) and AA:DGLA ratios (TT 3·4 (sd 0·8), GG 6·5 (sd 2·3); P = 2·2 × 10??) but higher DGLA levels (TT 1·9 (sd 0·4), GG 1·4 (sd 0·4); P = 3·3 × 10??) compared with those homozygous for the major allele (GG). Allele frequency patterns suggest that the GG genotype at rs174537 (associated with higher circulating levels of AA) is much higher in AfAm (0·81) compared with EAm (0·46). Similarly, marked differences in rs174537 genotypic frequencies were observed in HapMap populations. These data suggest that there are probably important differences in the capacity of different populations to synthesise LC-PUFA. These differences may provide a genetic mechanism contributing to health disparities between populations of African and European descent.     

Essential and long-chain polyunsaturated fatty acid status and fatty acid composition of breast milk of lactating adolescents

The aims of the present study were to evaluate essential fatty acids (EFA) and long-chain PUFA (LCPUFA) status in lactating adolescents and its association with breast milk composition. Healthy nursing adolescents from Rio de Janeiro, Brazil (n 30; 14-19 years; 30-120 d postpartum), exclusively or predominantly breast-feeding, participated in this study. Breast milk and blood samples were collected after overnight fasting. Fatty acid composition of breast milk, erythrocyte membrane (EM) and plasma NEFA were determined by GC. Indices of fatty acid status (mean melting point (MMP); EFA status index; DHA status indices, 22 : 5n-6:22 : 4n-6 and 22 : 6n-3:22 : 5n-6 ratios) were calculated from EM fatty acid composition. Dietary intake of n-3 fatty acids was low when compared with current recommendations for lactating women. MMP was associated with indices of DHA status, some individual fatty acids in EM and years post-menarche and weeks postpartum, suggesting the use of erythrocyte MMP as a possible comprehensive biochemical marker of LCPUFA status in this physiological condition. The DHA status of lactating adolescents and their milk DHA concentrations were similar to the values of Brazilian lactating adults, but lower compared with the values of lactating adults from other countries. Therefore, these lactating adolescents were apparently not disadvantaged, as compared with the Brazilian adults, when EM and breast milk fatty acid composition were considered. In general, PUFA in milk from adolescents presented few associations with their concentrations in plasma NEFA and with maternal status. However, milk DHA was associated with maternal LCPUFA and DHA states.     

Ethnic differences in early pregnancy maternal n-3 and n-6 fatty acid concentrations: an explorative analysis

Ethnicity-related differences in maternal n-3 and n-6 fatty acid status may be relevant to ethnic disparities in birth outcomes observed worldwide. The present study explored differences in early pregnancy n-3 and n-6 fatty acid composition of maternal plasma phospholipids between Dutch and ethnic minority pregnant women in Amsterdam, the Netherlands, with a focus on the major functional fatty acids EPA (20 : 5n-3), DHA (22 : 6n-3), dihomo-gamma-linolenic acid (DGLA; 20 : 3n-6) and arachidonic acid (AA; 20 : 4n-6). Data were derived from the Amsterdam Born Children and their Development (ABCD) cohort (inclusion January 2003 to March 2004). Compared with Dutch women (n 2443), Surinamese (n 286), Antillean (n 63), Turkish (n 167) and Moroccan (n 241) women had generally lower proportions of n-3 fatty acids (expressed as percentage of total fatty acids) but higher proportions of n-6 fatty acids (general linear model; P < 0.001). Ghanaian women (n 54) had higher proportions of EPA and DHA, but generally lower proportions of n-6 fatty acids (P < 0.001). Differences were most pronounced in Turkish and Ghanaian women, who, by means of a simple questionnaire, reported the lowest and highest fish consumption respectively. Adjustment for fish intake, however, hardly attenuated the differences in relative EPA, DHA, DGLA and AA concentrations between the various ethnic groups. Given the limitations of this observational study, further research into the ethnicity-related differences in maternal n-3 and n-6 fatty acid patterns is warranted, particularly to elucidate the explanatory role of fatty acid intake v. metabolic differences.     

Flaxseed oil and fish-oil capsule consumption alters human red blood cell n-3 fatty acid composition: a multiple-dosing trial comparing 2 sources of n-3 fatty acid

