N-3 fatty acids

Reference: Am J Clin Nutr 2000;71(1S):1S-398S.

Lessons from the story of n-3 fatty acids.

The discovery of the effects of n-3 fatty acids came about as a result of contacts between scientists in different countries and disciplines who followed up some unexpected observations. There are probably other fields of research in which discoveries of similar importance await the application of lessons from this story.

Role of polyunsaturated fatty acids in lung disease.

DF Horrobin hypothesized that the low prevalence of lung disease among Eskimos is the result of their diet, which is high in n-3 fatty acids. The n-3 and n-6 fatty acids shunt eicosanoid production away from the arachidonic acid pathway, and hence decrease the production of bronchoconstrictive leukotrienes. Animal studies showed that eicosapentaenoic acid or gamma-linolenic acid supplementation of animals exposed to endotoxins results in decreased effects on thromboxane B(2) and pulmonary vascular resistance. Small human trials confirmed that supplementation with eicosapentaenoic acid results in increased eicosapentaenoic acid in phospholipids and decreased generation of leukotrienes by neutrophils. Hence, a protective effect of such fatty acids in lung disease is biologically plausible. The results of human intervention studies looking at respiratory outcomes have been mixed, but they do suggest a possible difference between long-term and short-term effects. Epidemiologic studies showed possible protective effects against asthma in children, but weak to no evidence of such effects in adults. Results for bronchitis are more positive, although intervention trials are lacking. Recently, a cross-sectional analysis of data from the first National Health and Nutrition Examination Survey reported an approximately 80-mL difference in forced expiratory volume at 1 s between adults with high compared with low fish consumption. This response was not limited to asthmatic subjects. Others found that both fish consumption and n-3 fatty acid consumption (as estimated from food-frequency questionnaires) were protective against physician-diagnosed emphysema and chronic bronchitis and low spirometry values. Only smokers were included in this analysis. These results suggest that dietary fatty acids may play a role in lung disease; further work is needed to elucidate that role.

Prevention of nerve conduction deficit in diabetic rats by polyunsaturated fatty acids.

The influence of diets containing gamma-linolenic acid (GLA; 18:3n-6) on sciatic nerve conduction velocity (NCV) was determined in diabetic rats. NCV was lower in diabetic rats fed diets supplemented with olive oil or sunflower seed oil than in nondiabetic rats; rats supplemented with GLA during a 5-wk diabetic period, however, did not exhibit significantly lower NCV. The mean proportion of the phospholipid fatty acid linoleic acid (18:2n-6) was higher in the sciatic nerves of diabetic rats than in the nondiabetic groups irrespective of dietary lipid treatment. Additionally, the proportion of linoleic acid was higher in the diabetic rats fed sunflower oil than in all other groups. Dietary GLA supplementation did not significantly influence the fatty acid composition of nerve membrane phospholipids and there was no obvious correlation between the fatty acid composition of nerve membrane phospholipids and NCV. The content of fructose and glucose in sciatic nerves was higher, whereas that of myo-inositol was lower, in diabetic rats than in nondiabetic rats; however, this was not significantly influenced by dietary GLA. GLA administration did not significantly influence Na(+)-K(+)-exchanging ATPase or ouabain binding activity in sciatic nerve preparations, both of which remained nonsignificantly different in the diabetic and nondiabetic groups. The results suggest that dietary GLA can prevent the deficit in NCV induced by diabetes and that this effect is independent of the nerve phospholipid fatty acid profile, sugar and polyol content, Na(+)-K(+)-exchanging ATPase activity, and ouabain binding. GLA may prevent the deficit in NCV indirectly, possibly by its role as a precursor of vasodilatory prostaglandins. These results confirm that GLA is the active component of evening primrose oil.

Therapeutic effects of docosahexaenoic acid ethyl ester in patients with generalized peroxisomal disorders.

Generalized peroxisomal disorders are severe congenital diseases that involve the central nervous system, leading to severe psychomotor retardation, retinopathy, liver disease, and early death. In these disorders, peroxisomes are not normally formed and their enzymes are deficient. Characteristically, plasmalogen synthesis and beta-oxidation of very-long-chain fatty acids (VLCFAs) are affected. We found that patients with generalized peroxisomal disorders have a profound brain deficiency of docosahexaenoic acid (DHA; 22:6n-3) and low DHA concentrations in all tissues and the blood. Given the fundamental role of DHA in neuronal and retinal membranes, a DHA deficiency of this magnitude might be pathogenic. Thus, we studied the possible therapeutic effect of normalizing DHA concentrations in patients with peroxisomal disorders. We chose the DHA ethyl ester (DHA-EE) because of its high degree of purity at daily oral doses of 100-500 mg. This article summarizes the results of treatment of 13 patients with DHA-EE, with some follow-up evidence of clinical improvement. Supplementation with DHA-EE normalized blood DHA values within a few weeks. Plasmalogen concentrations increased in erythrocytes in most patients and after DHA concentrations were normalized, amounts of VLCFAs decreased in plasma. Liver enzymes returned almost to normal in most cases. From a clinical viewpoint, most patients showed improvement in vision, liver function, muscle tone, and social contact. In 3 patients, normalization of brain myelin was detected by magnetic resonance imaging. In 3 others, myelination improved. In a seventh patient, myelination is progressing at a normal rate. These results suggest a fundamental role of DHA in the pathogenesis of Zellweger syndrome. DHA therapy is thus strongly recommended, not only to alleviate symptoms in patients with life-threatening diseases, but also to clarify remaining questions regarding the role of DHA in health and disease.

Use of fish oil to treat patients with immunoglobulin A nephropathy.

This review describes the use of fish oil in the treatment of patients with immunoglobulin (Ig) A nephropathy. IgA nephropathy is the most common glomerular disease worldwide. It has a variable course and leads to end-stage renal disease in a substantial number of cases. Among the 4 published randomized clinical trials that tested the efficacy of fish-oil treatment of IgA nephropathy, 2 reported beneficial effects on renal function and 2 showed negative results. In the largest trial conducted by my collaborative study group, convincing evidence was provided for protection against progressive renal disease after daily treatment for 2 y with fish oil providing 1.8 g eicosapentaenoic acid and 1.2 g docosahexaenoic acid-the 2 major n-3 polyunsaturated fatty acids in fish oil. Oral prednisone has also been advocated, especially in the treatment of children with IgA nephropathy. Two randomized trials are currently underway in the United States to resolve the discrepancy of results in previous fish-oil trials and to determine whether corticosteroids or fish oil is the better treatment of patients at risk for developing progressive disease; results of these studies are not yet available.

