Incorporation and clearance of omega-3 fatty acids in erythrocyte membranes and plasma phospholipids

BACKGROUND: The sum of eicosapentaenoic acid (EPA, 20:5 omega3) and docosahexaenoic acid (DHA, 22:6 omega3) in erythrocyte membranes, termed the omega-3 index, can indicate suboptimal intake of omega-3 fatty acids, a risk factor for cardiovascular disease (CVD). To study the effects of fatty acid supplementation, we investigated the rate of incorporation and clearance of these fatty acids in erythrocyte membranes and plasma after intake of supplements. METHODS: Twenty study participants received supplementation with either fish oil (1296 mg EPA + 864 mg DHA/day) or flaxseed oil (3510 mg alpha-linolenic acid + 900 mg linoleic acid/day) for 8 weeks. We obtained erythrocyte membrane and plasma samples at weeks 0, 4, 8, 10, 12, 14, 16, and 24 and extracted and analyzed fatty acids by gas chromatography. RESULTS: After 8 weeks of fish oil supplementation, erythrocyte membrane EPA and DHA increased 300% (P < 0.001) and 42% (P < 0.001), respectively. The mean erythrocyte omega-3 index reached a near optimal value of 7.8%, and remained relatively high until week 12. EPA and DHA showed greater increases and more rapid washout period decreases in plasma phospholipids than in erythrocyte membranes. Flaxseed oil supplementation increased erythrocyte membrane EPA to 133% (P < 0.05) and docosapentaenoic acid (DPA, 22:5 omega3) to 120% (P < 0.01) of baseline, but DHA was unchanged. In plasma phospholipids, EPA, DPA, and DHA showed a slight but statistically insignificant increase. CONCLUSIONS: Erythrocyte membrane EPA+DHA increases during relatively short intervals in response to supplementation at rates related to amount of supplementation. These results may be useful to establish appropriate dosage for omega-3 fatty acid supplementation.     

Effects of n-3 Fatty Acids Supplementation on Plasma Phospholipids Fatty Acid Composition in Patients with Obstructive Jaundice- a Pilot Study

Nutritional and immunological status of patients with obstructive jaundice is usually severely altered, with high mortality rates. The n-3 polyunsaturate fatty acids (PUFA), particularly eicosapentaenoic acid (EPA, 20:5 n-3), posess potent immunomodulatory activities. Thus, our aim was to compare the plasma phospholipid fatty acid (FA) composition of these patients with healthy subjects, as well as before and after 7 days preoperative supplementation with high doses of EPA (0.9 g per day) and docosahexaenoic acid (DHA, 22:6 n-3, 0.6 g per day). We found impaired FA status in obstructive jaundice patients, especially EPA, DHA and PUFA, but significantly increased content of total n-3 FA, 22:5 n-3 FA and particularly EPA, which increased more than 3 fold, after 7 days supplementation. In addition, the n6/n3 ratio significantly decreased from 14.24 to 10.24, demonstrating severely improved plasma phospholipid profile in these patients after the intervention.     

Intravenous fish oil blunts the physiological response to endotoxin in healthy subjects

Objective To assess the effects of intravenous fish oil fat emulsion on the metabolic alterations induced by lipopolysaccharide (LPS) challenge in healthy volunteers. Design Two groups of eight healthy subjects were randomized to receive either two pharmacological doses of intravenous FO fat emulsion or no treatment. The FO group received twice 0.5 g/kg 10% emulsion (Omegaven) 48 and 24 h before investigation. LPS (2 ng/kg) was injected as a bolus on the investigation day. Systemic parameters, indirect calorimetry, heart rate variability, and platelet membrane phospholipid composition were measured. Results Basal EPA and DHA content in platelet phospholipids was low (0.28% and 2.54%, respectively) and increased significantly after FO to 1.68% and 3.32%. LPS induced reproducible effects in all subjects. Fever was higher in the FO group than in controls; the difference was significant from t ₁₂₀ until t ₃₆₀. FO blunted the neuroendocrine response: the rise in plasma norepinephrine was sevenfold lower at t ₁₂₀ while the ACTH peak was fourfold lower. Tumor necrosis factor α was significantly lower between t ₃₆₀ and t ₁₈₀ in the FO group. Conclusions Two doses of intravenous FO fat emulsion modified the phospholipid composition of platelets in healthy subjects. FO blunted fever and increased the neuroendocrine and the inflammatory responses to LPS.     

