DHA attenuates postprandial hyperlipidemia via activating PPARα in intestinal epithelial cells

It is known that peroxisome proliferator-activated receptor (PPAR)α, whose activation reduces hyperlipidemia, is highly expressed in intestinal epithelial cells. Docosahexaenoic acid (DHA) could improve postprandial hyperlipidemia, however, its relationship with intestinal PPARα activation is not revealed. In this study, we investigated whether DHA can affect postprandial hyperlipidemia by activating intestinal PPARα using Caco-2 cells and C57BL/6 mice. The genes involved in fatty acid (FA) oxidation and oxygen consumption rate were increased, and the secretion of triacylglyceride (TG) and apolipoprotein B (apoB) was decreased in DHA-treated Caco-2 cells. Additionally, intestinal FA oxidation was induced, and TG and apoB secretion from intestinal epithelial cells was reduced, resulting in the attenuation of plasma TG and apoB levels after oral administration of olive oil in DHA-rich oil-fed mice compared with controls. However, no increase in genes involved in FA oxidation was observed in the liver. Furthermore, the effects of DHA on intestinal lipid secretion and postprandial hyperlipidemia were abolished in PPARα knockout mice. In conclusion, the present work suggests that DHA can inhibit the secretion of TG from intestinal epithelial cells via PPARα activation, which attenuates postprandial hyperlipidemia.     

Selective decrease of bis(monoacylglycero)phosphate content in macrophages by high supplementation with docosahexaenoic acid

Bis(monoacylglycero)phosphate (BMP) is a unique phospholipid (PL) preferentially found in late endosomal membranes, where it forms specialized lipid domains. Recently, using cultured macrophages treated with anti-BMP antibody, we showed that BMP-rich domains are involved in cholesterol homeostasis. We had previously stressed the high propensity of BMP to accumulate docosahexaenoic acid (DHA), compared with other PUFAs. Because phosphatidylglycerol (PG) was reported as a precursor for BMP synthesis in RAW macrophages, we examined the effects of PG supplementation on both FA composition and amount of BMP in this cell line. Supplementation with dioleoyl-PG (18:1/18:1-PG) induced BMP accumulation, together with an increase of oleate proportion. Supplementation with high concentrations of didocosahexaenoyl-PG (22:6/22:6-PG) led to a marked enrichment of DHA in BMP, resulting in the formation of diDHA molecular species. However, the amount of BMP was selectively decreased. Similar effects were observed after supplementation with high concentrations of nonesterified DHA. Addition of vitamin E prevented the decrease of BMP and further increased its DHA content. Supplementation with 22:6/22:6-PG promoted BMP accumulation with an enhanced proportion of 22:6/22:6-BMP. DHA-rich BMP was significantly degraded after cell exposure to oxidant conditions, in contrast to oleic acid-rich BMP, which was not affected. Using a cell-free system, we showed that 22:6/22:6-BMP is highly oxidizable and partially protects cholesterol oxidation, compared with 18:1/18:1-BMP. Our data suggest that high DHA content in BMP led to specific degradation of this PL, possibly through the diDHA molecular species, which is very prone to peroxidation and, as such, a potential antioxidant in its immediate vicinity.     

Erythrocyte eicosapentaenoic acid versus docosahexaenoic acid as a marker for fish and fish oil consumption.

The fatty acid composition of erythrocyte membranes was investigated in 21 healthy men after 6 wk of varying intakes of eicosapentaenoic acid (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3). In one experiment, 12 subjects were fed three diets in a 3 x 3 crossover design: an essentially fish-free control diet, a fish diet (0.15 g EPA/d, 0.41 g DHA/d) and the same fish-based diet supplemented with 5 g/d fish oil (Fish + Oil: 0.99 g EPA/d, 0.99 g DHA/d). A 6 wk wash-out period was allowed between each diet. In another experiment, 11 subjects were supplemented with 5 g/d fish oil alone for 6 wk (0.84 g EPA/d, 0.48 g DHA/d). After fish or fish oil feeding, the percent proportion of EPA and DHA in the erythrocyte membranes rose at the expense of linoleic and arachidonic acids. After 6 wk on the fish-based diets, EPA incorporation approached saturation, with the incremental increases being proportional to the amounts supplied by the diets. In contrast, parallel increases were observed for erythrocyte DHA even though the Fish + Oil diet was supplying twice as much DHA as the fish alone diet. These observations imply different metabolic rates for EPA and DHA and their importance is discussed in terms of the value of erythrocyte EPA versus DHA as markers for fish and fish oil consumption.     