Essential fatty acid metabolism and its modification in atopic eczema.

Research from the 1930s to the 1950s established that a deficit of n-6 essential fatty acids (EFAs) leads to an inflammatory skin condition in both animals and humans. In a common inherited skin condition, atopic dermatitis (eczema), there was evidence of low blood EFA concentrations and of a therapeutic response to exceptionally high doses of linoleic acid. More recently, it has been established that there is no deficit of linoleic acid in atopic eczema. Concentrations of linoleic acid instead tend to be elevated in blood, milk, and adipose tissue of patients with atopic eczema, whereas concentrations of linoleic acid metabolites are substantially reduced. This suggests reduced conversion of linoleic acid to gamma-linolenic acid (GLA). In most but not all studies, administration of GLA has been found to improve the clinically assessed skin condition, the objectively assessed skin roughness, and the elevated blood catecholamine concentrations of patients with atopic eczema. Atopic eczema may be a minor inherited abnormality of EFA metabolism.

Metabolism of polyunsaturated fatty acids by skin epidermal enzymes: generation of antiinflammatory and antiproliferative metabolites.

In the skin epidermis, the metabolism of polyunsaturated fatty acids (PUFAs) is highly active. Dietary deficiency of linoleic acid (LA), the major 18-carbon n-6 PUFA in normal epidermis, results in a characteristic scaly skin disorder and excessive epidermal water loss. Because of the inability of normal skin epidermis to desaturate LA to gamma-linolenic acid, it is transformed by epidermal 15-lipoxygenase to mainly 13-hydroxyoctadecadienoic acid, which functionally exerts antiproliferative properties in the tissue. In contrast, compared with LA, arachidonic acid (AA) is a relatively minor 20-carbon n-6 PUFA in the skin and is metabolized via the cyclooxygenase pathway, predominantly to the prostaglandins E(2), F(2)(alpha), and D(2). AA is also metabolized via the 15-lipoxygenase pathway, predominantly to 15-hydroxyeicosatetraenoic acid. At low concentrations, the prostaglandins function to modulate normal skin physiologic processes, whereas at high concentrations they induce inflammatory processes. PUFAs derived from other dietary oils are also transformed mainly into monohydroxy fatty acids. For instance, epidermal 15-lipoxygenase transforms dihomo-gamma-linolenic acid (20:3n-6) to 15-hydroxyeicosatrienoic acid, eicosapentaenoic acid (20:5n-3) to 15-hydroxyeicosapentaenoic acid, and docosahexaenoic acid (22:6n-3) to 17-hydroxydocosahexaenoic acid, respectively. These monohydroxy acids exhibit antiinflammatory properties in vitro. Thus, supplementation of diets with appropriate purified vegetable oils, fish oil, or both may generate local cutaneous antiinflammatory and antiproliferative metabolites which could serve as less toxic in vivo monotherapies or as adjuncts to standard therapeutic regimens for the management of inflammatory skin disorders.

n-3 polyunsaturated fatty acids inhibit the antigen-presenting function of human monocytes.

Diets rich in n-3 polyunsaturated fatty acids (PUFAs) are associated with suppression of cell-mediated immune responses, but the mechanisms are unclear. We hypothesized that n-3 PUFAs can inhibit the function of human antigen-presenting cells. A prerequisite for this role of blood monocytes is the cell surface expression of major histocompatibility complex (MHC) class II molecules [human leukocyte antigen (HLA)-DR, -DP, and -DQ], aided by the presence of intercellular adhesion molecule-1 (ICAM-1) and leukocyte function associated antigens 1 and 3. We showed previously that the n-3 PUFA eicosapentaenoic acid (EPA) inhibits the expression of HLA-DR on unstimulated human monocytes in vitro, but that docosahexaenoic acid (DHA) enhances its expression. However, both n-3 PUFAs suppress the expression of HLA-DR, HLA-DP, and ICAM-1 on interferon-gamma-activated monocytes. We also established that dietary fish-oil supplementation can inhibit the expression of these surface molecules on circulating human monocytes. We subsequently showed that when EPA and DHA were combined in the same ratio as is commonly found in fish-oil-supplement capsules (3:2), there was no significant effect in vitro on the expression of HLA-DR on unstimulated monocytes, but the expression on activated monocytes remained significantly inhibited. In the same in vitro system, the ability of activated monocytes to present antigen to autologous lymphocytes was significantly reduced after culture with the combined n-3 PUFAs. These findings provide one potential mechanism for the beneficial effect of fish oil in the treatment of rheumatoid arthritis, a disorder associated with elevated expression of MHC class II and adhesion molecules on monocytes present within affected joints.

Evening primrose oil and borage oil in rheumatologic conditions.

Diets rich in arachidonic acid (20:4n-6) lead to the formation of 2-series prostaglandins (PGs) and 4-series leukotrienes (LTs), with proinflammatory effects. Nonsteroidal antiinflammatory drugs are used in rheumatoid arthritis to inhibit cyclooxygenase (prostaglandin-endoperoxide synthase), thereby decreasing production of 2-series PGs. Lipoxygenase activity remains intact, however, allowing LT production (eg, synthesis of LTB(4), a potent inflammatory mediator) to continue. Altering the essential fatty acid (EFA) content of the diet can modify some of these effects. Ingestion of a diet rich in evening primrose oil elevates concentrations of dihomo-gamma-linolenic acid (DGLA; 20:3n-6), which results in the production of 1-series PGs, eg, PGE(1). DGLA itself cannot be converted to LTs but can form a 15-hydroxyl derivative that blocks the transformation of arachidonic acid to LTs. Increasing DGLA intake may allow DGLA to act as a competitive inhibitor of 2-series PGs and 4-series LTs and thus suppress inflammation. The results of in vitro and animal work evaluating EFAs in inflammatory situations are encouraging, which has stimulated clinical workers to evaluate these compounds in rheumatoid arthritis. Several well-controlled, randomized clinical studies have now been completed in which various EFAs were evaluated as treatments. The results of most of these studies suggest some clinical benefit to these treatments; these data are reviewed here.

n-3 fatty acid supplements in rheumatoid arthritis.