Influence of intravenous n-3 lipid supplementation on fatty acid profiles and lipid mediator generation in a patient with severe ulcerative colitis

Abstract. N-3 fatty acids were supplied to a 36-year-old female patient suffering from ulcerative colitis and severe steroid side-effects, in a sequence of parenteral and enteral administration. During a moderately active period of disease, 200 ml d^-1 fish oil-derived lipid emulsion (eicosapentaenoic acid [EPA], 4–2 g; docosahexaenoic acid [DHA], 4.2 g) was infused for 9 days, in parallel with rapid tapering of the steroid dose. Disease activity declined rapidly, and the patient was subsequently provided with 16 fish oil capsules per day (EPA, 2.9 g; DHA, 1.9 g) for 2 months. At the end of this period of therapy, severe colitis recurred with intestinal and extraintestinal manifestations. The n-3 lipid emulsion was then used for intravenous alimentation (29 days, maximum dose 300 ml per day); during this time, marked improvement of the inflammatory bowel disease was noted. During both periods of parenteral n-3 lipid administration, total plasma EPA and DHA contents increased several-fold, surpassing that of arachidonic acid; this plasma n-3 fatty acid enrichment was only maintained to a minor extent during the intermediate period of dietary fish oil supplementation. The intravenously administered EPA-containing triglycerides were rapidly hydrolyzed, as evidenced by the appearance of substantial quantities of EPA in the plasma free fatty acid fraction. Platelet and neutrophil total membrane content of EPA and DHA as well as n-3 fatty acid/AA membrane ratios similarly increased during the periods of intravenous n-3 lipid administration and declined during oral fish oil uptake. In contrast, erythrocyte membrane enrichment in EPA and DHA occurred only after the prolonged (2 month) period of dietary n-3 lipid supplementation. Ex vivo stimulation of neutrophils with A23187 showed progressive increase in 5-series leukotriene- and 5-HEPE-generation during both periods of n-3 lipid infusion, in parallel with the rise of plasma EPA contents. Maximum 5-series/4-series leukotriene ratios surpassed 0.25. Similarly, ratios of thromboxane B₃/B₂ liberated from ex vivo stimulated platelets surpassed 0.4 during ongoing n-3 lipid infusion. The profound changes in fatty acid profiles and lipid mediator generation may be related to the reduction in colitis activity observed during the periods of intravenous n-3 lipid supplementation.     

Dietary n-3 fatty acid effects on neutrophil lipid composition and mediator production. Influence of duration and dosage.

Healthy volunteers supplemented their usual Western diets with Promega fish oil supplement (eicosapentaenoic acid [EPA], 0.28 g; docosahexaenoic acid [DCHA], 0.12 g; other n-3 fatty acids 0.10 g per capsule) using three protocols. Initial experiments (protocol 1 and 2) investigated the kinetics of incorporation of n-3 fatty acids into serum and neutrophil lipids after 10 capsules/d of Promega. EPA was rapidly detected in both serum and neutrophil lipids; the arachidonic acid (AA) to EPA ratio in neutrophil phospholipids showed a maximal reduction of 49:1 to 8:1 within 1 wk of beginning supplementation. EPA was preferentially incorporated into phosphatidyl-ethanolamine and phosphatidylcholine but not phosphatidylinositol. Long-term supplementation for up to 7 wk did not influence the AA/EPA ratio or the distribution of EPA among neutrophil phospholipids in a manner that was not observed after the first week. Neutrophils produced similar quantities of platelet-activating factor and slightly lower quantities of leukotriene B4 during long-term supplementation when compared with presupplementation values. Experiments examining the influence of Promega dosage indicated that the AA/EPA ratio in neutrophil lipids decreased in a dose-dependent manner. Only when the dose was increased to 15 capsules/d was there a reduction in the AA/DCHA ratio in neutrophil lipids. The quantity of AA in neutrophil lipids remained relatively constant at all supplement doses. Taken together, the current study demonstrates the capacity of n-3 fatty acids provided with a Western diet to be rapidly incorporated into neutrophil lipids. However, dietary n-3 fatty acids appear not to significantly reduce arachidonate content within neutrophil phospholipids. Constant arachidonate levels may account for the lack of large reductions in the biosynthesis of lipid mediators by neutrophils after fish-oil supplementation.     