The effect of supplementation with docosahexaenoic and arachidonic acid derived from single cell oils on plasma and erythrocyte fatty acids of pregnant women in the second trimester

This study was performed to investigate whether supplementation of docosahexaenoic acid (DHA) and arachidonic acid (AA) to pregnant women would enhance their DHA levels, both in plasma and in erythrocyte phospholipids, without reducing the content of n-6 long-chain ployenes (LCP) usually seen when DHA is supplemented alone. Healthy pregnant women, in the second trimester, were randomly assigned to either the control group (n=12) or the intervention group (n=12). The control group received no supplements and the intervention group received daily during 4 weeks encapsulated algae-derived DHA oil (0.57 g DHA/day) and fungal-derived AA oil (0.26 g AA/day). The fatty acid compositions of plasma and erythrocyte phospholipids were determined in weekly-collected blood samples. DHA and n-6 LCP levels of the control group were unchanged after 4 weeks. Compared to the control group, DHA levels in plasma an erythrocytes of the intervention group increased significantly. No significant reductions were found in the levels of AA and total n-6 LCP. The supplement proved to be effective in increasing the DHA levels in both plasma and erythrocyte without a concomitant decline of the n-6 LCP.     

Suppression of platelet-activating factor generation and modulation of arachidonate metabolism by dietary enrichment with (n-9) eicosatrienoic acid or docosahexaenoic acid in mouse peritoneal cells

Several studies have shown that dietary n-3 polyunsaturated fatty acids (PUFAs) suppress platelet-activating factor (PAF) generation in leukocytes of humans and rodents, which is associated with the antagonism of arachidonic acid metabolism. Dietary eicosatrienoic acid (20:3n-9, ETrA) is also suggested to antagonize arachidonic acid (AA) metabolism, but its effect on PAF generation in leukocytes has not been defined. In the present study, we investigated the effects of an ETrA-rich diet on PAF generation and AA metabolism in mouse peritoneal cells, which were compared with those of a docosahexaenoic acid (DHA)-rich diet. Mice were fed a diet supplemented with a lipid preparation rich in ETrA, a DHA-rich fish oil (FO) or palm oil (PO) for 3 weeks, and peritoneal cells containing more than 80% of monocytes/macrophages were obtained. The peritoneal cells in the DHA and ETrA diet groups generated upon zymosan stimulation a smaller amount of PAF than cells in the PO diet group. In the peritoneal cells of the DHA diet group, AA contents in phosphatidylcholine (PC) and phosphatidylethanolamine (PE) were significantly lower than those in cells of the PO diet group, but those in phosphatidylinositol (PI) were not significantly different between the two dietary groups. A considerable amount of ETrA was incorporated into the peritoneal cells of the ETrA diet group, and AA was reduced as compared with the PO diet group. These changes occurred preferentially in PI but to a less extent in PC and PE. The amount of free AA released by the peritoneal cells upon zymosan stimulation was significantly reduced in the DHA diet group as compared with that in the PO diet group, whereas AA release was similar between the PO and ETrA diet groups. In conclusion, the effects of dietary ETrA on AA content in the phospholipid subclasses and AA release were quite different from those of dietary DHA, although both diets suppressed PAF generation in mouse peritoneal cells to a similar extent.     