Ingestion of dietary supplements of n-3 fatty acids has been consistently shown to reduce both the number of tender joints on physical examination and the amount of morning stiffness in patients with rheumatoid arthritis. In these cases, supplements were consumed daily in addition to background medications and the clinical benefits of the n-3 fatty acids were not apparent until they were consumed for >/=12 wk. It appears that a minimum daily dose of 3 g eicosapentaenoic and docosahexaenoic acids is necessary to derive the expected benefits. These doses of n-3 fatty acids are associated with significant reductions in the release of leukotriene B(4) from stimulated neutrophils and of interleukin 1 from monocytes. Both of these mediators of inflammation are thought to contribute to the inflammatory events that occur in the rheumatoid arthritis disease process. Several investigators have reported that rheumatoid arthritis patients consuming n-3 dietary supplements were able to lower or discontinue their background doses of nonsteroidal antiinflammatory drugs or disease-modifying antirheumatic drugs. Because the methods used to determine whether patients taking n-3 supplements can discontinue taking these agents are variable, confirmatory and definitive studies are needed to settle this issue. n-3 Fatty acids have virtually no reported serious toxicity in the dose range used in rheumatoid arthritis and are generally very well tolerated.

Dietary polyunsaturated fatty acids and inflammatory mediator production.

Many antiinflammatory pharmaceutical products inhibit the production of certain eicosanoids and cytokines and it is here that possibilities exist for therapies that incorporate n-3 and n-9 dietary fatty acids. The proinflammatory eicosanoids prostaglandin E(2) (PGE(2)) and leukotriene B(4) (LTB(4)) are derived from the n-6 fatty acid arachidonic acid (AA), which is maintained at high cellular concentrations by the high n-6 and low n-3 polyunsaturated fatty acid content of the modern Western diet. Flaxseed oil contains the 18-carbon n-3 fatty acid alpha-linolenic acid, which can be converted after ingestion to the 20-carbon n-3 fatty acid eicosapentaenoic acid (EPA). Fish oils contain both 20- and 22-carbon n-3 fatty acids, EPA and docosahexaenoic acid. EPA can act as a competitive inhibitor of AA conversion to PGE(2) and LTB(4), and decreased synthesis of one or both of these eicosanoids has been observed after inclusion of flaxseed oil or fish oil in the diet. Analogous to the effect of n-3 fatty acids, inclusion of the 20-carbon n-9 fatty acid eicosatrienoic acid in the diet also results in decreased synthesis of LTB(4). Regarding the proinflammatory ctyokines, tumor necrosis factor alpha and interleukin 1beta, studies of healthy volunteers and rheumatoid arthritis patients have shown </=90% inhibition of cytokine production after dietary supplementation with fish oil. Use of flaxseed oil in domestic food preparation also reduced production of these cytokines. Novel antiinflammatory therapies can be developed that take advantage of positive interactions between the dietary fats and existing or newly developed pharmaceutical products.

Polyunsaturated fatty acids and inflammatory bowel disease.

The rationale for supplementation with n-3 fatty acids to promote the health of the gastrointestinal tract lies in the antiinflammatory effects of these lipid compounds. The first evidence of the importance of dietary intake of n-3 polyunsaturated fatty acids was derived from epidemiologic observations of the low incidence of inflammatory bowel disease in Eskimos. The aim of this paper was to briefly review the literature on the use of n-3 fatty acids in inflammatory bowel disease (ulcerative colitis and Crohn disease), the results of which are controversial. The discrepancies between studies may reside in the different study designs used as well as in the various formulations and dosages used, some of which may lead to a high incidence of side effects. Choosing a formulation that lowers the incidence of side effects, selecting patients carefully, and paying strict attention to experimental design are critical when investigating further the therapeutic potential of these lipids in inflammatory bowel disease.

Plasma total cholesterol concentrations do not predict cerebrospinal fluid neurotransmitter metabolites: implications for the biophysical role of highly unsaturated fatty acids.

Low concentrations of a metabolite of serotonin found in cerebrospinal fluid (CSF), 5-hydroxyindolacetic acid (5-HIAA), are strongly associated with suicidal and violent behaviors. Although lowering of plasma total cholesterol has been suggested to increase mortality from suicide and violence by decreasing concentrations of CSF 5-HIAA via changes in membrane biophysical properties, highly unsaturated fatty acids may play a more important role. Violent and nonviolent comparison groups, early- and late-onset alcoholics, and healthy comparison subjects were studied to control for alcohol use and predisposition to violence. Fasting plasma total cholesterol and CSF were assayed under stringently controlled conditions. When all groups were combined (n = 234), plasma cholesterol concentrations had a weak positive correlation with CSF 5-HIAA (r = 0.18, P < 0.01). However, age correlated with both plasma total cholesterol and CSF 5-HIAA concentrations. When age was included in multiple regression models, the correlation between cholesterol and CSF 5-HIAA concentrations was not significant. Cholesterol correlated weakly with CSF 5-HIAA concentrations only in late-onset alcoholics after age was controlled for, but the relation was not significant after correction for multiple testing. CSF homovanillic acid did not correlate with plasma total cholesterol in any group. Plasma total cholesterol had no apparent relation to CSF neurotransmitter metabolites in any group of subjects. Highly unsaturated essential fatty acids, which are also critical determinants of membrane biophysical properties and may be linked to brain serotonin concentrations, should also be considered in studies examining the effect of lowering fat intake on the incidence of suicide and violence.

Long-chain polyunsaturated fatty acids in children with attention-deficit hyperactivity disorder.

Attention-deficit hyperactivity disorder (ADHD) is the diagnosis used to describe children who are inattentive, impulsive, and hyperactive. ADHD is a widespread condition that is of public health concern. In most children with ADHD the cause is unknown, but is thought to be biological and multifactorial. Several previous studies indicated that some physical symptoms reported in ADHD are similar to symptoms observed in essential fatty acid (EFA) deficiency in animals and humans deprived of EFAs. We reported previously that a subgroup of ADHD subjects reporting many symptoms indicative of EFA deficiency (L-ADHD) had significantly lower proportions of plasma arachidonic acid and docosahexaenoic acid than did ADHD subjects with few such symptoms or control subjects. In another study using contrast analysis of the plasma polar lipid data, subjects with lower compositions of total n-3 fatty acids had significantly more behavioral problems, temper tantrums, and learning, health, and sleep problems than did those with high proportions of n-3 fatty acids. The reasons for the lower proportions of long-chain polyunsaturated fatty acids (LCPUFAs) in these children are not clear; however, factors involving fatty acid intake, conversion of EFAs to LCPUFA products, and enhanced metabolism are discussed. The relation between LCPUFA status and the behavior problems that the children exhibited is also unclear. We are currently testing this relation in a double-blind, placebo-controlled intervention in a population of children with clinically diagnosed ADHD who exhibit symptoms of EFA deficiency.

Dark adaptation, motor skills, docosahexaenoic acid, and dyslexia.