Supplementation with fish oil affects the association between very long-chain n-3 polyunsaturated fatty acids in serum non-esterified fatty acids and soluble vascular cell adhesion molecule-1

We have investigated the effect of fish oil supplementation on the association between serum non-esterified fatty acid (NEFA) pattern and atherosclerotic activity. We studied correlations between serum non-esterified very long-chain eicosapentaenoic (EPA), docosahexaenoic acid (DHA) and arachidonic acid (AA) and biochemical markers of endothelial activation before and after 18-months intervention with fish oil supplementation. The fish oil supplementation consisted of 2.4 g of EPA and DHA per day, with corn oil as placebo. Elderly men ( n =171) with high risk for coronary heart disease were divided into four intervention groups in a factorial design: fish oil supplementation ( n =44), dietary intervention ( n =42), fish oil supplementation+dietary intervention ( n =47) or placebo ( n =38). The composition of fasting NEFA was analysed before and after intervention by GLC. Circulating endothelial markers were analysed by ELISA. A statistically significant positive correlation between the change in serum non-esterified DHA and soluble vascular cell adhesion molecule-1 (sVCAM-1) was found in the pooled group that received fish oil supplementation ( n =91; Spearman's correlation coefficient r =0.24, P =0.02). No such correlation was found in the pooled group without fish oil supplementation ( n =80). Furthermore, there was a significant negative correlation between the change in serum non-esterified EPA and the relative change in sVCAM-1 in the group that did not receive fish oil supplementation ( r =-0.34, P =0.002). No such correlation was found in the group with fish oil supplementation. We conclude that large increase in serum non-esterified EPA and DHA, which can only be attained by supplementation, might increase inflammation in vascular endothelium. A moderate dietary increase in fish oil intake may, however, have an effect on decreasing inflammatory markers.     

Dietary fish oil modulates macrophage fatty acids and decreases arthritis susceptibility in mice

B10.RIII and B10.G mice were transferred from a diet of laboratory rodent chow to a standard diet in which all the fat (5% by weight) was supplied as either fish oil (17% eicosapentaenoic acid [EPA], 12% docosahexaenoic acid [DHA], 0% arachidonic acid [AA], and 2% linoleic acid) or corn oil (0% EPA, 0% DHA, 0% AA, and 65% linoleic acid). The fatty acid composition of the macrophage phospholipids from mice on the chow diet was similar to that of mice on a corn oil diet. Mice fed the fish oil diet for only 1 wk showed substantial increases in macrophage phospholipid levels of the omega-3 fatty acids (of total fatty acid 4% was EPA, 10% docosapentaenoic acid [DPA], and 10% DHA), and decreases in omega-6 fatty acids (12% was AA, 2% docosatetraenoic acid [DTA], and 4% linoleic acid) compared to corn oil-fed mice (0% EPA, 0% DPA, 6% DHA, 20% AA, 9% DTA, and 8% linoleic acid). After 5 wk this difference between the fish oil-fed and corn oil-fed mice was even more pronounced. Further small changes occurred at 5-9 wk. We studied the prostaglandin (PG) and thromboxane (TX) profile of macrophages prepared from mice fed the two diets just before being immunized with collagen. Irrespective of diet, macrophages prepared from female mice and incubated for 24 h had significantly more PG and TX in the medium than similarly prepared macrophages from male mice. The increased percentage of EPA and decreased percentage of AA in the phospholipids of the macrophages prepared from the fish oil-fed mice was reflected in a reduction in the amount of PGE2 and PGI2 in the medium relative to identically incubated macrophages prepared from corn oil-fed mice. When this same fish oil diet was fed to B10.RIII mice for 26 d before immunization with type II collagen, the time of onset of arthritis was increased, and the incidence and severity of arthritis was reduced compared to arthritis induced in corn oil-fed mice. The females, especially those on the fish oil diet, tended to have less arthritis than the males. These alterations in the fatty acid pool available for PG and leukotriene synthesis suggest a pivotal role for the macrophage and PG in the immune and/or inflammatory response to type II collagen.     