Low essential fatty acid and B-vitamin status in a subgroup of patients with schizophrenia and its response to dietary supplementation

We assessed essential fatty acid (EFA) and B-vitamin status, together with their determinants, in 61 patients with schizophrenia and established whether those with poor status responded biochemically to the appropriate dietary supplements. As a group, the patients had high erythrocyte saturated fatty acids (FAs), monounsaturated FA and low polyunsaturated FA of the omega3 and omega6 series. Patients reporting not to take vitamin supplements had low vitamin B12 and high homocysteine. Homocysteine variance proved best explained by folate in both the total group and male patients, and by vitamins B12 and B6 in females. Alcohol consumption and duration of illness are risk factors for low polyunsaturated FA status (< P2.5 of reference range), while male gender and absence of fish consumption predict hyperhomocysteinemia (> P97.5 of reference range). Two patients exhibited biochemical EFA deficiency and seven showed biochemical signs of omega3/docosahexaenoic acid (DHA) marginality. Four patients exhibited moderate hyperhomocysteinemia with plasma values ranging from 57.5 to 74.8 micromol/L. None of the five patients with either moderate hyperhomocysteinemia, biochemical EFA deficiency, or both, was predicted by their clinicians to have poor diets. That diet was nevertheless at the basis of these abnormalities became confirmed after supplementing 4 of them with B vitamins and with soybean and fish oils. We conclude that a subgroup of patients with schizophrenia has biochemical EFA deficiency, omega3/DHA marginality, moderate hyperhomocysteinemia, or combinations. Correction seems indicated in view of the possible relation of poor EFA and B-vitamin status with some of their psychiatric symptoms, but notably to reduce their high risk of cardiovascular disease.     

Liver composition and lipid metabolism in NZB/W F1 female mice fed dehydroisoandrosterone

The beneficial effects obtained with dehydroisoandrosterone (DHA) feeding in the treatment of murine systemic lupus erythematosus are similar to those obtained with caloric restriction or with dietary manipulation of essential fatty acid availability. In this study, the fatty acid composition of selected tissues was examined in NZB/W F1 mice fed a diet containing 0.4% DHA. The effect of the DHA diet on liver composition and the activity of key hepatic enzymes involved in fatty acid synthesis and glucose metabolism was also investigated. The content of the essential fatty acid, arachidonate, was decreased in plasma cholesteryl esters and liver and kidney phospholipids in mice fed the DHA diet, yet no significant decrease in arachidonate content was observed in plasma phospholipid. The most striking change in both plasma and liver phospholipid was an increase in palmitic acid and a decrease in stearic acid, which could result from a decreased ability for fatty acid elongation. The liver mass was dramatically increased in the mice fed DHA, primarily from parenchymal cell hypertrophy, and contained little lipid. Significant changes in the activities of malic enzyme, glucose-6-phosphate dehydrogenase and pyruvate kinase, similar to those changes which occur with fasting, were observed during the initial adaptation to the DHA diet. The pyruvate kinase activity remained low, suggesting a decrease in liver glycolysis. These results are consistent with the concept that diets containing DHA result in an altered metabolism with a decreased dependence on carbohydrate metabolism and an increased metabolism of lipids.     

Reduced G protein-coupled signaling efficiency in retinal rod outer segments in response to n-3 fatty acid deficiency

