The Benefits and Risks of n-3 Polyunsaturated Fatty Acids

There is a growing number of animal models and clinical trials of n-3 polyunsaturated fatty acid (PUFAs) supplementation in disease. Epidemiologic and biochemical studies have suggested beneficial effects of n-3 PUFAs. But also, the use of n-3 PUFAs has some potential toxicological risks that can be circumvented by careless processing, storing, and preserving the PUFAs. The use of n-3 PUFAs is safe if appropriate preparations and dosages are selected. Much research is needed to clarify their use under different disease conditions. The newly established clinical and nutritional facts on n-3 PUFAs will induce industry to develop food products based on this knowledge.     

Long-Term Risk of Incident Type 2 Diabetes and Measures of Overall and Regional Obesity: The EPIC-InterAct Case-Cohort Study

Background

Waist circumference (WC) is a simple and reliable measure of fat distribution that may add to the prediction of type 2 diabetes (T2D), but previous studies have been too small to reliably quantify the relative and absolute risk of future diabetes by WC at different levels of body mass index (BMI).

Methods and Findings

The prospective InterAct case-cohort study was conducted in 26 centres in eight European countries and consists of 12,403 incident T2D cases and a stratified subcohort of 16,154 individuals from a total cohort of 340,234 participants with 3.99 million person-years of follow-up. We used Prentice-weighted Cox regression and random effects meta-analysis methods to estimate hazard ratios for T2D. Kaplan-Meier estimates of the cumulative incidence of T2D were calculated. BMI and WC were each independently associated with T2D, with WC being a stronger risk factor in women than in men. Risk increased across groups defined by BMI and WC; compared to low normal weight individuals (BMI 18.5–22.4 kg/m²) with a low WC (<94/80 cm in men/women), the hazard ratio of T2D was 22.0 (95% confidence interval 14.3; 33.8) in men and 31.8 (25.2; 40.2) in women with grade 2 obesity (BMI≥35 kg/m²) and a high WC (>102/88 cm). Among the large group of overweight individuals, WC measurement was highly informative and facilitated the identification of a subgroup of overweight people with high WC whose 10-y T2D cumulative incidence (men, 70 per 1,000 person-years; women, 44 per 1,000 person-years) was comparable to that of the obese group (50–103 per 1,000 person-years in men and 28–74 per 1,000 person-years in women).

Conclusions

WC is independently and strongly associated with T2D, particularly in women, and should be more widely measured for risk stratification. If targeted measurement is necessary for reasons of resource scarcity, measuring WC in overweight individuals may be an effective strategy, since it identifies a high-risk subgroup of individuals who could benefit from individualised preventive action. Please see later in the article for the Editors'' Summary     

Genome-Wide Association Study of Plasma Polyunsaturated Fatty Acids in the InCHIANTI Study

Polyunsaturated fatty acids (PUFA) have a role in many physiological processes, including energy production, modulation of inflammation, and maintenance of cell membrane integrity. High plasma PUFA concentrations have been shown to have beneficial effects on cardiovascular disease and mortality. To identify genetic contributors of plasma PUFA concentrations, we conducted a genome-wide association study of plasma levels of six omega-3 and omega-6 fatty acids in 1,075 participants in the InCHIANTI study on aging. The strongest evidence for association was observed in a region of chromosome 11 that encodes three fatty acid desaturases (FADS1, FADS2, FADS3). The SNP with the most significant association was rs174537 near FADS1 in the analysis of arachidonic acid (AA; p=5.95×10⁻⁴⁶). Minor allele homozygotes had lower AA compared to the major allele homozygotes and rs174537 accounted for 18.6% of the additive variance in AA concentrations. This SNP was also associated with levels of eicosadienoic acid (EDA; p=6.78×10⁻⁹) and eicosapentanoic acid (EPA; p=1.07×10⁻¹⁴). Participants carrying the allele associated with higher AA, EDA, and EPA also had higher low-density lipoprotein (LDL-C) and total cholesterol levels. Outside the FADS gene cluster, the strongest region of association mapped to chromosome 6 in the region encoding an elongase of very long fatty acids 2 (ELOVL2). In this region, association was observed with EPA (rs953413; p=1.1×10⁻⁶). The effects of rs174537 were confirmed in an independent sample of 1,076 subjects participating in the GOLDN study. The ELOVL2 SNP was associated with docosapentanoic and DHA but not with EPA in GOLDN. These findings show that polymorphisms of genes encoding enzymes in the metabolism of PUFA contribute to plasma concentrations of fatty acids.     