Effects of dietary fish oil supplementation on the fatty acid composition of the human platelet membrane: demonstration of selectivity in the incorporation of eicosapentaenoic acid into membrane phospholipid pools

The fatty acid composition of membrane phospholipids of stimulated and unstimulated platelets was studied in six normal volunteers given a daily dietary supplement of a fish oil rich in eicosapentaenoic acid (EPA) for 4 weeks. The supplement was equivalent to 1.8 g of EPA daily. Thromboxane synthesis and platelet aggregation responses to sodium arachidonate, thrombin and the ionophore A23187 were also investigated. A marked increase in the relative EPA content of phosphatidylcholine (PC) and phosphatidylethanolamine (PE) was noted after 2 and 4 weeks fish oil supplementation. However, there was no incorporation into phosphatidylinositol (PI) or phosphatidylserine (PS). The relative arachidonic acid (AA) content of PC and PE was significantly reduced at 2 and 4 weeks but that of PI and PS remained unchanged. Significant reductions in the relative linoleic acid content of total phospholipids, PC and PE were also noted. Stimulation of platelets obtained after 4 weeks fish oil supplementation by thrombin and A23187 was associated with a marked reduction in the AA content of PI and a minor reduction in that of PE. There was no change in the relative proportions of EPA in PI, PS, PC or PE after stimulation. Throughout the study there were no significant changes in platelet aggregation responses or in platelet thromboxane production. Our results indicate that the incorporation of EPA into the platelet membrane phospholipids is selective and that if PI is the major source of AA for platelet prostaglandin biosynthesis then the reported beneficial effects of EPA on haemostasis cannot be explained on the basis of its incorporation into and mobilization from the platelet membrane phospholipid pool.     

Dietary supplementation with very long-chain n-3 fatty acids in man decreases expression of the interleukin-2 receptor (CD25) on mitogen-stimulated lymphocytes from patients with inflammatory skin diseases

Abstract T-cell activation and cytokine production play an important role in several chronic inflammatory diseases. Because n-3 fatty acids exert beneficial effects on the clinical state of some of these diseases, we examined the effect of dietary supplementation of n-3 fatty acids on T-cell proliferation, expression of CD25 (interleukin-2 receptor alpha-chain), secretion of interleukin-2, interleukin-6 and tumour necrosis factor from T-cells from patients with psoriasis and atopic dermatitis. During 4 months, 21 patients supplied 6 g of highly concentrated ethyl esters of EPA and DHA in gelatin capsules daily to their diet. In the control group 20 patients supplied 6 g per day of corn oil in gelatin capsules to their diet. Eicosapentaenoic acid (20:5, n-3) of serum phospholipids increased from 14 (min 4-max 42) to 81 (min 59-max 144) mg l^-1 (P < 0·01) in patients with atopic dermatitis receiving n-3 fatty acids, and from 25 (min 7-max 66) to 74 (min 46-max 142) mg l^-1 (P < 0·01) in patients with psoriasis, whereas docosahexaenoic acid (22:6, n-3) increased from 65 (min 46-max 120) to 92 (min 54-max 121) mg l^-1 (P < 0·05) and from 81 (min 38-max 122) to 92 (min 63-max 169) mg l^-1 (NS) in atopic and psoriatic patients, respectively. The changes in the serum phospholipid fatty acid profile in the groups receiving n-3 fatty acids, correlate to the dietary intake of corresponding fatty acids. There was no significant change in the fatty acid pattern of serum phospholipids in the corn oil group before and after supplementation. Mitogen-induced secretion of interleukin-6 was significantly higher in patients with psoriasis compared to patients with atopic dermatitis, whereas the secretion of interleukin-2, tumour necrosis factor, PHA-induced T-cell proliferation and expression of CD25 on lymphocytes were similar in the two groups of patients. Patients receiving supplementation of n-3 fatty acids decreased significantly the percentage of CD25 positive lymphocytes from 40·5 before start to 35·5 (P < 0·05) after the trial. The patients who received corn oil increased the level of tumour necrosis factor from 1095 pg ml^-1 before start to 1536 pg ml^-1 after the trial (P < 0·05). In conclusion, dietary intake of very long-chain n-3 fatty acids may suppress the expression of CD25 positive lymphocytes, which may partly account for the anti-inflammatory effect exerted by these fatty acids.     

Differential effects of low-dose docosahexaenoic acid and eicosapentaenoic acid on the regulation of mitogenic signaling pathways in mesangial cells