BACKGROUND: An increase in plasma n-3 fatty acid content, particularly eicosapentaenoic acid (20:5n-3; EPA) and docosahexaenoic acid (22:6n-3; DHA), is observed after consumption of fish oil-enriched supplements. Because alpha-linolenic acid (18:3n-3; ALA) is the direct precursor of EPA and DHA, ALA-enriched supplements such as flax may have a similar effect, although this hypothesis has been challenged because of reported low conversion of ALA into DHA. OBJECTIVE: To address this question, we designed a clinical trial in which flax oil, fish-oil, and sunflower oil (placebo group) capsules were given to firefighters (n = 62), a group traditionally exposed to cardiovascular disease risk factors. DESIGN: Firefighters were randomly divided into 6 experimental groups receiving 1.2, 2.4, or 3.6 g flax oil/d; 0.6 or 1.2 g fish oil/d; or 1 g sunflower oil/d for 12 wk. Blood was drawn every 2 wk, and the total phospholipid fatty acid composition of red blood cells was determined. RESULTS: As expected, fish oil produced a rapid increase in erythrocyte DHA and total n-3 fatty acids. The consumption of either 2.4 or 3.6 g flax oil/d (in capsules) was sufficient to significantly increase erythrocyte total phospholipid ALA, EPA, and docosapentaenoic acid (22:5n-3) fatty acid content. There were no differences among groups in plasma inflammatory markers or lipid profile. CONCLUSIONS: The consumption of ALA-enriched supplements for 12 wk was sufficient to elevate erythrocyte EPA and docosapentaenoic acid content, which shows the effectiveness of ALA conversion and accretion into erythrocytes. The amounts of ALA required to obtain these effects are amounts that are easily achieved in the general population by dietary modification.     

Metabolism of stearidonic acid in human subjects: comparison with the metabolism of other n-3 fatty acids

BACKGROUND: For many persons who wish to obtain the health benefits provided by dietary n-3 fatty acids, daily ingestion of fish or fish oil is not a sustainable long-term approach. To increase the number of sustainable dietary options, a land-based source of n-3 fatty acids that is effective in increasing tissue concentrations of the long-chain n-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) is required. OBJECTIVE: The objective of the study was to examine the ability of dietary stearidonic acid (SDA) to increase tissue concentrations of EPA and DHA in healthy human subjects and to compare the effectiveness of SDA with that of the n-3 fatty acids alpha-linolenic acid (ALA) and EPA. DESIGN: Encapsulated SDA, ALA, or EPA was ingested daily in doses of 0.75 g and then 1.5 g for periods of 3 wk each by healthy male and postmenopausal female subjects (n = 15/group) in a double-blind, parallel-group design. RESULTS: Dietary SDA increased EPA and docosapentaenoic acid concentrations but not DHA concentrations in erythrocyte and in plasma phospholipids. The relative effectiveness of the tested dietary fatty acids in increasing tissue EPA was 1:0.3:0.07 for EPA:SDA:ALA. CONCLUSIONS: Vegetable oils containing SDA could be a dietary source of n-3 fatty acids that would be more effective in increasing tissue EPA concentrations than are current ALA-containing vegetable oils. The use of SDA-containing oils in food manufacture could provide a wide range of dietary alternatives for increasing tissue EPA concentrations.     

Dietary supplementation with eicosapentaenoic acid, but not with other long-chain n-3 or n-6 polyunsaturated fatty acids, decreases natural killer cell activity in healthy subjects aged >55 y

BACKGROUND: Animal studies showed that dietary flaxseed oil [rich in the n-3 polyunsaturated fatty acid alpha-linolenic acid (ALA)], evening primrose oil [rich in the n-6 polyunsaturated fatty acid gamma-linolenic acid (GLA)], and fish oil [rich in the long-chain n-3 polyunsaturated fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)] can decrease natural killer (NK) cell activity. There have been no studies of the effect on NK cell activity of adding these oils to the diet of humans. OBJECTIVE: Our objective was to determine the effect of dietary supplementation with oil blends rich in ALA, GLA, arachidonic acid (AA), DHA, or EPA plus DHA (fish oil) on the NK cell activity of human peripheral blood mononuclear cells. DESIGN: A randomized, placebo-controlled, double-blind, parallel study was conducted. Healthy subjects aged 55-75 y consumed 9 capsules/d for 12 wk; the capsules contained placebo oil (an 80:20 mix of palm and sunflower seed oils) or blends of placebo oil and oils rich in ALA, GLA, AA, DHA, or EPA plus DHA. Subjects in these groups consumed 2 g ALA, 770 mg GLA, 680 mg AA, 720 mg DHA, or 1 g EPA plus DHA (720 mg EPA + 280 mg DHA) daily, respectively. Total fat intake from the capsules was 4 g/d. RESULTS: The fatty acid composition of plasma phospholipids changed significantly in the GLA, AA, DHA, and fish oil groups. NK cell activity was not significantly affected by the placebo, ALA, GLA, AA, or DHA treatment. Fish oil caused a significant reduction (mean decline: 48%) in NK cell activity that was fully reversed by 4 wk after supplementation had ceased. CONCLUSION: A moderate amount of EPA but not of other n-6 or n-3 polyunsaturated fatty acids can decrease NK cell activity in healthy subjects.     

