There is an increased use of vegetable oils containing n-6 fatty acids (FA) in aquafeeds, and several trials indicate that there might be an increased requirement of EPA and DHA for Atlantic salmon when they are fed higher dietary n-6 FA. With a limited supply of EPA and DHA for production of aquafeeds, it is important to know how to efficiently use these FA to maintain growth and health of the fish. In the present trial, three diets containing equal amounts of n-3 FA (about 7·7 % of total FA) and different n-6:n-3 FA ratios (about 1, 2 and 6), as well as one diet with n-6:n-3 FA ratio at about 1 but twice as much n-3 FA, were fed to Atlantic salmon. Despite constant dietary n-3, increasing dietary n-6 led to significantly reduced n-3 in tissue polar lipids. Interestingly, EPA was significantly reduced while DHA was not. Maintaining a stable n-3 content in the polar lipids when increasing dietary n-6 FA was only obtained by simultaneously increasing the dietary n-3 content and with this maintaining the same n-6:n-3 FA ratio. Polar lipid n-6 FA in tissues thus primarily reflected the dietary n-6:n-3 FA ratio and not the absolute dietary n-6 FA content. Neutral lipids, on the other hand, reflected the dietary absolute levels of both n-3 and n-6 FA. This study indicates that a better use of dietary EPA is achieved by keeping the dietary n-6:n-3 FA ratio low.

We conducted a systematic review of randomised controlled trials (RCT) of increased intake of arachidonic acid (ARA) on fatty acid status and health outcomes in humans. We identified twenty-two articles from fourteen RCT. Most studies were conducted in adults. These used between 80 and 2000 mg ARA per d and were of 1–12 weeks duration. Supplementation with ARA doses as low as 80 mg/d increased the content of ARA in different blood fractions. Overall there seem to be few marked benefits for adults of increasing ARA intake from the typical usual intake of 100–200 mg/d to as much as 1000 mg/d; the few studies using higher doses (1500 or 2000 mg/d) also report little benefit. However, there may be an impact of ARA on cognitive and muscle function which could be particularly relevant in the ageing population. The studies reviewed here suggest no adverse effects in adults of increased ARA intake up to at least 1000–1500 mg/d on blood lipids, platelet aggregation and blood clotting, immune function, inflammation or urinary excretion of ARA metabolites. However, in many areas there are insufficient studies to make firm conclusions, and higher intakes of ARA are deserving of further study. Based on the RCT reviewed, there are not enough data to make any recommendations for specific health effects of ARA intake.

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.

Few trials have evaluated the metabolic effects and health outcomes of lowering dietary n-6 PUFA. The objectives of the present paper were (1) to report the methods employed to lower dietary n-6 PUFA, while either increasing or maintaining n-3 PUFA intake and (2) to validate our methods with 24 h recalls and erythrocyte fatty acid analyses. A total of sixty-seven subjects were randomised to either (1) an average-n-3 PUFA, low-n-6 PUFA (L6) intervention designed to lower linoleic acid (LA; ≤ 2·5 % of energy (en%)) and arachidonic acid ( ≤ 60 mg/d), while maintaining an average US intake of n-3 PUFA or (2) a high-n-3 PUFA, low-n-6 PUFA (H3-L6) intervention designed to lower n-6 LA, while increasing the n-3 PUFA α-linolenic acid (ALA; ≥ 1·5 en%) and EPA+DHA ( ≥ 1000 mg/d). Pre- and intra-intervention nutrient intakes were estimated with six 24 h dietary recalls per subject. Both groups achieved the targeted reductions in dietary LA to ≤ 2·5 en% (median LA 2·45 (2·1, 3·1); P< 0·001). Intakes of n-3 PUFA did not change for the L6 group. Target increases in n-3 ALA (median 1·6 en%, (1·3, 2·0), P< 0·001) and EPA+DHA (1482 mg, (374, 2558), P< 0·001) were achieved in the H3-L6 group. Dietary changes were validated by corresponding changes in erythrocyte n-6 and n-3 fatty acid composition. Dietary LA can be lowered to ≤ 2·5 en%, with or without concurrent increases in dietary n-3 PUFA, in an outpatient clinical trial setting using this integrated diet method.

The main objective of the present study was to determine the potential of n-3 and n-6 fatty acids or coenzyme Q10 (CoQ10) to alter serum prostate-specific antigen (PSA) levels in normal healthy men. A total of 504 healthy men with serum PSA level ≤ 2·5 ng/ml were recruited into the study. Serum PSA values were not segregated by decade of age. Participants were randomly assigned to a daily dietary supplement containing n-3 fatty acids (1·12 g of EPA and 0·72 g of DHA per capsule) (group 1, n 126), n-6 fatty acid (600 mg γ-linolenic acid (GLA) each capsule) (group 2, n 126), CoQ10 (100 mg per capsule) (group 3, n 126) or a similar regimen of placebo (group 4, n 126) for 12 weeks. Study medication was administered as two capsules to be taken twice daily. Serum levels of PSA, EPA, DHA, GLA, lipid profile and reproductive hormones were also measured. EPA treatment significantly reduced serum PSA level by 30·0 (95 % CI 25, 36) % (P= 0·004) from baseline. In contrast, GLA therapy significantly increased serum PSA concentration by 15·0 (95 % CI 11, 20) % (P= 0·02). CoQ10 therapy also significantly reduced serum PSA level by 33·0 (95 % CI 27, 40) % (P= 0·002). In multivariable analysis, serum values of PSA were strongly correlated with duration of EPA (r − 0·62; 95 % CI − 0·42, − 0·77; P= 0·003), n-6 (r 0·42; 95 % CI 0·31, 0·58; P= 0·02) and CoQ10 use (r − 0·77; 95 % CI − 0·56, − 0·87; P= 0·001). There were also significant correlations between serum values of DHA, EPA, GLA and CoQ10 and serum PSA levels. The present study demonstrates that dietary supplements containing EPA, GLA or CoQ10 may significantly affect serum PSA levels.