膳食中高n-6/n-3多不饱和脂肪酸比值对小鼠肠道菌群的影响

目的:探讨小鼠膳食中高n-6/n-3多不饱和脂肪酸比值对肠道菌群的影响。方法:随机选取健康的30只C57/B6小鼠分为对照组(基础饲料)、花生四烯酸组(基础饲料+10%花生四烯酸)、鱼油组(基础饲料+10%鱼油)。喂食16周,16周后提取小鼠肠道菌群宏基因组DNA,采用Roche 454测序技术对肠道菌群16Sr RNA基因V3-V5区域进行测序,对菌群的组成结构以及含量的变化进行分析。结果:花生四烯酸组小鼠体内厚壁菌门的含量达到(55.3±5.26)%,与对照组小鼠体内厚壁菌门的含量(30.23±8.75)%相比显著性升高(P0.05)。并且花生四烯酸组小鼠体内变形菌门的含量(3±0.762)%与对照组(1.5±0.265)%相比也显著性上升(P0.05)。结论:膳食中高n-6/n-3多不饱和脂肪酸比值会造成小鼠体内肠道菌群组成结构的失衡,导致厚壁菌门以及变形菌门的含量上升。     

High Levels of Both n-3 and n-6 Long-Chain Polyunsaturated Fatty Acids in Cord Serum Phospholipids Predict Allergy Development

Background

Long-chain polyunsaturated fatty acids (LCPUFAs) reduce T-cell activation and dampen inflammation. They might thereby counteract the neonatal immune activation and hamper normal tolerance development to harmless environmental antigens. We investigated whether fatty acid composition of cord serum phospholipids affects allergy development up to age 13 years.

Methods

From a population-based birth-cohort born in 1996/7 and followed until 13 years of age (n = 794), we selected cases with atopic eczema (n = 37) or respiratory allergy (n = 44), as well as non-allergic non-sensitized controls (n = 48) based on diagnosis at 13 years of age. Cord and maternal sera obtained at delivery from cases and controls were analysed for proportions of saturated, monounsaturated and polyunsaturated fatty acids among serum phospholipids.

Results

The cord serum phospholipids from subject who later developed either respiratory allergy or atopic eczema had significantly higher proportions of 5/8 LCPUFA species, as well as total n-3 LCPUFA, total n-6 LCPUFA and total LCPUFA compared to cord serum phospholipids from controls who did not develop allergy (P<0.001 for all comparisons). Conversely, individuals later developing allergy had lower proportion of the monounsaturated fatty acid 18∶1n-9 as well as total MUFA (p<0.001) among cord serum phospholipids. The risk of respiratory allergy at age 13 increased linearly with the proportion of n-3 LCPUFA (P_trend<0.001), n-6 LCPUFA (P_trend = 0.001), and total LCPUFA (P_trend<0.001) and decreased linearly with the proportions of total MUFA (P_trend = 0.025) in cord serum phospholipids. Furthermore, Kaplan-Meier estimates of allergy development demonstrated that total LCPUFA proportion in cord serum phospholipids was significantly associated with respiratory allergy (P = 0.008) and sensitization (P = 0.002), after control for sex and parental allergy.

Conclusion

A high proportion of long-chain PUFAs among cord serum phospholipids may predispose to allergy development. The mechanism is unknown, but may involve dampening of the physiologic immune activation in infancy needed for proper maturation of the infant''s immune system.     

Gene-Lifestyle Interaction and Type 2 Diabetes: The EPIC InterAct Case-Cohort Study

Background

Understanding of the genetic basis of type 2 diabetes (T2D) has progressed rapidly, but the interactions between common genetic variants and lifestyle risk factors have not been systematically investigated in studies with adequate statistical power. Therefore, we aimed to quantify the combined effects of genetic and lifestyle factors on risk of T2D in order to inform strategies for prevention.