Although dietary fish oil supplementation has been used to prevent the progression of kidney disease in patients with IgA nephropathy, relatively few studies provide a mechanistic rationale for its use. Using an antithymocyte (ATS) model of mesangial proliferative glomerulonephritis, we recently demonstrated that fish oil inhibits mesangial cell (MC) activation and proliferation, reduces proteinuria, and decreases histologic evidence of glomerular damage. We therefore sought to define potential mechanisms underlying the antiproliferative effect of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), the predominant omega-3 polyunsaturated fatty acids found in fish oil, in cultured MC. DHA and EPA were administered to MC as bovine serum albumin fatty-acid complexes. Low-dose (10-50 micromol/L) DHA, but not EPA, inhibited basal and epidermal growth factor (EGF)-stimulated [(3)H]-thymidine incorporation in MCs. At higher doses (100 micromol/L), EPA and DHA were equally effective in suppressing basal and EGF-stimulated MC mitogenesis. Low-dose DHA, but not EPA, decreased ERK activation by 30% (P <.01), as assessed with Western-blot analysis using phosphospecific antibodies. JNK activity was increased by low-dose DHA but not by EPA. p38 activity was not significantly altered by DHA or EPA. Cyclin E activity, as assessed with a histone H1 kinase assay, was inhibited by low-dose DHA but not by EPA. DHA increased expression of the cell cycle inhibitor p21 but not p27; EPA had no effect on p21 or p27. We propose that the differential effect of low-dose DHA vs EPA in suppressing MC mitogenesis is related to down-regulation of ERK and cyclin E activity and to induction of p21.     

Inhibition of leukotriene synthesis,pharmacokinetics, and tolerability of a novel dietary fatty acid formulation in healthy adult subjects

BACKGROUND: Numerous studies have explored dietary-management strategies for decreasing leukotriene synthesis by inflammatory cells through supplementation with polyunsaturated fatty acids such as gamma-linolenic acid (GLA) and eicosapentaenoic acid (EPA). OBJECTIVES: This study sought to determine the optimal daily intake, ratios, and formulation of dietary GLA and EPA required to safely reduce leukotriene biosynthesis in healthy individuals, and to evaluate the pharmacokinetics and safety profile of such a formulation. METHODS: Two preliminary trials were conducted to determine the minimum effective levels of GLA and EPA intake needed to reduce leukotriene biosynthesis and prevent increases in plasma arachidonic acid (AA) concentrations. These preliminary trials were followed by a single-center, randomized, double-blind, placebo-controlled, parallel-group, escalating-intake inpatient trial of a dietary GLA/EPA emulsion (PLT 3514) in healthy adult subjects. Subjects consumed either 10, 20, or 100 g of the PLT 3514 emulsion (respectively containing 0.75 g GLA + 0.5 g EPA, 1.5 g GLA + 1 g EPA, and 7.5 g GLA + 5 g EPA), or a placebo emulsion containing olive oil daily for 14 days. Plasma fatty acids were measured by gas chromatography Stimulated whole blood leukotrienes were measured by high-performance liquid chromatography with ultraviolet detection. RESULTS: Thirty subjects were included in the preliminary trials; 47 subjects were enrolled in the escalating-intake trial, of whom 42 completed the study. In the preliminary trials, intake of GLA 1.5 g/d in gelatin capsules decreased the capacity to synthesize leukotrienes but increased plasma levels of AA (both, P < 0.05). Inclusion of 0.25 or 1 g of dietary EPA prevented the increase in plasma AA concentrations. Dietary GLA and EPA showed significantly enhanced bioavailability when consumed in 20 g PLT 3514 emulsion compared with consumption in gelatin capsules (P < 0.05), resulting in a reduction in the amount of intake required to block leukotriene biosynthesis. Pharmacokinetic analyses indicated that fasting plasma GLA and EPA levels plateaued within 7 days' daily consumption at all levels of intake, whereas the time to maximum plasma concentration (Tmax) was shorter for GLA than for EPA. The Tmax was similar on days 1 and 14 for both GLA and EPA. There were no clinically significant between-group differences in changes in vital signs, mean clinical laboratory values, or abbreviated hematology laboratory tests, or significant differences in the occurrence of treatment-emergent adverse events between the group consuming up to 20 g/d of the GLA/EPA emulsion and the group consuming placebo. CONCLUSION: Consumption of specific proportions and intake levels of dietary GLA and EPA in a novel emulsion formulation inhibited leukotriene biosynthesis and appeared to be well tolerated in this population of healthy adult subjects.     