Mechanisms of action of (n-3) fatty acids

(n-3) PUFA are a family of biologically active fatty acids. The simplest member of this family, α-linolenic acid, can be converted to the more biologically active very long-chain (n-3) PUFA EPA and DHA; this process occurs by a series of desaturation and elongation reactions, with stearidonic acid being an intermediate in the pathway. Biological activity of α-linolenic and stearidonic acids most likely relates to their conversion to EPA. The very long-chain (n-3) PUFA have a range of physiological roles that relate to optimal cell membrane structure and optimal cell function and responses. Thus, (n-3) PUFA play a key role in preventing, and perhaps treating, many conditions of poor health and well-being. The multiple actions of (n-3) PUFA appear to involve multiple mechanisms that connect the cell membrane, the cytosol, and the nucleus. For some actions, (n-3) PUFA appear to act via receptors or sensors, so regulating signaling processes that influence patterns of gene expression. Some effects of (n-3) PUFA seem to involve changes in cell membrane fatty acid composition. Changing membrane composition can in turn affect membrane order, formation of lipid rafts, intracellular signaling processes, gene expression, and the production of both lipid and peptide mediators. Under typical Western dietary conditions, human cells tend to have a fairly high content of the (n-6) fatty acid arachidonic acid. Increased oral intake of EPA and DHA modifies the content of arachidonic acid as well as of EPA and DHA. Arachidonic acid is the substrate for eicosanoids involved in physiology and pathophysiology. The eicosanoids produced from EPA frequently have properties that are different from those that are produced from arachidonic acid. EPA and DHA are also substrates for production of resolvins and protectins, which seem to be biologically extremely potent. Increasing the contents of EPA and DHA in membranes modifies the pattern of production of these different lipid mediators.     

Effects of n-3 polyunsaturated fatty acid supplementation in pregnancy on maternal and fetal erythrocyte fatty acid composition

OBJECTIVE: The aim of this study was to assess the effects of fish oil supplementation in pregnancy on maternal erythrocyte fatty acid composition at different stages of pregnancy and in the post-partum period, and on neonatal erythrocyte fatty acid composition. DESIGN: A double-blind, randomised, placebo-controlled study. SETTING:: Subiaco, Western Australia. SUBJECTS: In all, 98 women booked for delivery at St John of God Hospital, Subiaco, were recruited from private rooms of obstetricians. In total, 83 women and their healthy full-term babies completed the study. INTERVENTION: Women received either 4 g of fish oil (n=52) (56% docosahexaenoic acid (DHA) and 28% eicosapentaenoic acid (EPA) or placebo (olive oil) (n=46) per day from 20 weeks gestation until delivery. MAIN OUTCOME MEASURES: Erythrocyte phospholipid fatty acids were measured in maternal peripheral blood at 20, 30 and 37 weeks of pregnancy and at 6 weeks post partum, and from cord blood collected at birth. RESULTS: Compared to the control group, maternal EPA and DHA were significantly higher in the fish oil group at 30 and 37 weeks gestation, and remained elevated at 6 weeks post partum (P<0.001). The proportions of n-6 polyunsaturated (arachidonic acid, 22:3n-6 and 22:4n-6) were significantly lower in the fish oil supplemented group at the same time periods (P<0.001). Similarly, the proportions of EPA and DHA were significantly higher (P<0.001), and those of n-6 polyunsaturated fatty acids arachidonic acid, 20:3n-6, 22:3n-6 and 22:4n-6 were significantly lower (P<0.001), in erythrocytes from neonates in the fish oil group, compared to those in the control group. CONCLUSION: Fish oil supplementation from 20 weeks of pregnancy until birth is an effective means of enhancing n-3 fatty acid status of both mothers and neonates. Furthermore, the changes in maternal erythrocyte fatty acid composition are retained until at least 6 weeks post partum. It is essential to assess the effects of concomitant decreases in arachidonic acid status before any dietary recommendations can be made. SPONSORSHIP: The study was supported by grants from the NH & MRC and Raine Medical Research Foundation, Australia.     

Efficacy and safety of docosahexaenoic acid and arachidonic acid addition to infant formulas: can one buy better vision and intelligence?

Long chain polyunsaturated fatty acids (LCPUFA) namely arachidonic acid (ARA, 20:4n-6) and docosahexaenoic acid (DHA, 22:6n-3) are highly concentrated in the phospholipid bilayer of biologically active brain and retinal neural membranes and are important in phototransduction and neuronal function. The rationale for adding these LCPUFA to infant formula (IF) was primarily because of their presence in large quantities in the retina and brain and in human milk. In addition, infants fed IF containing LCPUFA and breastfed infants have comparable ARA and DHA levels in red cell and plasma, in contrast to the lower ARA and DHA levels in those fed IF containing only the essential fatty acids: linoleic (LA, 18:2n-6) and linolenic (LNA, 18:3n-3), the precursors to ARA and DHA, respectively. However, functional benefits in particular visual or neural development from IF containing LCPUFA remains controversial. Potential for excessive and/or imbalanced intake of n-6 and n-3 fatty acids exists with increasing fortification of LCPUFA to infant foods other than IF.