Dyslexia is a widespread condition characterized by difficulty with learning and movement skills. It is frequently comorbid with dyspraxia (developmental coordination disorder), the chief characteristic of which is impaired movement skills, indicating that there may be some common biological basis to the conditions. Visual and central processing deficits have been found. The long-chain polyunsaturated fatty acids (LCPUFAs) are important components of retinal and brain membranes. In the preliminary studies reported here, dark adaptation was shown to be impaired in 10 dyslexic young adults when compared with a similar control group (P < 0.05, repeated-measures analysis of variance); dark adaptation improved in 5 dyslexia patients after supplementation with a docosahexaenoic acid (DHA)-rich fish oil for 1 mo (P < 0.05, paired t test on final rod threshold); and movement skills in a group of 15 dyspraxic children improved after 4 mo of supplementation with a mixture of high-DHA fish oil, evening primrose oil, and thyme oil (P < 0.007 for manual dexterity, P < 0.02 for ball skills, and P < 0.03 for static and dynamic balance; paired t tests). The studies were small and had designs that did not allow firm conclusions to be made. However, when considered with other evidence from another closely related condition, attention-deficit hyperactivity disorder, for which reduced ability to elongate and desaturate the essential fatty acids linoleic acid and alpha-linolenic acid to arachidonic acid and DHA, respectively, has been proposed, the studies suggest that more research, including double-blind, placebo-controlled studies, would be useful to clarify the benefits of LCPUFAs in dyslexia and other closely related conditions.

Transport mechanisms for long-chain polyunsaturated fatty acids in the human placenta.

To understand the placental role in the processes responsible for the preferential accumulation of maternal long-chain polyunsaturated fatty acids (LCPUFAs) in the fetus, we investigated fatty acid uptake and metabolism in the human placenta. A preference for LCPUFAs over nonessential fatty acids has been observed in isolated human placental membranes as well as in BeWo cells, a human placental choriocarcinoma cell line. A placental plasma membrane fatty acid binding protein (p-FABP(pm)) with a molecular mass of approximately 40 kDa was identified. The purified p-FABP(pm) preferentially bound with essential fatty acids (EFAs) and LCPUFAs over nonessential fatty acids. Oleic acid was taken up least and docosahexaenoic acid (DHA) most by BeWo cells, whereas no such discrimination was observed in HepG2 liver cells. Studies on the distribution of radiolabeled fatty acids in the cellular lipids of BeWo cells showed that DHA is incorporated mainly into the triacylglycerol fraction, followed by the phospholipid fraction; the reverse is true for arachidonic acid (AA). The greater cellular uptake of DHA and its preferential incorporation into the triacylglycerol fraction suggests that both uptake and transport modes of DHA by the placenta to the fetus are different from those of AA. p-FABP(pm) antiserum preferentially decreased the uptake of LCPUFAs and EFAs by BeWo cells compared with preimmune serum. Together, these results show the preferential uptake of LCPUFAs by the placenta that is most probably mediated via the p-FABP(pm).

Dietary n-3 fatty acid restriction during gestation in rats: neuronal cell body and growth-cone fatty acids.

Growth cones are membrane-rich structures found at the distal end of growing axons and are the predecessors of the synaptic membranes of nerve endings. This study examined whether n-3 fatty acid restriction during gestation in rats alters the composition of growth cone and neuronal cell body membrane fatty acids in newborns. Female rats were fed a standard control diet containing soy oil (8% of fatty acids as 18:3n-3 by wt) or a semisynthetic n-3 fatty acid-deficient diet with safflower oil (0.3% of fatty acids as 18:3n-3 by wt) throughout normal pregnancy. Experiments were conducted on postnatal day 2 to minimize the potential for contamination from synaptic membranes and glial cells. Dietary n-3 fatty acid restriction resulted in lower docosahexaenoic acid (DHA) concentrations and a corresponding higher docosapentaenoic acid concentration in neuronal growth cones, but had no effects on neuronal cell body fatty acid concentrations. These studies suggest that accretion of DHA in growth cones, but not neuronal cell bodies, is affected by n-3 fatty acid restriction during gestation. Differences in other fatty acids or components between the semisynthetic and the standard diet, however, could have been involved in the effects on growth-cone DHA content. The results also provide evidence to suggest that the addition of new membrane fatty acids to neurons during development occurs along the shaft of the axon or at the growth cone, rather than originating at the cell body.

Long-chain polyunsaturated fatty acid requirements during pregnancy and lactation.

Much interest has been expressed about the long-chain polyunsaturated fatty acid (LCPUFA) requirements of both preterm and term infants, whereas relatively little attention has been given to the LCPUFA needs of mothers, who may provide the primary source of LCPUFAs for their fetuses and breast-fed infants. Although maternal requirements for LCPUFAs are difficult to estimate because of large body stores and the capacity to synthesize LCPUFAs from precursors, biochemical and clinical intervention studies have provided some clues. From a biochemical viewpoint, there appears to be no detectable reduction in plasma n-3 LCPUFA concentrations during pregnancy, whereas there is a clear decline during the early postpartum period. The postpartum decrease in maternal plasma docosahexaenoic acid (DHA) concentration is not instantaneous, may be long-term, is independent of lactation, and is reversible with dietary DHA supplementation (200-400 mg/d). From a functional standpoint, the results of randomized clinical studies suggest that n-3 LCPUFA supplementation during pregnancy does not affect the incidences of pregnancy-induced hypertension and preeclampsia without edema. However, n-3 LCPUFA supplementation may cause modest increases in the duration of gestation, birth weight, or both. To date, there is little evidence of harm as a result of n-3 LCPUFA supplementation during either pregnancy or lactation. However, researchers need to further elucidate any potential benefits of supplementation for mothers and infants. Careful attention should be paid to study design, measurement of appropriate health outcomes, and defining minimum and maximum plasma n-3 LCPUFA concentrations that are optimal for both mothers and infants.

Effects of gestational alcohol exposure on the fatty acid composition of umbilical cord serum in humans.