Dietary n-6 fatty acids inhibit the incorporation of dietary n-3 fatty acids in thrombocyte and serum phospholipids in humans: a controlled dietetic study

The effect of a high dietary intake of n-6 fatty acids (36 g daily) vs a low intake (4-6 g daily) on the incorporation of fatty acids from a dietary supplementation of n-3 fatty acids (6 g daily) was studied for 8 weeks in 15 healthy, normolipaemic volunteers. The importance of a high (43.6) vs a low (20.6) energy percentage from fat was also investigated in the participants on a low n-6 intake. Fatty acid analyses of serum and thrombocyte phospholipids showed a marked increase in docosahexaenoic acid (22:6 (n-3), DHA) and especially eicosapentaenoic acid (20:5 (n-3), EPA) in both the high and low n-6 groups after 14 days, but the changes were significantly greater in the low n-6 diet groups. Changes of the ratio between EPA and arachidonic acid (20:4 (n-6), AA) in phospholipids followed an identical pattern in serum and thrombocytes. This indicates that thrombocytes are influenced by the fatty acid composition in serum. The results showed that incorporation of n-3 fatty acids in phospholipids was reduced by a high intake of dietary n-6 fatty acids in the cells and lipid fractions studied. The observed effect of dietary n-6 fatty acids was independent of the energy percentage provided by dietary fat. In order to obtain an optimal effect of n-3 supplementation, the intake of linoleic acid has to be considered and kept at a low level. The serum content of cholesterol was unaffected, but the concentration of triacylglycerol was reduced during the supplementation period.     

Long-term effects of dietary marine omega-3 fatty acids upon plasma and cellular lipids, platelet function, and eicosanoid formation in humans.

We studied the incorporation and metabolism of eicosapentanoic (EPA) and docosahexaenoic acid in six human volunteers who supplemented their normal Western diet for 5 mo daily with 10-40 ml of cod liver oil, rich in omega-3 polyunsaturated fatty acids. EPA and docosahexaenoic acid were incorporated into the total phospholipids of plasma, platelets, and erythrocytes in a dose- and time-dependent manner. During omega-3 fatty acid ingestion serum triacylglycerols were lowered and platelet aggregation upon low doses of collagen was reduced. Concomitantly, formation and excretion of prostanoids showed a characteristic change. As measured in serum from whole clotted blood, thromboxane A3 was formed in small amounts, whereas thromboxane A2 formation was reduced to 50% of control values. Excretion of the main urinary thromboxane A metabolites was unaltered in subjects with low basal excretion rates, but decreased markedly in two subjects with high control values. As determined from the main urinary metabolite, prostaglandin I3 was formed from EPA at rates up to 50% of unaltered prostaglandin I2 formation. The biochemical and functional changes observed lasted for the entire supplementation period of 5 mo and were reversible within 12 wk after cessation of cod liver oil intake. Favorable changes induced by long-chain omega-3 fatty acids include a dose-related and sustained shift of the prostaglandin I/thromboxane A balance to a more antiaggregatory and vasodilatory state.     

Dietary omega-3 fatty acids for women.

This review details the specific needs of women for omega-3 fatty acids, including alpha linoleic acid (ALA) and the very long chain fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Omega-3 fatty acid (dietary or in capsules) ensures that a woman's adipose tissue contains a reserve of these fatty acids for the developing fetus and the breast-fed newborn infant. This ensures the optimal cerebral and cognitive development of the infant. The presence of large quantities of EPA and DHA in the diet slightly lengthens pregnancy, and improves its quality. Human milk contains both ALA and DHA, unlike that of other mammals. Conditions such as diabetes can alter the fatty acid profile of mother's milk, while certain diets, like those of vegetarians, vegans, or even macrobiotic diets, can have the same effect, if they do not include seafood. ALA, DHA and EPA, are important for preventing ischemic cardiovascular disease in women of all ages. Omega-3 fatty acids can help to prevent the development of certain cancers, particularly those of the breast and colon, and possibly of the uterus and the skin, and are likely to reduce the risk of postpartum depression, manic-depressive psychosis, dementias (Alzheimer's disease and others), hypertension, toxemia, diabetes and, to a certain extend, age-related macular degeneration. Omega-3 fatty acids could play a positive role in the prevention of menstrual syndrome and postmenopausal hot flushes. The normal western diet contains little ALA (less than 50% of the RDA). The only adequate sources are rapeseed oil (canola), walnuts and so-called "omega-3" eggs (similar to wild-type or Cretan eggs). The amounts of EPA and DHA in the diet vary greatly from person to person. The only good sources are fish and seafood, together with "omega-3" eggs.     

Metabolism and effects on platelet function of the purified eicosapentaenoic and docosahexaenoic acids in humans.