Methods and Findings

The InterAct study includes 12,403 incident T2D cases and a representative sub-cohort of 16,154 individuals from a cohort of 340,234 European participants with 3.99 million person-years of follow-up. We studied the combined effects of an additive genetic T2D risk score and modifiable and non-modifiable risk factors using Prentice-weighted Cox regression and random effects meta-analysis methods. The effect of the genetic score was significantly greater in younger individuals (p for interaction  = 1.20×10⁻⁴). Relative genetic risk (per standard deviation [4.4 risk alleles]) was also larger in participants who were leaner, both in terms of body mass index (p for interaction  = 1.50×10⁻³) and waist circumference (p for interaction  = 7.49×10⁻⁹). Examination of absolute risks by strata showed the importance of obesity for T2D risk. The 10-y cumulative incidence of T2D rose from 0.25% to 0.89% across extreme quartiles of the genetic score in normal weight individuals, compared to 4.22% to 7.99% in obese individuals. We detected no significant interactions between the genetic score and sex, diabetes family history, physical activity, or dietary habits assessed by a Mediterranean diet score.

Conclusions

The relative effect of a T2D genetic risk score is greater in younger and leaner participants. However, this sub-group is at low absolute risk and would not be a logical target for preventive interventions. The high absolute risk associated with obesity at any level of genetic risk highlights the importance of universal rather than targeted approaches to lifestyle intervention. Please see later in the article for the Editors'' Summary     

Ratio of Dietary n-6/n-3 Polyunsaturated Fatty Acids Independently Related to Muscle Mass Decline in Hemodialysis Patients

Background

n-3 polyunsaturated fatty acids (PUFAs) might be useful nutritional strategy for treating patients with sarcopenia. We evaluated the effect of the intake of dietary n-3 PUFAs on the skeletal muscle mass (SMM), appendicular skeletal muscle mass (ASM), and its determinants in patients receiving standard hemodialysis (HD) treatment for the management of end stage renal disease.

Methods

In this cross-sectional study, data of 111 HD patients were analyzed. Anthropometric and bioelectrical impedance measurements used to estimate the muscle mass were performed the day of dialysis immediately after the dialysis session. Routine laboratory and 3-day dietary data were also collected. The cutoff value of adequate intake (AI) for both n-3 PUFAs and alpha-linolenic acid (ALA) was 1.6 g/day and 1.1 g/day for men and women, respectively.

Results

The mean age, mean dietary n-3 PUFAs intake, ALA intake, ratio of n-6/n-3 PUFAs intake, SMM, and ASM of patients were 61.4 ± 10.4 years, 2.0 ± 1.3 g/day, 1.5 ± 1.0 g/day, 9.5 ± 6.7 g/day, 23.9 ± 5.5 kg, and 17.5 ± 4.5 kg, respectively. A higher SMM and ASM significantly observed in patients who achieved an AI of n-3 PUFAs. Similar trends appeared to be observed among those patients who achieved the AI of ALA, but the difference was not significantly, except for ASM (P = 0.047). No relevant differences in demographics, laboratory and nutritional parameters were observed, regardless of whether the patients achieved an AI of n-3 PUFAs. Multivariate analysis showed that the BMI and equilibrated Kt/V were independent determinants of the muscle mass. Moreover, the ratio of n-6/n-3 PUFAs was an independent risk determinant of reduced ASM in HD patients.

Conclusion

Patients with an AI of n-3 PUFAs had better total-body SMM and ASM. A higher dietary ratio of n-6/n-3 PUFAs seemed to be associated with a reduced muscle mass in HD patients.     

Marine N-3 Polyunsaturated Fatty Acids Are Inversely Associated with Risk of Type 2 Diabetes in Asians: A Systematic Review and Meta-Analysis

Background

Prospective cohort studies in relation to the associations between n-3 polyunsaturated fatty acids (PUFA) and risk of type 2 diabetes (T2D) were inconsistent. Differences in tissue n-3 PUFA compositions in subjects with and without T2D were also inconsistent in both cohort and case-control studies. We conducted a systematic review and meta-analysis of prospective cohort studies to examine the associations of fish and n-3 PUFA intake with T2D risk. The differences in tissue n-3 PUFA compositions in subjects with and without T2D were investigated based on cohort and case-control studies.