This study examined the effects of maternal periconceptional alcohol intake on polyunsaturated fatty acid (PUFA) concentrations in human neonates. The area percentage of each fatty acid in cord blood serum from 12 infants born to control women (who consumed <2 mL absolute ethanol/d) was compared with that of 9 infants born to women whose periconceptional alcohol intake averaged >/=30 mL absolute ethanol/d. Periconceptional alcohol use was associated with a 30% increase in the proportion of docosahexaenoic acid (22:6n-3) in cord blood (3.0% of total lipid in control infants compared with 3.9% in alcohol-exposed infants; P < 0.01). The rise in the proportion of 22:6n-3 was responsible for increases in the ratio of n-3 to n-6 fatty acids and the ratio of long-chain n-3 to n-6 fatty acids (P < 0.055). Examination of the lipid-class fatty acid profile indicated that serum lipid alterations were localized to the cholesterol esters; 22:6n-3 in the cholesterol esters of alcohol-exposed infants increased 54% (P < 0.011) and arachidonic acid increased 55% (P < 0. 005). The relative fatty acyl composition of maternal serum showed a significant increase in 18:0 fatty acids in the alcohol-exposed group (25%, P < 0.005) but there were no changes in the other fatty acids. The increase in the proportion of 22:6n-3 was unexpected but is consistent with the hypothesis that this essential lipid may be conserved selectively. These results imply that the lifelong neurobehavioral and sensory dysfunction in fetal alcohol syndrome and other alcohol-related neurodevelopmental disorders may be due in part to PUFA dysregulation.

Effect of docosahexaenoic acid supplementation of lactating women on the fatty acid composition of breast milk lipids and maternal and infant plasma phospholipids.

To determine whether docosahexaenoic acid (DHA) supplementation of breast-feeding mothers increases the DHA contents of breast milk and infant plasma phospholipids (PPs), breast-feeding women were randomly assigned to 3 DHA-supplementation groups (170-260 mg/d) or a control group. Group 1 (n = 6) consumed an algae-produced high-DHA triacylglycerol; group 2 (n = 6) consumed high-DHA eggs; group 3 (n = 6) consumed a high-DHA, low-eicosapentaenoic acid marine oil; and group 4 (n = 6) received no supplementation. From before to after supplementation (2 and 8 wk postpartum), mean (+/-SD) maternal PP DHA increased in groups 1, 2, and 3 by 1.20 +/- 0.53, 0.63 +/- 0.82, and 0.76 +/- 0.35 mol% of fatty acids, respectively (23-41%), but decreased in group 4 by 0.44 +/- 0.34 mol% (15%). Breast-milk DHA of groups 1, 2, and 3 increased by 0.21 +/- 0.16, 0.07 +/- 0.11, and 0. 12 +/- 0.07 mol%, respectively (32-91%) but decreased in group 4 by 0.03 +/- 0.04 mol% (17%). Mean infant PP DHA in groups 1, 2, and 3 increased by 1.63 +/- 0.79, 0.40 +/- 1.0, and 0.98 +/- 0.61 mol%, respectively (11-42%), but only by 0.18 +/- 0.74 mol% (5%) in group 4. Correlations between the DHA contents of maternal plasma and breast milk and of milk and infant PPs were significant. Breast-milk and maternal and infant PP 22:5n-6 concentrations were lowest in group 2. DHA supplementation increases the plasma and breast-milk DHA concentrations of lactating women, resulting in higher PP DHA concentrations in infants.

Long-chain polyunsaturated fatty acids, pregnancy, and pregnancy outcome.

During pregnancy, essential long-chain polyunsaturated fatty acids (LCPUFAs) play important roles as precursors of prostaglandins and as structural elements of cell membranes. Throughout gestation, accretion of maternal, placental, and fetal tissue occurs and consequently the LCPUFA requirements of pregnant women and their developing fetuses are high. This is particularly true for docosahexaenoic acid (DHA; 22:6n-3). The ratio of DHA to its status marker, docosapentaenoic acid (22:5n-6), in maternal plasma phospholipids decreases significantly during pregnancy. This suggests that pregnancy is associated with maternal difficulty in coping with the high demand for DHA. The DHA status of newborn multiplets is significantly lower than that of singletons; the same is true for infants of multigravidas as compared with those of primigravidas and for preterm compared with term neonates. Because the LCPUFA status at birth seems to have a long-term effect, the fetus should receive an adequate supply of LCPUFAs. Data from an international comparative study indicated that, especially for n-3 LCPUFAs, the fetus is dependent on maternal fatty acid intake; maternal supplementation with LCPUFAs, their precursors, or both increased LCPUFA concentrations in maternal and umbilical plasma phospholipids. However, significant competition between the 2 LCPUFA families was observed, which implies that effective supplementation requires a mixture of n-6 and n-3 fatty acids. Further research is needed to determine whether higher LCPUFA concentrations in plasma phospholipid will have functional benefits for mothers and children.

Placental delivery of arachidonic and docosahexaenoic acids: implications for the lipid nutrition of preterm infants.

Arachidonic (AA) and docosahexaenoic (DHA) acids are major components of cell membranes and are of special importance to the brain and blood vessels. In utero, the placenta selectively and substantially extracts AA and DHA from the mother and enriches the fetal circulation. Studies indicate that there is little placental conversion of the parent essential fatty acids to AA and DHA. Similarly, analyses of desaturation and reductase activity have shown the placenta to be less functional than the maternal or fetal livers. There appears to be a correlation with placental size and plasma AA and DHA proportions in cord blood; therefore, placental development may be an important variable in determining nutrient transfer to the fetus and, hence, fetal growth itself. In preterm infants, both parenteral and enteral feeding methods are modeled on term breast milk. Consequently, there is a rapid decline of the plasma proportions of AA and DHA to one quarter or one third of the intrauterine amounts that would have been delivered by the placenta. Simultaneously, the proportion of linoleic acid, the precursor for AA, rises in the plasma phosphoglycerides 3-fold. An inadequate supply of AA and DHA during the period of high demand from rapid vascular and brain growth could lead to fragility, leakage, and membrane breakdown. Such breakdown would predictably be followed by peroxidation of free AA, vasoconstriction, inflammation, and ischemia with its biological sequelae. In the brain, cell death would be an extreme consequence.

Behavioral methods used in the study of long-chain polyunsaturated fatty acid nutrition in primate infants.

Domains of behavior may be broadly categorized as sensory, motor, motivational and arousal, cognitive, and social. Differences in these domains occur because of changes in brain structure and function. Docosahexaenoic acid (DHA; 22:6-23) and arachidonic acid (AA; 20:4-26) are major structural components of the brain that decrease when diets deficient in the essential fatty acids (EFA) alpha-linolenic acid and linoleic acid are consumed. Early electrophysiologic and behavioral studies in EFA-deficient rodents showed behavioral effects attributable to lower-than-normal accumulation of DHA and AA in the brain. More recently, electrophysiologic and behavioral studies in EFA-deficient primate infants and analogous studies in human infants have been conducted. The human infants were fed formulas that could result in lower-than-optimal accumulation of long-chain polyunsaturated fatty acids (LCPUFAs) in the brain during critical periods of development. This article describes the behavioral methods that have been used to study primate infants. These methods may be unfamiliar to many physicians and nutritionists who wish to read and interpret the human studies. The behavioral outcomes that have been evaluated in LCPUFA studies represent only a fraction of those available in the behavioral sciences. Specific developmental domains have been studied less often than global development, even though studies of nonhuman primates deficient in EFAs suggest that the former provide more information that could help target the underlying mechanisms of action of LCPUFAs in the brain.