The fatty acid (FA) docosahexaenoic acid (DHA, 22: 6n-3) is highly enriched in membrane phospholipids of the central nervous system and retina. Loss of DHA because of n-3 FA deficiency leads to suboptimal function in learning, memory, olfactory-based discrimination, spatial learning, and visual acuity. G protein-coupled receptor (GPCR) signal transduction is a common signaling motif in these neuronal pathways. Here we investigated the effect of n-3 FA deficiency on GPCR signaling in retinal rod outer segment (ROS) membranes isolated from rats raised on n-3-adequate or -deficient diets. ROS membranes of second generation n-3 FA-deficient rats had approximately 80% less DHA than n-3-adequate rats. DHA was replaced by docosapentaenoic acid (22:5n-6), an n-6 FA. This replacement correlated with desensitization of visual signaling in n-3 FA-deficient ROS, as evidenced by reduced rhodopsin activation, rhodopsin-transducin (G(t)) coupling, cGMP phosphodiesterase activity, and slower formation of metarhodopsin II (MII) and the MII-G(t) complex relative to n-3 FA-adequate ROS. ROS membranes from n-3 FA-deficient rats exhibited a higher degree of phospholipid acyl chain order relative to n-3 FA-adequate rats. These findings reported here provide an explanation for the reduced amplitude and delayed response of the electroretinogram a-wave observed in n-3 FA deficiency in rodents and nonhuman primates. Because members of the GPCR family are widespread in signaling pathways in the nervous system, the effect of reduced GPCR signaling due to the loss of membrane DHA may serve as an explanation for the suboptimal neural signaling observed in n-3 FA deficiency.     

Effects of selenium deficiency on fatty acid metabolism in rats fed fish oil-enriched diets.

The hepatic fatty acid metabolism was investigated in rats stressed by selenium deficiency and enhanced fish oil intake. Changes in the composition of lipids, peroxides, and fatty acids were studied in the liver of rats fed either a Sedeficient (8 microg Se/kg) or a Se-adequate (300 microg Se/kg) diet, both rich in n-3 fatty acid-containing fish oil (100 g/kg diet) and vitamin E (146 mg alpha-tocopherol/kg diet). The two diets were identical except for their Se content. Se deficiency led to a decrease in hair coat density and quality as well as to changes in liver lipids, individual lipid fractions and phospholipid fatty acid composition of the liver. The low Se status did reduce total and reduced glutathione in the liver but did not affect the hepatic malondialdehyde level. In liver phospholipids (PL), Se deficiency significantly reduced levels of palmitic acid [16:0], fatty acids of the n-3 series such as DHA [22:6 n-3], and other long-chain polyunsaturates C-20-C-22, but increased n-6 fatty acids such as linoleic acid (LA) [18:2 n-6]. Thus, the conversion of LA to arachidonic acid was reduced and the ratio of n-6/n-3 fatty acids was increased. As in liver PL, an increase in the n-6/n-3 ratio was also observed in the mucosal total fatty acids of the small intestine. These results suggest that in rats with adequate vitamin E and enhanced fish oil intake, Se deficiency affects the lipid concentration and fatty acid composition in the liver. The changes may be related to the decreased levels of selenoenzymes with antioxidative functions. Possible effects of Se on absorption, storage and desaturation of fatty acids were also discussed.     

Omega-3 fatty acids modify human cortical visual processing--a double-blind, crossover study

While cardiovascular and mood benefits of dietary omega-3 fatty acids such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are manifest, direct neurophysiological evidence of their effects on cortical activity is still limited. Hence we chose to examine the effects of two proprietary fish oil products with different EPA:DHA ratios (EPA-rich, high EPA:DHA; DHA-rich) on mental processing speed and visual evoked brain activity. We proposed that nonlinear multifocal visual evoked potentials (mfVEP) would be sensitive to any alteration of the neural function induced by omega-3 fatty acid supplementation, because the higher order kernel responses directly measure the degree of recovery of the neural system as a function of time following stimulation. Twenty-two healthy participants aged 18-34, with no known neurological or psychiatric disorder and not currently taking any nutritional supplementation, were recruited. A double-blind, crossover design was utilized, including a 30-day washout period, between two 30-day supplementation periods of the EPA-rich and DHA-rich diets (with order of diet randomized). Psychophysical choice reaction times and multi-focal nonlinear visual evoked potential (VEP) testing were performed at baseline (No Diet), and after each supplementation period. Following the EPA-rich supplementation, for stimulation at high luminance contrast, a significant reduction in the amplitude of the first slice of the second order VEP kernel response, previously related to activation in the magnocellular pathway, was observed. The correlations between the amplitude changes of short latency second and first order components were significantly different for the two supplementations. Significantly faster choice reaction times were observed psychophysically (compared with baseline performance) under the EPA-rich (but not DHA-rich) supplementation, while simple reaction times were not affected. The reduced nonlinearities observed under the EPA-rich diet suggest a mechanism involving more efficient neural recovery of magnocellular-like visual responses following cortical activation.     