Methods and Findings

PubMed, Embase, Cochrane library, China National Knowledge Infrastructure (CNKI) and Chinese VIP database up to January 2012 was used to identify relevant studies, and reference lists from retrieved studies were reviewed. Two authors independently extracted the data. Random-effects models were used to pool the summary relative risk (RR). Twenty-four studies including 24,509 T2D patients and 545,275 participants were identified. For cohort studies, the summary RR of T2D for the highest vs lowest categories of total fish, marine n-3 PUFA and alpha-linolenic acid intake was 1.07 (95% CI: 0.91, 1.25), 1.07 (95% CI: 0.95, 1.20) and 0.93 (95% CI: 0.81, 1.07), respectively. Subgroup analyses indicated that summary RR (highest vs lowest category) of T2D for fish and marine n-3 PUFA intake was 0.89 (95% CI: 0.81, 0.98) and 0.87 (95% CI: 0.79, 0.96) for Asian populations, and 1.20 (95% CI: 1.01, 1.44) and 1.16 (95% CI: 1.04, 1.28) for Western populations. Asian subjects with T2D had significantly lower tissue compositions of C22∶6n-3 (SMD: −1.43; 95% CI: −1.75, −1.12) and total n-3 PUFA (SMD: −1.41; 95% CI: −2.23, −0.59) compared with those without T2D.

Conclusion

This systematic review and meta-analysis provides evidence that marine n-3 PUFA have beneficial effects on the prevention of T2D in Asian populations.     

Fluorescent n-3 and n-6 Very Long Chain Polyunsaturated Fatty Acids: THREE-PHOTON IMAGING IN LIVING CELLS EXPRESSING LIVER FATTY ACID-BINDING PROTEIN*

Despite the considerable beneficial effects of n-3 and n-6 very long chain polyunsaturated fatty acids (VLC-PUFAs), very little is known about the factors that regulate their uptake and intracellular distribution in living cells. This issue was addressed in cells expressing liver-type fatty acid-binding protein (L-FABP) by real time multiphoton laser scanning microscopy of novel fluorescent VLC-PUFAs containing a conjugated tetraene fluorophore near the carboxyl group and natural methylene-interrupted n-3 or n-6 grouping. The fluorescent VLC-PUFAs mimicked many properties of their native nonfluorescent counterparts, including uptake, distribution, and metabolism in living cells. The unesterified fluorescent VLC-PUFAs distributed either equally in nuclei versus cytoplasm (22-carbon n-3 VLC-PUFA) or preferentially to cytoplasm (20-carbon n-3 and n-6 VLC-PUFAs). L-FABP bound fluorescent VLC-PUFA with affinity and specificity similar to their nonfluorescent natural counterparts. Regarding n-3 and n-6 VLC-PUFA, L-FABP expression enhanced uptake into the cell and cytoplasm, selectively altered the pattern of fluorescent n-6 and n-3 VLC-PUFA distribution in cytoplasm versus nuclei, and preferentially distributed fluorescent VLC-PUFA into nucleoplasm versus nuclear envelope, especially for the 22-carbon n-3 VLC-PUFA, correlating with its high binding by L-FABP. Multiphoton laser scanning microscopy data showed for the first time VLC-PUFA in nuclei of living cells and suggested a model, whereby L-FABP facilitated VLC-PUFA targeting to nuclei by enhancing VLC-PUFA uptake and distribution into the cytoplasm and nucleoplasm.     

The Antiarrhythmic Effect of n-3 Polyunsaturated Fatty Acids: Modulation of Cardiac Ion Channels as a Potential Mechanism

Sudden cardiac death remains one of the most serious medical challenges in Western countries. Increasing evidence in recent years has demonstrated that the n-3 polyunsaturated fatty acids (PUFAs) can prevent fatal ventricular arrhythmias in experimental animals and probably in humans. Dietary supplement of fish oils or intravenous infusion of the n-3 PUFAs prevents ventricular fibrillation caused by ischemia/reperfusion. Similar antiarrhythmic effects of these fatty acids are also observed in cultured mammalian cardiomyocytes. Based on clinical observations and experimental studies in vitro and in vivo, several mechanisms have been postulated for the antiarrhythmic effect of the n-3 PUFAs. The data from our laboratory and others have shown that the n-3 PUFAs are able to affect the activities of cardiac ion channels. The modulation of channel activities, especially voltage-gated Na⁺ and L-type Ca²⁺ channels, by the n-3 fatty acids may explain, at least partially, the antiarrhythmic action. It is not clear, however, whether one or more than one mechanism involves the beneficial effect of the n-3 PUFAs on the heart. This article summarizes our recent studies on the specific effects of the n-3 PUFAs on cardiac ion channels. In addition, the effect of the n-3 PUFAs on the human hyperpolarization-activated cyclic-nucleotide-modulated channel is presented.     