Randomised controlled trials (RCT) of mixed n-6 and n-3 PUFA diets, and meta-analyses of their CHD outcomes, have been considered decisive evidence in specifically advising consumption of ‘at least 5–10 % of energy as n-6 PUFA’. Here we (1) performed an extensive literature search and extracted detailed dietary and outcome data enabling a critical examination of all RCT that increased PUFA and reported relevant CHD outcomes; (2) determined if dietary interventions increased n-6 PUFA with specificity, or increased both n-3 and n-6 PUFA (i.e. mixed n-3/n-6 PUFA diets); (3) compared mixed n-3/n-6 PUFA to n-6 specific PUFA diets on relevant CHD outcomes in meta-analyses; (4) evaluated the potential confounding role of trans-fatty acids (TFA). n-3 PUFA intakes were increased substantially in four of eight datasets, and the n-6 PUFA linoleic acid was raised with specificity in four datasets. n-3 and n-6 PUFA replaced a combination of TFA and SFA in all eight datasets. For non-fatal myocardial infarction (MI)+CHD death, the pooled risk reduction for mixed n-3/n-6 PUFA diets was 22 % (risk ratio (RR) 0·78; 95 % CI 0·65, 0·93) compared to an increased risk of 13 % for n-6 specific PUFA diets (RR 1·13; 95 % CI 0·84, 1·53). Risk of non-fatal MI+CHD death was significantly higher in n-6 specific PUFA diets compared to mixed n-3/n-6 PUFA diets (P = 0·02). RCT that substituted n-6 PUFA for TFA and SFA without simultaneously increasing n-3 PUFA produced an increase in risk of death that approached statistical significance (RR 1·16; 95 % CI 0·95, 1·42). Advice to specifically increase n-6 PUFA intake, based on mixed n-3/n-6 RCT data, is unlikely to provide the intended benefits, and may actually increase the risks of CHD and death.

Dietary long-chain PUFA, both n-3 and n-6, have unique benefits with respect to CVD risk. The aim of the present study was to determine the mechanisms by which n-3 PUFA (EPA, DHA) and n-6 PUFA (linoleic acid (LA), arachidonic acid (AA)) relative to SFA (myristic acid (MA), palmitic acid (PA)) alter markers of inflammation and cholesterol accumulation in macrophages (MΦ). Cells treated with AA and EPA elicited significantly less inflammatory response than control cells or those treated with MA, PA and LA, with intermediate effects for DHA, as indicated by lower levels of mRNA and secretion of TNFα, IL-6 and monocyte chemoattractant protein-1. Differences in cholesterol accumulation after exposure to minimally modified LDL were modest. AA and EPA resulted in significantly lower MΦ scavenger receptor 1 mRNA levels relative to control or MA-, PA-, LA- and DHA-treated cells, and ATP-binding cassette A1 mRNA levels relative to control or MA-, PA- and LA-treated cells. These data suggest changes in the rate of bidirectional cellular cholesterol flux. In summary, individual long-chain PUFA have differential effects on inflammatory response and markers of cholesterol flux in MΦ which are not related to the n position of the first double bond, chain length or degree of saturation.

A positive energy balance (energy intake>energy expenditure), in which total fat intake plays an important role, is commonly regarded as a major factor contributing to obesity. Adipose tissue development, i.e. both size (hypertrophy) and number (hyperplasia), is stimulated by high dietary fat intake during early postnatal development, a susceptibility that now appears to continue well into adulthood. Recent human and animal studies suggest that by altering rates of adipocyte differentiation and proliferation, differences in the composition of dietary fat may also contribute to adipose tissue development. At least in rodent models, the relative intake of n-6 to n-3 PUFA is clearly emerging as a new factor in this development. In these models, higher linoleate intake raises tissue arachidonic acid, which increases prostacyclin production and, in turn, stimulates signalling pathways implicated in adipogenesis. Signalling pathways stimulated by arachidonic acid probably include phospholipase and/or cyclo-oxygenase activation and may be linked as much to relatively low intake of n-3 PUFA as to excessive dietary linoleate. One factor potentially contributing to oversight about the apparent role of dietary n-6 PUFA (especially excess dietary linoleate) in adipose tissue development is the historical overestimation of linoleate requirements and the enthusiasm for higher intake of ‘essential fatty acids’. More research is needed to address whether disequilibration of dietary PUFA intake contributes to the risk of obesity in humans.