Reversibility of n-3 fatty acid deficiency-induced alterations of learning behavior in the rat: level of n-6 fatty acids as another critical factor

Rats fed a semipurified diet supplemented with 3% (w/w) safflower oil [Saf, n-3 fatty acid deficient, high linoleic acid (18:2n-6)] through two generations exhibit decreased correct response ratios in a brightness-discrimination learning test compared with rats fed 3% perilla oil [Per, high alpha-linolenic acid (18:3n-3)]. This is associated with a decreased DHA (22:6n-3)-to-arachidonic acid (20:4n-6) ratio in brain lipids. In the first set of experiments, dietary oil was shifted from Saf to a mixture of 2.4% safflower oil plus 0.6% DHA after weaning (Saf-DHA), but all parameters measured in the learning test were essentially unchanged. Brain 22:6n-3 content of the Saf-DHA group reached that of the Per group but the levels of 20:4n-6 and docosatetraenoic acid (22:4n-6) did not decrease to those of the Per group at the start of the test. In the second set of experiments, dietary oil was shifted to a mixture of 0.6% safflower oil plus 1.2% oleic acid (OA) plus 1.2% DHA (Saf-OA-DHA group) with 18:2n-6 content comparable to that of the Per group. The Saf-OA-DHA group exhibited a learning performance similar to that of the Per group; brain 22:6n-3, 20:4n-6, and 22:4n-6 contents were also comparable to those of the Per group. These results indicate that the altered learning behavior associated with a long-term n-3 fatty acid deficiency is reversed by supplementing 22:6n-3 after weaning, when the levels of competing n-6 fatty acids in the diet and brain lipids are limited.     

Polyunsaturated fatty acid pattern in liver and erythrocyte phospholipids from obese patients

Objective: Our aim was to study the fatty acid (FA) composition of liver phospholipids and its relation to that in erythrocyte membranes from patients with obese nonalcoholic fatty liver disease (NAFLD), as an indication of lipid metabolism alterations leading to steatosis. Research Methods and Procedures: Eight control subjects who underwent antireflux surgery and 12 obese patients with NAFLD who underwent subtotal gastrectomy with a gastro‐jejunal anastomosis in Roux‐en‐Y were studied. The oxidative stress status of patients was assessed by serum F₂‐isoprostanes levels (gas chromatography/negative ion chemical ionization tandem mass spectrometry). Analysis of FA composition of liver and erythrocyte phospholipids was carried out by gas‐liquid chromatography. Results: Patients with NAFLD showed serum F₂‐isoprostanes levels 84% higher than controls. Compared with controls, liver phospholipids from obese patients exhibited significantly 1) lower levels of 20:4n‐6, 22:5n‐3, 22:6n‐3 [docosahexaenoic acid (DHA)], total long‐chain polyunsaturated FA (LCPUFA), and total n‐3 LCPUFA, 2) higher 22:5n‐6 [docosapentaenoic acid (DPAn‐6)] levels and n‐6/n‐3 LCPUFA ratios, and 3) comparable levels of n‐6 LCPUFA. Levels of DHA and DPAn‐6 in liver were positively correlated with those in erythrocytes (r = 0.77 and r = 0.90, respectively; p < 0.0001), whereas DHA and DPAn‐6 showed a negative association in both tissues (r = ?0.79, p < 0.0001 and r = ?0.58, p < 0.01, respectively), associated with lower DHA/DPAn‐6 ratios. Discussion: Obese patients with NAFLD showed marked alterations in the polyunsaturated fatty acid pattern of the liver. These changes are significantly correlated with those found in erythrocytes, thus suggesting that erythrocyte FA composition could be a reliable indicator of derangements in liver lipid metabolism in obese patients.     