Effects of Dietary n-3 Fatty Acids on the Phospholipid Molecular Species of Monkey Brain

Y-79 human retinoblastoma cells grown in serum-free medium in monolayer culture have previously been shown to undergo differentiation in response to dibutyryl cyclic AMP (Bt2cAMP). We report here that Y-79 cells treated in this manner also express very high levels of functional D2 dopamine receptors. In control Y-79 cells, cultured in suspension, D2 dopamine receptors, quantified via saturation analysis with the D2 antagonist [3H]methylspiperone, are expressed at a level of approximately 3 fmol/10(6) cells (approximately 1,800 receptor sites/cell). Differentiation is initiated by attachment of the cells to the culture dish with poly-D-lysine and fibronectin and continued culture in serum-free medium. After 8 days in serum-free culture, differentiation is further induced with continuous Bt2cAMP treatment. Using this differentiation protocol, D2 receptor levels increase up to a maximum of 30 fmol/10(6) cells (18,000 receptors/cell) on day 20, the limit of culture viability. Cultures of 15-17 days (7-9 days of Bt2cAMP treatment) expressing receptor levels of 15-20 fmol/10(6) cells are used for pharmacological and functional characterization of D2 dopamine receptors. The pharmacology of competition for [3H]methylspiperone binding to differentiated Y-79 (dY-79) cell membranes by a series of dopaminergic antagonists verifies the D2 receptor nature of this site, exhibiting appropriate affinities and the following rank order of potency: YM-09151-2 approximately spiperone greater than domperidone approximately (+)-butaclamol approximately fluphenazine greater than chlorpromazine greater than (-)-sulpiride greater than (+)-sulpiride greater than promethazine greater than (+)-SCH 23390 much greater than (-)-butaclamol.(ABSTRACT TRUNCATED AT 250 WORDS)     

Type 2 Diabetes Associated Changes in the Plasma Non-Esterified Fatty Acids,Oxylipins and Endocannabinoids

Type 2 diabetes has profound effects on metabolism that can be detected in plasma. While increases in circulating non-esterified fatty acids (NEFA) are well-described in diabetes, effects on signaling lipids have received little attention. Oxylipins and endocannabinoids are classes of bioactive fatty acid metabolites with many structural members that influence insulin signaling, adipose function and inflammation through autocrine, paracrine and endocrine mechanisms. To link diabetes-associated changes in plasma NEFA and signaling lipids, we quantitatively targeted >150 plasma lipidome components in age- and body mass index-matched, overweight to obese, non-diabetic (n = 12) and type 2 diabetic (n = 43) African-American women. Diabetes related NEFA patterns indicated ∼60% increase in steroyl-CoA desaturase activity and ∼40% decrease in very long chain polyunsaturated fatty acid chain shortening, patterns previously associated with the development of nonalcoholic fatty liver disease. Further, epoxides and ketones of eighteen carbon polyunsaturated fatty acids were elevated >80% in diabetes and strongly correlated with changes in NEFA, consistent with their liberation during adipose lipolysis. Endocannabinoid behavior differed by class with diabetes increasing an array of N-acylethanolamides which were positively correlated with pro-inflammatory 5-lipooxygenase-derived metabolites, while monoacylglycerols were negatively correlated with body mass. These results clearly show that diabetes not only results in an increase in plasma NEFA, but shifts the plasma lipidomic profiles in ways that reflect the biochemical and physiological changes of this pathological state which are independent of obesity associated changes.     

Relationships between 4-Hydroxy-2-nonenal, 2-Thiobarbituric Acid Reactive Substances and n-6 Polyunsaturated Fatty Acids in Refrigerated and Frozen Pork

The relationships between 4-hydroxy-2-nonenal (HNE), 2-thiobarbituric acid reactive substances (TBARS) and n-6 polyunsaturated fatty acids (n-6 PUFAs) were investigated for pork stored at 0, -20 and -80°C. A significant linear correlation was apparent between HNE and TBARS for the pork stored at each temperature. However, the n-6 PUFA content remained unchanged during storage.     

Polyunsaturated Fatty Acids Modulate the Association between PIK3CA-KCNMB3 Genetic Variants and Insulin Resistance

Background

Neighboring genes PIK3CA and KCNMB3 are both important for insulin signaling and β-cell function, but their associations with glucose-related traits are unclear.

Objective

The objective was to examine associations of PIK3CA-KCNMB3 variants with glucose-related traits and potential interaction with dietary fat.