Metabolism and effects on platelet function of 6 g/d for 6 d of either eicosapentaenoic acid (EPA, C20:5 omega-3) or docosahexaenoic acid (DCHA, C22:6 omega-3) in volunteers were compared in a randomized crossover study. Incorporation kinetics revealed that EPA appeared in plasma free fatty acids and plasma phospholipids after 4 h, but was not incorporated into platelet phosphatidylcholine and -ethanolamine until day 6. This indicates that platelet fatty acid composition does not immediately reflect that of the surrounding plasma milieu, but rather may be determined during megakaryocyte maturation. Importantly, EPA was not incorporated into platelet phosphatidylinositol or -serine in vivo, thus reflecting selective biosynthesis of platelet phospholipids. After dietary EPA, C22:5 omega-3 increased in plasma and platelet phospholipids. In contrast, DCHA-levels were unaltered. After DCHA-ingestion, C20:5 omega-3 concentrations rose in plasma phospholipids, implying that retroconversion took place. These findings indicate that dietary DCHA can serve as a source of EPA. During this short-term study, ingestion of both EPA and DCHA resulted in reduced platelet aggregation in response to collagen. The response to ADP was lowered significantly only by DCHA. After either EPA or DCHA, thromboxane formation was unchanged in serum derived from clotted whole blood as was total in vivo synthesis measured by excretion of immunoreactive 2,3-dinor thromboxane B2/3. We conclude that DCHA reduces platelet responsiveness, contributing to the antithrombotic effects of omega-3 fatty acid-rich fish oil ingestion, of which DCHA is a major component.     

Effect of fish oil on LDL oxidation and plasma homocysteine concentrations in health

Oxidation of low-density lipoprotein (LDL) and hyperhomocysteinemia are believed to play a role in therogenesis. Whether n-3 polyunsaturated fatty acids increase LDL susceptibility to oxidation or influence homocysteine (Hcy) metabolism has long been a subject of controversy. In this study, we evaluated the effect of 8 weeks of dietary supplementation with 6 g/day of fish oil (FO; 3 g of n-3 fatty acids) on plasma lipoproteins, in vitro LDL peroxidation, antioxidant status, and plasma Hcy concentrations in 16 normolipidemic subjects. FO rapidly and significantly (P < .01) decreased plasma total and very low density lipoprotein triglyceride concentrations and had no effect on LDL or high-density-lipoprotein cholesterol. The mean lag time before onset of Cu(2+)-induced LDL oxidation, as well as plasma and LDL alpha-tocopherol and beta-carotene concentrations, was unchanged. However, changes in plasma aminothiol concentrations occurred during the study. Specifically, a progressive and significant increase in total Hcy plasma concentrations was observed (13.4% and 20% after 4 and 8 weeks, respectively; P < .01). Total glutathione concentrations were significantly higher after 8 weeks (P < .05). The tHcy increase was not associated with changes in plasma folate or vitamin B(12) concentrations. However, concentrations of plasma nitric oxide metabolites (NO(x) = NO(2) + NO(3)) were significantly higher than at baseline after 8 weeks of FO intake (74%; P < .01). Further, the changes in total Hcy and NO(x) plasma concentrations observed after 8 weeks of FO were found to be significantly correlated (r = .78, P < .001). With this study, we report for the first time the apparent interaction of n-3 fatty acids and nitric oxide on Hcy metabolism.     

Omega-3 fatty acids for cardioprotection

The most compelling evidence for the cardiovascular benefit provided by omega-3 fatty acids comes from 3 large controlled trials of 32,000 participants randomized to receive omega-3 fatty acid supplements containing docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) or to act as controls. These trials showed reductions in cardiovascular events of 19% to 45%. These findings suggest that intake of omega-3 fatty acids, whether from dietary sources or fish oil supplements, should be increased, especially in those with or at risk for coronary artery disease. Patients should consume both DHA and EPA. The target DHA and EPA consumption levels are about 1 g/d for those with known coronary artery disease and at least 500 mg/d for those without disease. Patients with hypertriglyceridemia benefit from treatment with 3 to 4 g/d of DHA and EPA, a dosage that lowers triglyceride levels by 20% to 50%. Although 2 meals of oily fish per week can provide 400 to 500 mg/d of DHA and EPA, secondary prevention patients and those with hypertriglyceridemia must use fish oil supplements if they are to reach 1 g/d and 3 to 4 g/d of DHA and EPA, respectively. Combination therapy with omega-3 fatty acids and a statin is a safe and effective way to improve lipid levels and cardiovascular prognosis beyond the benefits provided by statin therapy alone. Blood DHA and EPA levels could one day be used to identify patients with deficient levels and to individualize therapeutic recommendations.     