Effect of polyunsaturated fatty acids on dexamethasone-induced gastric mucosal damage

BACKGROUND: Increased dietary intake of polyunsaturated fatty acids (PUFAs) is known to be associated with a decrease in the incidence of peptic ulcer disease possibly due to increase in the synthesis of prostaglandins. But, it is also likely that conversion of PUFAs to PGs may not always be required for gastric mucosal protection. Present study was designed to study the role of PUFAs in pathobiology of steroid induce gastric damage in rats. METHODS: Wistar rats were treated with 5 mg/kg bodyweight of dexamethasone to induce gastric mucosal ulcers. Effects of PUFAs was studied by supplementation of Fish oil (rich in n-3 EPA and DHA) and AA rich oil. Famotidine was used as a positive control. Generation of lipid peroxides, nitric oxide and the activity of anti-oxidant enzymes were also studied. RESULTS: Dexamethasone induced ulceration was associated with changes in the phospholipid fatty acid profile, levels of lipid peroxidation products, nitric oxide and activity of anti-oxidant enzymes. The fatty acid profile showed an increase in LA and a decrease in other PUFAs like GLA, AA, EPA and DHA. When PUFAs were supplemented in the form of Fish oil and AA rich oil or when the animals were treated with H2-blocker, famotidine, there was a decrease in the incidence of ulceration in the animals associated with near normalization of changes in the phospholipid fatty acid profile. The levels of lipid peroxides, nitric oxide, and anti-oxidant activity also reverted to control values. CONCLUSIONS: Dexamethasone induced gastric ulceration was prevented by PUFAs. This is supported by the results of our earlier study where in it was noted that in patients with DU plasma lipid peroxides, nitric oxide and phospholipid fatty acid pattern and red cell antioxidant activity were altered similar to those seen in dexamethasone treated group of the present study. These abnormalities, similar to the PUFA treated groups of the present study, reverted to normalcy following treatment of the patients with lansoprazole, a proton pump inhibitor. Further, PUFAs are known to inhibit the growth of Helicobacter pylori in vitro. Hence, it is concluded that PUFAs, free radicals, nitric oxide and anti-oxidants play a significant role in the pathobiology of peptic ulcer.     

Long-term effect of dietary {alpha}-linolenic acid or decosahexaenoic acid on incorporation of decosahexaenoic acid in membranes and its influence on rat heart in vivo

The present study was designed to evaluate whether long-term intake of dietary alpha-linolenic acid (ALA), supplied as whole grain-extruded linseed, can increase endogenous production of n-3 long-chain polyunsaturated fatty acids (FAs) in healthy adult rats and influence the heart rate (HR) and adrenergic response in the same way as docosahexaenoic acid (DHA)-rich diets. DHA enrichment was evaluated using FA analysis of tissue phospholipids after 8, 16, 24, and 32 wk of feeding in male Wistar rats randomly assigned to three dietary groups (n = 8 in each group): a reference fat diet (RFD), an ALA-rich (ALA) diet, and a DHA-rich (DHA) diet. At 1 wk before the animals were killed, under anesthesia, HR was measured from ECG recordings during an adrenergic stimulation challenge (n = 8). There was a significant increase of DHA in the cardiac membrane in the ALA group compared with the RFD group. DHA content in the cardiac membrane was approximately 10% in the ALA group vs. 20% in the DHA group and 4% in the RFD group. The cardiac FA profile was established after 2 mo and remained essentially unchanged thereafter. Regardless of the diet, DHA in the heart decreased with age. Nevertheless, DHA content in the heart remained at >15% in the DHA group and remained greater in older rats fed the ALA diet than in younger RFD-fed rats. Basal HR decreased in the ALA group (395 +/- 24.9 beats/min) to a level between that of the DHA and RFD groups (375 +/- 26.4 and 407 +/- 36.7 beats/min, respectively). Both n-3 dietary intakes contribute to enhancement of the chronotropic response to adrenergic agonist stimulation. Regulation of HR by neurohumoral mediators may be controlled by lower content of DHA, e.g., by a dietary supply of extruded linseed (ALA).     