Infant vision and retinal function in studies of dietary long-chain polyunsaturated fatty acids: methods, results, and implications.

Animal and human studies have documented several effects of different dietary and tissue concentrations of long-chain polyunsaturated fatty acids (LCPUFAs) on retinal function and vision. The enhanced visual development associated with increased intakes of LCPUFAs, particularly docosahexaenoic acid (DHA), provides the strongest evidence for the importance of these fatty acids in infant nutrition. The 2 primary visual measures used to assess the efficacy of infant formula LCPUFA supplementation are the electroretinogram and visual acuity. This review briefly describes the methodology, neural basis, and interpretation of these measures, as well as other measures of visual development that may be used to extend the functional evaluation of infants fed formulas with different fatty acid compositions.

n-3 polyunsaturated fatty acid requirements of term infants.

The benchmarks for human nutrient requirements are the recommended dietary intakes (RDIs). However, the RDIs are set to prevent a clinical deficiency state in an otherwise healthy population and there are few nutrient recommendations set with the goal of achieving an optimal or maximal state of nutrition and health. This is becoming an increasing challenge with the introduction of many nutraceuticals and functional foods, a prime example being the debate surrounding the introduction of long-chain polyunsaturated fatty acids (LCPUFAs) into infant formulas. Most expert nutrition committees have used the fatty acid composition of breast milk as a basis for recommendations for infant formulas, with little information on the minimum absolute requirement for essential PUFAs. It has been difficult to determine a minimum requirement for fatty acids because 1) LCPUFAs can be synthesized from precursor fatty acids, 2) plasma n-3 LCPUFA concentrations representing deficiency and sufficiency are not clearly defined, and 3) there are no recognized clinical tests for n-3 LCPUFA deficiency and sufficiency. Therefore, there is a clear need to associate a measure of LCPUFA status with a specific functional outcome before any recommendations can be made for achieving optimal or maximal LCPUFA status.

Essential fat requirements of preterm infants.

The interest in factors that modify early infant development has led investigators to focus on n-3 and n-6 long-chain polyunsaturated fatty acids (LCPUFAs) in the past 2 decades. The presence of docosahexaenoic acid (DHA) and arachidonic acid (AA) in breast milk, compared with their absence from infant formulas available in the United States, has prompted clinical trials designed to examine whether LCPUFA enrichment of infant formula has beneficial effects on maturational events of the visual system. These trials have shown significant functional advantages of LCPUFA supplementation for preterm infants, whereas benefits for full-term infants remain controversial. The growth and safety of preterm infants was not compromised by LCPUFA enrichment, although these issues remain to be resolved in clinical trials with full-term infants.

Essential fatty acids in infant nutrition: lessons and limitations from animal studies in relation to studies on infant fatty acid requirements.

Animal studies have been of pivotal importance in advancing knowledge of the metabolism and roles of n-6 and n-3 fatty acids and the effects of specific dietary intakes on membrane composition and related functions. Advantages of animal studies include the rigid control of fatty acid and other nutrient intakes and the degree, timing, and duration of deficiency or excess, the absence of confounding environmental and clinical variables, and the tissue analysis and testing procedures that cannot be performed in human studies. However, differences among species in nutrient requirements and metabolism and the severity and duration of the dietary treatment must be considered before extrapolating results to humans. Studies in rodents and nonhuman primates fed diets severely deficient in alpha-linolenic acid (18:3n-3) showed altered visual function and behavioral problems, and played a fundamental role by identifying neural systems that may be sensitive to dietary n-3 fatty acid intakes; this information has assisted researchers in planning clinical studies. However, whereas animal studies have focused mainly on 18:3n-3 deficiency, there is considerable clinical interest in docosahexaenoic acid (22:6n-3) and arachidonic acid (20:4n-6) supplementation. Information from animal studies suggests that brain and retinal concentrations of 22:6n-3 plateau with 18:3n-3 intakes of approximately 0.7% of energy, but this requirement is influenced by dietary 18:2n-6 intake. Blood and tissue concentrations of 22:6n-3 increase as 22:6n-3 intake increases, with adverse effects on growth and function at high intakes. Animal studies can provide important information on the mechanisms of both beneficial and adverse effects and the pathways of brain 22:6n-3 uptake.

Effect of long-chain n-3 polyunsaturated fatty acids on fasting and postprandial triacylglycerol metabolism.

Elevated plasma triacylglycerol concentrations have been associated with increased risk of coronary heart disease (CHD). In the past, the epidemiologic evidence about the causal role of triacylglycerols in CHD has not been well regarded, but recent prospective evidence shows that nonfasting plasma triacylglycerol concentration is a strong and independent predictor of future myocardial infarction. Elevated plasma triacylglycerol concentrations are associated with other CHD risk factors, namely reduced HDL-cholesterol concentrations and a preponderance of highly atherogenic, small, dense LDL particles. Plasma triacylglycerol concentrations increase after the ingestion of a fat-containing meal, and elevated postprandial triacylglycerolemia leads to a series of metabolic reactions that reduce HDL-cholesterol concentrations and promote the formation of small, dense LDL particles. The magnitude of the postprandial response is largely determined by fasting plasma triacylglycerol concentrations. Metabolism of plasma triacylglycerols also influences postprandial factor VII activation and the postprandial lipemic responsiveness to dietary cholesterol. Therefore, dietary factors that improve fasting plasma triacylglycerol concentrations must have a role in a healthy diet. Eicosapentaenoic and docosahexaenoic acids are n-3 polyunsaturated fatty acids (PUFAs) in fish oil that effectively reduce plasma triacylglycerol concentrations. Because n-3 PUFAs are effective at low doses (1 g n-3 PUFA/d), they provide a realistic option for the optimization of plasma triacylglycerol metabolism.