Design

We first investigated genetic associations and their modulation by dietary fat in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study (n = 820). Nine single-nucleotide polymorphisms (SNPs) were selected for analysis, covering more than 80% of the SNPs in the region. We then sought to replicate the findings in the Boston Puerto Rican Health Study (BPRHS) (n = 844).

Results

For KCNMB3 missense mutation rs7645550, meta-analysis indicated that homeostasis model assessment of insulin resistance (HOMA-IR) was significantly lower in minor allele T homozygotes compared with major allele C carriers (pooled P-value = 0.004); for another SNP rs1183319, which is in moderate LD with rs7645550, minor allele G carriers had higher HOMA-IR compared with non-carriers in both populations (pooled P-value = 0.028). In GOLDN, rs7645550 T allele homozygotes had lower HOMA-IR only when dietary n-3: n-6 PUFA ratio was low (≤0.11, P = 0.001), but not when it was high (>0.11, P-interaction = 0.033). Similar interaction was observed between rs1183319 and n-3: n-6 PUFA ratio on HOMA-IR (P-interaction = 0.001) in GOLDN. Variance contribution analyses in GOLDN confirmed the genetic association and gene-diet interaction. In BPRHS, dietary n-3: n-6 PUFA ratio significantly modulated the association between rs1183319 and HbA1c (P-interaction = 0.034).

Conclusion

PIK3CA-KCNMB3 variants are associated with insulin resistance in populations of different ancestries, and are modified by dietary PUFA.     

The Beneficial Effects of n-3 Polyunsaturated Fatty Acids on Diet Induced Obesity and Impaired Glucose Control Do Not Require Gpr120

GPR120 (Ffar4) has been postulated to represent an important receptor mediating the improved metabolic profile seen upon ingestion of a diet enriched in polyunsaturated fatty acids (PUFAs). GPR120 is highly expressed in the digestive system, adipose tissue, lung and macrophages and also present in the endocrine pancreas. A new Gpr120 deficient mouse model on pure C57bl/6N background was developed to investigate the importance of the receptor for long-term feeding with a diet enriched with fish oil. Male Gpr120 deficient mice were fed two different high fat diets (HFDs) for 18 weeks. The diets contained lipids that were mainly saturated (SAT) or mainly n-3 polyunsaturated fatty acids (PUFA). Body composition, as well as glucose, lipid and energy metabolism, was studied. As expected, wild type mice fed the PUFA HFD gained less body weight and had lower body fat mass, hepatic lipid levels, plasma cholesterol and insulin levels and better glucose tolerance as compared to those fed the SAT HFD. Gpr120 deficient mice showed a similar improvement on the PUFA HFD as was observed for wild type mice. If anything, the Gpr120 deficient mice responded better to the PUFA HFD as compared to wild type mice with respect to liver fat content, plasma glucose levels and islet morphology. Gpr120 deficient animals were found to have similar energy, glucose and lipid metabolism when fed HFD PUFA compared to wild type mice. Therefore, GPR120 appears to be dispensable for the improved metabolic profile associated with intake of a diet enriched in n-3 PUFA fatty acids.     

Brain Phospholipids as Dietary Source of (n-3) Polyunsaturated Fatty Acids for Nervous Tissue in the Rat

Abstract: In a previous work, we calculated the dietary α-linolenic requirements (from vegetable oil triglycerides) for obtaining and maintaining a physiological level of (n-3) fatty acids in developing animal membranes as determined by the cervonic acid content [22:6(n-3), docosahexaenoic acid]. The aim of the present study was to measure the phospholipid requirement, as these compounds directly provide the very long polyunsaturated fatty acids found in membranes. Two weeks before mating, eight groups of female rats (previously fed peanut oil deficient in α-linolenic acid) were fed different semisynthetic diets containing 6% African peanut oil supplemented with different quantities of phospholipids obtained from bovine brain lipid extract, so as to add (n-3) polyunsaturated fatty acids to the diet. An additional group was fed peanut oil with rapeseed oil, and served as control. Pups were fed the same diet as their respective mothers, and were killed at weaning. Forebrain, sciatic nerve, retina, nerve endings, myelin, and liver were analyzed. We conclude that during the combined maternal and perinatal period, the (n-3) fatty acid requirement for adequate deposition of (n-3) polyunsaturated fatty acids in the nervous tissue (and in liver) of pups is lower if animals are fed (n-3) very long chain polyunsaturated fatty acids found in brain phospholipids [this study, ˜60 mg of (n-3) fatty acids/100 g of diet, i.e., ˜130 mg/1,000 kcal] rather than α-linolenic acid from vegetable oil triglycerides [200 mg of (n-3) fatty acids/100 g of diet, i.e., ˜440 mg/1,000 kcal].     