Long-chain conversion of [13C]linoleic acid and alpha-linolenic acid in response to marked changes in their dietary intake in men

We studied the long-chain conversion of [U-13C]alpha-linolenic acid (ALA) and linoleic acid (LA) and responses of erythrocyte phospholipid composition to variation in the dietary ratios of 18:3n-3 (ALA) and 18:2n-6 (LA) for 12 weeks in 38 moderately hyperlipidemic men. Diets were enriched with either flaxseed oil (FXO; 17 g/day ALA, n=21) or sunflower oil (SO; 17 g/day LA, n=17). The FXO diet induced increases in phospholipid ALA (>3-fold), 20:5n-3 [eicosapentaenoic acid (EPA), >2-fold], and 22:5n-3 [docosapentaenoic acid (DPA), 50%] but no change in 22:6n-3 [docosahexanoic acid (DHA)], LA, or 20:4n-6 [arachidonic acid (AA)]. The increases in EPA and DPA but not DHA were similar to those in subjects given the SO diet enriched with 3 g of EPA plus DHA from fish oil (n=19). The SO diet induced a small increase in LA but no change in AA. Long-chain conversion of [U-13C]ALA and [U-13C]LA, calculated from peak plasma 13C concentrations after simple modeling for tracer dilution in subsets from the FXO (n=6) and SO (n=5) diets, was similar but low for the two tracers (i.e., AA, 0.2%; EPA, 0.3%; and DPA, 0.02%) and varied directly with precursor concentrations and inversely with concentrations of fatty acids of the alternative series. [13C]DHA formation was very low (<0.01%) with no dietary influences.     

Toxicology and safety of DHA

Docosahexaenoic acid (DHA) is a long-chain polyunsaturated fatty acid with activities in both infants and adults. The objective of the current work was to evaluate the published literature concerning the toxicological assessment of DHA-rich oils in animals and the safety profile of DHA consumption in humans. Structured literature searches concerning DHA toxicology and DHA effects on platelet function, lipid levels, oxidative potential, glycemic control, and immune function were conducted. The toxicological profile of DHA derived from single-cell organisms demonstrates that these oils are safe in rats (up to a consumption level of 3290 mg/kg body weight/d) in 90-d toxicology evaluations, as well as in reproductive and developmental toxicology studies. The maximum DHA level in human breast milk exceeds 1% of total fatty acids in high-fish-consuming populations. Consumption of DHA-rich human milk as sole source of nutrition provides approximately 315 mg/d in infants 1–6 months of age, and appears to be a safe level of intake. DHA supplementation studies in adults have employed doses ranging from less than 1 to 7.5 g/d, and have not resulted in any consistent adverse responses in platelet function, lipid levels, in vivo oxidation parameters, glycemic control, or immune function. In conclusion, DHA consumption does not result in consistent adverse events in infants or adults. Safe intake levels may be modeled on DHA intake from human milk in infants, and may be at least as high as the upper doses studied in adults.     

Dietary effects on brain fatty acid composition: the reversibility of n-3 fatty acid deficiency and turnover of docosahexaenoic acid in the brain, erythrocytes, and plasma of rhesus monkeys