Omacor® (prescription omega-3-acid ethyl esters 90): From severe rhythm disorders to hypertriglyceridemia

Despite progress made in post-myocardial infarction (MI) revascularization and background therapy for the failing heart, the prevention of adverse cardiac remodeling associated with severe rhythm disorders remains an important drug target. Part of the remodeling can be counteracted by modulating the activity of ion channels and exchangers by omega-3 acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). In the GISSI-Prevenzione and GISSI-HF trials, omega-3 fatty acids were administered as ethyl esters (Omacor® Solvay Pharmaceuticals) and not as triglycerides present in fish oil. Ethyl esters result in a sustained intestinal absorption of EPA and DHA and require various purification steps during production, thereby minimizing the content of environmental toxins. Also the rather high (38%) DHA content of Omacor® should not be ignored since in rats with low dose intake of omega-3 acids, DHA but not EPA inhibited ischemia-induced arrhythmias. In patients on multiple tablets, 840 mg EPA+DHA in one capsule is preferred to increase compliance. It is not justified to refer to Omacor® as “n-3 polyunsaturated fatty acid supplementation” or even “fish oil” and, based on controlled clinical trials, there is no evidence that fish oil could be a substitute of Omacor®. To avoid further confusion, guidelines should be precise and refer to the medication, eg, as in NICE guideline CG48: “Omega-3-acid ethyl esters treatment licensed for secondary prevention post-MI.” The anti-arrhythmogenic action of Omacor® should be seen in the context of implantable cardioverter-defibrillator trials (DINAMIT, IRIS) where non-sudden death was increased and total mortality unaltered. However, Omacor® administered in the GISSI-HF trial reduced the incidence of severe arrhythmic events and mortality. Also in the GISSI-Prevenzione trial, arrhythmic death and mortality were reduced. At higher dosages (daily, 3–4 g) Omacor® exhibits more pronounced cardiovascular benefits and, as a licensed indication, improves hypertriglyceridemia and related lipid parameters.     

Plasma and red cell lipids in alcoholics with macrocytosis

The cholesterol and phospholipid content and the fatty acid composition in plasma and red cell membranes was determined in 10 alcoholics with macrocytic erythrocytes. None of the patients had anemia. Red cells exhibited macrocytosis up to 108 fl in all patients. Bilirubin, albumin, prothrombin, and cholinesterase were in the normal range, whereas transaminases and gamma-glutamyl transpeptidase activities in serum were elevated in most of the patients. The molar ratio cholesterol/phospholipids in red cells was not altered in alcoholics. An abnormally high ratio of saturated/unsaturated fatty acids was found in plasma as well as in red cell phospholipids from alcoholics. Linoleic acid was substantially decreased in plasma of alcoholics (controls 32.3%, alcoholics 21.8%). This fatty acid abnormality was reflected by a decrease of linoleic acid in red cell phosphatidylcholine. The present data may suggest that fatty acid changes taking place in membranes of macrocytes were a consequence of changes in the plasma and reflect plasma/membrane exchanges rather than direct effects of ethanol on red cell membranes. Lipid alterations of red cell membranes may be involved in the development of macrocytosis in chronic alcoholism.     

DHA 与 EPA 合成超长链多不饱和脂肪酸的效率比较

目的：比较在ELOVL4蛋白酶催化作用下,DHA和EPA合成超长链多不饱和脂肪酸VLC-PUFA的效率。方法构建携带ELOVL4基因和绿色荧光蛋白的重组腺病毒,转入培养的 PC12细胞,通过qRT-PCR定量分析ELOVL 4基因的表达量,WB检测ELOVL4蛋白的表达;1∶1加入DHA和EPA,孵育48 h之后进行脂肪酸提取,通过气相质谱 GC-MS分析超长链脂肪酸的成分。结果 GC-MS检测到分别用DHA及EPA处理后的PC12＋Ad-ELOVL4的细胞中有n3 VLC-PUFA的表达,34：5n3和36：5n3分别为0.85％和1.11％;34：6n3和36：63n分别为0.16％和0.29％;EPA所产生的五烯酸总和是DHA所产生的六烯酸总和的4倍。结论 EPA合成VLC-PUFA的效率远远高于DHA,为患者提供更高比例的 EPA,而非DHA,可能是治疗STGD3疾病的方式之一。