Fish oil and cardiovascular disease: lipids and arterial function.

n-3 Fatty acids have been shown to modify several key risk factors for cardiovascular disease. However, it is not clear whether the apparent protection against cardiovascular disease is directly related to antiatherogenic functions of these fatty acids or is mediated through their modification of the risk factors through mechanisms not directly related to lipids. A major question concerns the importance of lipid modification, which is a potent outcome of fish-oil supplementation. On balance, lipid modification is likely to represent a significant antiatherogenic factor. The benefits include increased HDL(2)-cholesterol concentrations, reduced triacylglycerol-rich lipoprotein concentrations, reduced postprandial lipemia, and reduced remnant concentrations. In contrast, LDL-cholesterol concentrations have often been noted to rise and the potential of increased oxidizability of LDLs is potentially adverse with lipid modification, but this potential can be overcome with vitamin E supplementation. The characteristic lipid changes and the underlying mechanisms are reviewed. Additional benefits of fish oils include improved endothelial function and better arterial compliance (elasticity). Future trials will be needed to determine minimum effective dosages of eicosapentaenoic and docosahexaenoic acids over lengthy periods and to show cardiovascular disease reduction through intervention.

n-3 fatty acids and the prevention of coronary atherosclerosis.

Epidemiologic studies have shown an inverse correlation between consumption of fish or other sources of dietary n-3 fatty acids and cardiovascular events. Numerous mechanisms of action for the favorable effect of dietary n-3 fatty acids on factors implicated in the pathogenesis of atherosclerosis have been described. Studies in dogs, swine, and nonhuman primates have consistently shown beneficial effects in various models of vasoocclusive diseases. Studies published currently do not indicate that dietary n-3 fatty acids prevent restenosis after percutaneous coronary angioplasty or induce regression of coronary atherosclerosis. However, in a recent study, occlusion of aortocoronary venous bypass grafts was reduced after 1 y by daily ingestion of 4 g fish-oil concentrate. In the Diet and Reinfarction Trial, 2-y overall mortality was reduced by 29% in survivors of a first myocardial infarction after consumption of n-3 fatty acid-rich fatty fish at least twice a week had been advised (Lancet 1989;2:757-61). When n-3 fatty acids were integrated into a diet resembling a traditional Mediterranean diet, 5-y cardiovascular mortality after a first myocardial infarction was reduced by 70% (Lancet 1994; 343:1454-9). Preliminary studies indicate that cardiac transplant patients could be an interesting focus of investigation. Currently, food sources rich in n-3 fatty acids are thought to be beneficial in secondary prophylaxis after a myocardial infarction. Large-scale clinical studies with endpoints such as morbidity and mortality are needed to more precisely define the role of n-3 fatty acids in primary and secondary prophylaxis of coronary atherosclerosis.

Fatty acid modulation of endothelial activation.

Dietary balance of long-chain fatty acids may influence processes involving leukocyte-endothelial interactions, such as atherogenesis and inflammation, that involve increased endothelial expression of leukocyte adhesion molecules, or endothelial activation. We compared the ability of various saturated, monounsaturated, and polyunsaturated fatty acids to modulate endothelial activation. Consumption of the n-3 fatty acid docosahexaenoic acid (DHA; 22:6n-3) reduced endothelial expression of vascular cell adhesion molecule 1 (VCAM-1), E-selectin, intercellular adhesion molecule 1 (ICAM-1), interleukin 6 (IL-6), and IL-8 in response to IL-1, IL-4, tumor necrosis factor, or bacterial endotoxin, with a half-maximal inhibitory concentration (IC(50)) of 1-25 &mgr;mol, ie, in the range of nutritionally achievable plasma concentrations. The magnitude of this effect paralleled its incorporation into cellular phospholipids. DHA also reduced the adhesion of human monocytes and monocytic U937 cells to cytokine-stimulated endothelial cells. These effects were accompanied by a reduction in VCAM-1 messenger RNA, indicating a pretranslational effect. To assess structural fatty acid determinants of VCAM-1 inhibitory activity, we compared various saturated, monounsaturated, and n-6 and n-3 polyunsaturated fatty acids for their VCAM-1 inhibitory activity. Saturated fatty acids did not inhibit cytokine-induced expression of adhesion molecules. However, a progressive increase in inhibitory activity was observed with dietary intake of fatty acids with the same chain length but increasing double bonds, ie, from monounsaturated to n-6 and, further, to n-3 fatty acids. Thus, the greater number of double bonds seems critical for the greater activity of n-3 compared with n-6 fatty acids in inhibiting endothelial activation. These properties are likely to be relevant to the antiatherogenic and antiinflammatory properties of n-3 fatty acids.

Dietary intake of long-chain n-3 polyunsaturated fatty acids and the risk of primary cardiac arrest.

Whether the dietary intake of long-chain n-3 polyunsaturated fatty acids (PUFAs) from seafood reduces the risk of ischemic heart disease remains a source of controversy, in part because studies have yielded inconsistent findings. Results from experimental studies in animals suggest that recent dietary intake of long-chain n-3 PUFAs, compared with saturated and monounsaturated fats, reduces vulnerability to ventricular fibrillation, a life-threatening cardiac arrhythmia that is a major cause of ischemic heart disease mortality. Until recently, whether a similar effect of long-chain n-3 PUFAs from seafood occurred in humans was unknown. We summarize the findings from a population-based case-control study that showed that the dietary intake of long-chain n-3 PUFAs from seafood, measured both directly with a questionnaire and indirectly with a biomarker, is associated with a reduced risk of primary cardiac arrest in humans. The findings also suggest that 1) compared with no seafood intake, modest dietary intake of long-chain n-3 PUFAs from seafood (equivalent to 1 fatty fish meal/wk) is associated with a reduction in the risk of primary cardiac arrest; 2) compared with modest intake, higher intakes of these fatty acids are not associated with a further reduction in such risk; and 3) the reduced risk of primary cardiac arrest may be mediated, at least in part, by the effect of dietary n-3 PUFA intake on cell membrane fatty acid composition. These findings also may help to explain the apparent inconsistencies in earlier studies of long-chain n-3 PUFA intake and ischemic heart disease.

Prevention of fatal cardiac arrhythmias by polyunsaturated fatty acids.