Rhesus monkeys given pre- and postnatal diets deficient in n-3 essential fatty acids develop low levels of docosahexaenoic acid (22:6 n-3, DHA) in the cerebral cortex and retina and impaired visual function. This highly polyunsaturated fatty acid is an important component of retinal photoreceptors and brain synaptic membranes. To study the turnover of polyunsaturated fatty acids in the brain and the reversibility of n-3 fatty acid deficiency, we fed five deficient juvenile rhesus monkeys a fish oil diet rich in DHA and other n-3 fatty acids for up to 129 weeks. The results of serial biopsy samples of the cerebral cortex indicated that the changes of brain fatty acid composition began as early as 1 week after fish oil feeding and stabilized at 12 weeks. The DHA content of the phosphatidylethanolamine of the frontal cortex increased progressively from 3.9 +/- 1.2 to 28.4 +/- 1.7 percent of total fatty acids. The n-6 fatty acid, 22:5, abnormally high in the cerebral cortex of n-3 deficient monkeys, decreased reciprocally from 16.2 +/- 3.1 to 1.6 +/- 0.4%. The half-life (t 1/2) of DHA in brain phosphatidylethanolamine was estimated to be 21 days. The fatty acids of other phospholipids in the brain (phosphatidylcholine, -serine, and -inositol) showed similar changes. The DHA content of plasma and erythrocyte phospholipids also increased greatly, with estimated half-lives of 29 and 21 days, respectively. We conclude that monkey cerebral cortex with an abnormal fatty acid composition produced by dietary n-3 fatty acid deficiency has a remarkable capacity to change its fatty acid content after dietary fish oil, both to increase 22:6 n-3 and to decrease 22:5 n-6 fatty acids. The biochemical evidence of n-3 fatty acid deficiency was completely corrected. These data imply a greater lability of the fatty acids of the phospholipids of the cerebral cortex than has been hitherto appreciated.     

Anti-stress effects of DHA

DHA is abundant in the brain. Deficiency of DHA changes behavior in animals. The purpose of the present studies was to clarify the effect of DHA intake on hostility and plasma catecholamines. In study 1, forty-one students took either DHA-rich oil capsules containing 1.5-1.8 g DHA/d (17 females and 5 males) or control oil capsules containing 97% soybean oil plus 3% fish oil (12 females and 7 males) for 3 mon in a double blind fashion. They took a psychological test (P-F Study) at the start and end of the study. Study I started at the end of summer vacation and ended in the middle of mental stress of final exams. In the control group, hostility measured by P-F Study was significantly increased at the end of the study as compared with that measured at the start (+58%), whereas it was not significantly changed in the DHA group (-14%). In a similar double blind two-mon study (study 2), we measured plasma catecholamines and cortisol of students (3 females and 4 males for the DHA group and the same numbers for the control) at the start and end of the study. In study 2 the students were under a continuous stress of final exams that lasted for two mon throughout the whole study period. The plasma cortisol did not change in either group, but the norepinephrine concentration was significantly decreased in the DHA group (-31%), whereas it stayed at the same level in the control group. These effects of DHA intake may be applied to people under psychological stress.     

Neonatal lamb vigour is improved by feeding docosahexaenoic acid in the form of algal biomass during late gestation

To determine whether feeding a sustainable, algal source of docosahexaenoic acid (DHA) to sheep during late pregnancy would improve neonatal lamb vigour, 48 English mule ewes, of known conception date, were divided into four treatment groups. For the last 9 weeks of gestation, ewes received one of two dietary supplements: either a DHA-rich algal biomass providing 12 g DHA/ewe per day, or a control supplement based on vegetable oil. The four dietary treatment groups (n = 12) were: control supplement for the duration of the trial (C), DHA supplement from 9 to 6 weeks before parturition (3 week), DHA supplement from 9 to 3 weeks before parturition (6 week) and DHA supplement for the duration of the trial (9 week). Dietary supplements were fed alongside grass silage and commercial concentrate. There was a tendency for gestation length to be extended with increased duration of DHA supplementation (P = 0.08). After parturition, the concentrations of eicosapentaenoic acid (EPA) and DHA in ewe and lamb plasma and colostrum were elevated in line with increased periods of DHA supplementation. Lambs from the 6-week and 9-week groups stood significantly sooner after birth than lambs from the C group (P < 0.05). These data show that neonatal vigour may be improved by the supplementation of maternal diets with DHA-rich algal biomass and that this beneficial effect depends upon the timing and/or duration of DHA allocation.