Dietary Omega-3 Polyunsaturated Fatty Acids Alter the Fatty Acid Composition of Hepatic and Plasma Bioactive Lipids in C57BL/6 Mice: A Lipidomic Approach

Background

Omega (n)-3 polyunsaturated fatty acids (PUFA) are converted to bioactive lipid components that are important mediators in metabolic and physiological pathways; however, which bioactive compounds are metabolically active, and their mechanisms of action are still not clear. We investigated using lipidomic techniques, the effects of diets high in n-3 PUFA on the fatty acid composition of various bioactive lipids in plasma and liver.

Methodology and Principal Findings

Female C57BL/6 mice were fed semi-purified diets (20% w/w fat) containing varying amounts of n-3 PUFA before mating, during gestation and lactation, and until weaning. Male offspring were continued on their mothers’ diets for 16 weeks. Hepatic and plasma lipids were extracted in the presence of non-naturally occurring internal standards, and tandem electrospray ionization mass spectrometry methods were used to measure the fatty acyl compositions. There was no significant difference in total concentrations of phospholipids in both groups. However, there was a significantly higher concentration of eicosapentaenoic acid containing phosphatidylcholine (PC), lysophosphatidylcholine (LPC), and cholesteryl esters (CE) (p < 0.01) in the high n-3 PUFA group compared to the low n-3 PUFA group in both liver and plasma. Plasma and liver from the high n-3 PUFA group also had a higher concentration of free n-3 PUFA (p < 0.05). There were no significant differences in plasma concentrations of different fatty acyl species of phosphatidylethanolamine, triglycerides, sphingomyelin and ceramides.

Conclusions/Significance

Our findings reveal for the first time that a diet high in n-3 PUFA caused enrichment of n-3 PUFA in PC, LPC, CE and free fatty acids in the plasma and liver of C57BL/6 mice. PC, LPC, and unesterified free n-3 PUFA are important bioactive lipids, thus altering their fatty acyl composition will have important metabolic and physiological roles.     

Effect of Marine-Derived n-3 Polyunsaturated Fatty Acids on Major Eicosanoids: A Systematic Review and Meta-Analysis from 18 Randomized Controlled Trials

Background

Marine-derived n-3 polyunsaturated fatty acids (PUFA) may have a beneficial effect on inflammation via lowering pro-inflammatory eicosanoid concentrations. We aimed to assess the effect of marine-derived n-3 PUFA on prostaglandin E₂ (PGE₂), thromboxane B₂ (TXB₂), and leukotriene B₄ (LTB₄) through systematic review and meta-analysis of randomized controlled trials.

Method and Findings

A structured search strategy on PubMed, Web of Science and Cochrane up to November 2015 was undertaken in this meta-analysis. Standard mean difference was used to calculate the effect size of marine-derived n-3 PUFA on PGE₂, TXB₂ and LTB₄ in a random-effect model. A total of 18 RCTs with 826 subjects were included in this systematic review and meta-analysis. Supplementation of marine-derived n-3 PUFA significantly decreased concentrations of TXB₂ in serum/plasma in subjects with high risk of cardiovascular diseases (SMD:-1.26; 95% CI: -1.65, -0.86) and LTB₄ in neutrophils in unhealthy subjects (subjects with non-autoimmune chronic diseases or auto-immune diseases) (SMD:-0.59: 95% CI: -1.02, -0.16). Subgroup analyses showed a significant reduction of LTB₄ in subjects with rheumatoid arthritis (SMD: -0.83; 95% CI: -1.37, -0.29), but not in non-autoimmune chronic disease patients (SMD: -0.33; 95% CI: -0.97, 0.31). No significant publication bias was shown in the meta-analysis.

Conclusions

Marine-derived n-3 PUFA had a beneficial effect on reducing the concentration of TXB₂ in blood of subjects with high risk of CVD as well as LTB₄ in neutrophils in unhealthy subjects, and that subjects with RA showed lower LTB₄ content with supplementation of marine-derived n-3 PUFA.