In animal feeding studies, and probably in humans, n-3 polyunsaturated fatty acids (PUFAs) prevent fatal ischemia-induced cardiac arrhythmias. We showed that n-3 PUFAs also prevented such arrhythmias in surgically prepared, conscious, exercising dogs. The mechanism of the antiarrhythmic action of n-3 PUFAs has been studied in spontaneously contracting cultured cardiac myocytes of neonatal rats. Adding arrhythmogenic toxins (eg, ouabain, high Ca(2+), lysophosphatidylcholine, beta-adrenergic agonist, acylcarnitine, and the Ca(2+) ionophore) to the myocyte perfusate caused tachycardia, contracture, and fibrillation of the cultured myocytes. Adding eicosapentaenoic acid (EPA: 5-15 &mgr;mol/L) to the superfusate before adding the toxins prevented the expected tachyarrhythmias. If the arrhythmias were first induced, adding the EPA to the superfusate terminated the arrhythmias. This antiarrhythmic action occurred with dietary n-3 and n-6 PUFAs; saturated fatty acids and the monounsaturated oleic acid induced no such action. Arachidonic acid (AA; 20:4n-6) is anomalous because in one-third of the tests it provoked severe arrhythmias, which were found to result from cyclooxygenase metabolites of AA. When cyclooxygenase inhibitors were added with the AA, the antiarrhythmic effect was like those of EPA and DHA. The action of the n-3 and n-6 PUFAs is to stabilize electrically every myocyte in the heart by increasing the electrical stimulus required to elicit an action potential by approximately 50% and prolonging the relative refractory time by approximately 150%. These electrophysiologic effects result from an action of the free PUFAs to modulate sodium and calcium currents in the myocytes. The PUFAs also modulate sodium and calcium channels and have anticonvulsant activity in brain cells.

Safety considerations of polyunsaturated fatty acids.

The n-6 and n-3 polyunsaturated fatty acids (PUFAs) are essential nutrients; intake of relatively small amounts of these fatty acids prevents nutritional deficiencies. Replacing dietary saturated fat with PUFAs may confer health gains. Experimental data support the notion that high intake of n-6 PUFAs may increase in vivo lipid peroxidation. This effect may be counteracted by dietary antioxidant supplementation. The influence of a high n-3 PUFA intake on measures of lipid peroxidation has been equivocal. In clinical trials, subjects who consumed diets rich in n-6 or n-3 PUFAs had fewer atherothrombotic endpoints than did control groups. In this report, data regarding the influence of PUFAs on lipid peroxidation as well as on cholesterol and glucose metabolism, hemostasis, and other aspects of interest are reviewed and discussed. Currently, daily intake of PUFAs as >10% of total energy is not recommended. Below this ceiling there is little evidence that high dietary intake of n-6 or n-3 PUFAs implies health risks.

Polyunsaturated fatty acids in the food chain in japan.

The amount of polyunsaturated fatty acids (PUFAs) in the food chain in Japan is reviewed on the basis of the newest nutrition survey data. The Japanese are currently consuming, on average, approximately 26% of energy as fats with ratios of polyunsaturated to saturated fats and n-6 to n-3 fatty acids of approximately 1.2:1 and 4:1, respectively. The significant contributors to this relatively high n-3 PUFA intake are not only fish and shellfish but also edible vegetable oils, almost exclusively rapeseed and soybean oils. Thus, the dietary habits of the Japanese have made possible a high n-3 PUFA intake within a low-fat regimen. In this context, the gradual decline, particularly in younger persons, in fish consumption habits weighs on our minds. Analyses of health indexes, including the increased average life span, support the superiority of the current Japanese eating pattern that harmonizes with the Western regimens. However, at present it cannot be disregarded that food intake varies considerably in all age groups, and only a limited number of people are consuming the recommended allowance for dietary fats.

Polyunsaturated fatty acids in the food chain in the united states.

In the United States, intake of n-3 fatty acids is approximately 1.6 g/d ( approximately 0.7% of energy), of which 1.4 g is alpha-linolenic acid (ALA; 18:3) and 0.1-0.2 g is eicosapentaenoic acid (EPA; 20:5) and docosahexaenoic acid (DHA; 22:6). The primary sources of ALA are vegetable oils, principally soybean and canola. The predominant sources of EPA and DHA are fish and fish oils. Intake data indicate that the ratio of n-6 to n-3 fatty acids is approximately 9.8:1. Food disappearance data between 1985 and 1994 indicate that the ratio of n-6 to n-3 fatty acids has decreased from 12.4:1 to 10.6:1. This reflects a change in the profile of vegetable oils consumed and, in particular, an approximate 5.5-fold increase in canola oil use. The ratio of n-6 to n-3 fatty acids is still much higher than that recommended (ie, 2.3:1). Lower ratios increase endogenous conversion of ALA to EPA and DHA. Attaining the proposed recommended combined EPA and DHA intake of 0.65 g/d will require an approximately 4-fold increase in fish consumption in the United States. Alternative strategies, such as food enrichment and the use of biotechnology to manipulate the EPA and DHA as well as ALA contents of the food supply, will become increasingly important in increasing n-3 fatty acid intake in the US population.

Polyunsaturated fatty acids in the food chain in europe.

Intakes of partially hydrogenated fish oil and animal fats have declined and those of palm, soybean, sunflower, and rapeseed oils have increased in northern Europe in the past 30 y. Soybean and rapeseed oils are currently the most plentiful liquid vegetable oils and both have desirable ratios of n-6 to n-3 fatty acids. However, soybean and rapeseed oils are commonly partially hydrogenated for use in commercial frying to decrease susceptibility to oxidative degradation. This process leads to selective losses of alpha-linolenic acid (18:3n-3). Intake of linoleic acid (18:2n-6) has risen in many northern European countries. In the United Kingdom, intakes have increased from approximately 10 g/d in the late 1970s to approximately 15 g/d in the 1990s. The intake of alpha-linolenic acid is estimated to be approximately 1-2 g/d but varies with the type of culinary oil used. There are few reliable estimates of the intake of long-chain n-3 fatty acids, but those are generally approximately 0.1-0.5 g/d. The increased use of intensive, cereal-based livestock production systems has resulted in a lower proportion of n-3 fatty acids in meat compared with traditional extensive production systems. Overall, there has been a shift in the balance between n-6 and n-3 fatty acids over the past 30 y. This shift is reflected in the declining concentrations of docosahexaenoic acid and rising concentrations of linoleic acid in breast milk.

Importance of n-3 fatty acids in health and disease.

In the past 2 decades, views about dietary n-3 fatty acids have moved from speculation about their functions to solid evidence that they are not only essential nutrients but also may favorably modulate many diseases. Docosahexaenoic acid (22:6n-3), which is a vital component of the phospholipids of cellular membranes, especially in the brain and retina, is necessary for their proper functioning. n-3 Fatty acids favorably affect atherosclerosis, coronary heart disease, inflammatory disease, and perhaps even behavioral disorders. The 38 articles in this supplement document the importance of n-3 fatty acids in both health and disease.