Dietary n-3 fatty acids in the prevention of cardiac arrhythmias

It has been shown that in animals, and probably in humans, n-3 polyunsaturated fatty acids (PUFAs) are antiarrhythmic. We discuss recent studies on the antiarrhythmic actions of polyunsaturated fatty acids. Polyunsaturated fatty acids stabilize the electrical activity of isolated cardiac myocytes by inhibiting sarcolemmal ion channels so that a stronger electrical stimulus is required to elicit an action potential and the relative refractory period is markedly prolonged. This appears at present to be the probable major antiarrhythmic mechanism of polyunsaturated fatty acids.     

Effect of n-3 polyunsaturated fatty acids on risk reduction of sudden death

Two recent reports confirm the role of n-3 polyunsaturated fatty acid (PUFA) consumption in risk reduction for sudden death. The mechanism likely involves an antiarrhythmic effect, further supporting the role of dietary n-3 PUFA in maintenance of human health.     

Dietary fatty acids and inflammation

Introduction:  It is commonly believed that inflammation can be reduced by lowering the dietary ratio of n-6 (linoleic acid) to n-3 polyunsaturated fatty acids as a means of lowering arachidonic acid levels in cell membranes. This review will examine this proposition.
Results:  Although many pro-inflammatory molecules can be produced from arachidonic acid and this long-chain n-6 fatty acid can be produced from linoleic acid, changing dietary linoleic acid intake over a wide range does not have any significant effect on arachidonic acid levels in cell membranes, inflammation or immune functions. There are no data that show lowering dietary n-6 polyunsaturated fats reduces inflammation. In contrast, arachidonic acid levels in cell membranes and inflammatory parameters are lowered by increasing intakes of long-chain n-3 polyunsaturated fatty acids. Resolvins and protectins, both derivatives of long-chain n-3 fats, also have potential anti-inflammatory activity. In high doses, long-chain n-3 fats may have modest, beneficial effects on inflammation in rheumatoid arthritis. However, many studies have shown no effects of fish oil on inflammation parameters.
Conclusions:  The dietary n-6/n-3 ratio is not a useful measure of the inflammatory nature of a diet, though the absolute amount of dietary long-chain n-3 polyunsaturated fatty acids may be a guide.     

Efficiency of conversion of alpha-linolenic acid to long chain n-3 fatty acids in man

Alpha-linolenic acid (18:3n-3) is the major n-3 (omega 3) fatty acid in the human diet. It is derived mainly from terrestrial plant consumption and it has long been thought that its major biochemical role is as the principal precursor for long chain polyunsaturated fatty acids, of which eicosapentaenoic (20:5n-3) and docosahexaenoic acid (22:6n-3) are the most prevalent. For infants, n-3 long chain polyunsaturated fatty acids are required for rapid growth of neural tissue in the perinatal period and a nutritional supply is particularly important for development of premature infants. For adults, n-3 long chain polyunsaturated fatty acid supplementation is implicated in improving a wide range of clinical pathologies involving cardiac, kidney, and neural tissues. Studies generally agree that whole body conversion of 18:3n-3 to 22:6n-3 is below 5% in humans, and depends on the concentration of n-6 fatty acids and long chain polyunsaturated fatty acids in the diet. Complete oxidation of dietary 18:3n-3 to CO2 accounts for about 25% of 18:3n-3 in the first 24 h, reaching 60% by 7 days. Much of the remaining 18:3n-3 serves as a source of acetate for synthesis of saturates and monounsaturates, with very little stored as 18:3n-3. In term and preterm infants, studies show wide variability in the plasma kinetics of 13C n-3 long chain polyunsaturated fatty acids after 13C-18:3n-3 dosing, suggesting wide variability among human infants in the development of biosynthetic capability to convert 18:3n-3 to 22:6n3. Tracer studies show that humans of all ages can perform the conversion of 18:3n-3 to 22:6n3. Further studies are required to establish quantitatively the partitioning of dietary 18:3n-3 among metabolic pathways and the influence of other dietary components and of physiological states on these processes.     

Fish, n-3 polyunsaturated fatty acid and colorectal cancer prevention: a review of experimental and epidemiological studies

Colorectal cancer demonstrates high incidences in the developed countries and is the second largest cause of deaths from neoplasia. In Japan, about 12% of all cancer deaths are due to colorectal cancer and the rate continues to increase remarkably. Dietary factors are clearly linked to the development of tumors in the colorectum, and the increase in mortality from colorectal cancer over the last few decades in Japan has been attributed to Westernization of the diet. On the other hand, the intake of fish/n-3 polyunsaturated fatty acids has long been considered as a factor decreasing the risk of colorectal cancer. In the present study, we investigated the effect of fish/n-3 polyunsaturated fatty acids on colorectal cancer by reviewing papers on both experimental and epidemiological studies overall to obtain a perspective for research and practice for prevention. This review covers the following areas. 1. Relationships between n-3 polyunsaturated fatty acids and colon carcinogenesis in experimental studies. 1) Aberrant crypt foci (ACF). 2) Tumors. 2. Relationships between fish intake and colorectal cancer in epidemiological studies. 1) Ecological studies. 2) Case-control studies. 3) Cohort studies. 4) Randomized controlled trials. There are substantial data from experimental studies in support of anticarcinogenic effects of fish/ n-3 polyunsaturated fatty acids in the colon. Several epidemiological studies have also provided evidence that fish/n-3 polyunsaturated fatty acids have anticarcinogenic effects in the colon, but not all data are consistent. However, increasing intake of fish/n-3 polyunsaturated fatty acids for preventing colon cancer is suggested from review of experimental and epidemiological research overall. In the future, it is necessary to improve precision regarding exposure to carcinogens and fish/n-3 polyunsaturated fatty acids intake using a detoiled dietary survey and biomarkers in epidemiological studies.     

n-3 Polyunsaturated fatty acids,fatal ischemic heart disease,and nonfatal myocardial infarction in older adults: the Cardiovascular Health Study

BACKGROUND: Little is known about the relation of the dietary intake of n-3 polyunsaturated fatty acids, ie, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) from fatty fish and alpha-linolenic acid from vegetable oils, with ischemic heart disease among older adults. OBJECTIVE: We investigated the associations of plasma phospholipid concentrations of DHA, EPA, and alpha-linolenic acid as biomarkers of intake with the risk of incident fatal ischemic heart disease and incident nonfatal myocardial infarction in older adults. DESIGN: We conducted a case-control study nested in the Cardiovascular Health Study, a cohort study of adults aged > or = 65 y. Cases experienced incident fatal myocardial infarction and other ischemic heart disease death (n = 54) and incident nonfatal myocardial infarction (n = 125). Matched controls were randomly selected (n = 179). We measured plasma phospholipid concentrations of n-3 polyunsaturated fatty acids in blood samples drawn approximately 2 y before the event. RESULTS: A higher concentration of combined DHA and EPA was associated with a lower risk of fatal ischemic heart disease, and a higher concentration of alpha-linolenic acid with a tendency to lower risk, after adjustment for risk factors [odds ratio: 0.32 (95% CI: 0.13, 0.78; P = 0.01) and 0.52 (0.24, 1.15; P = 0.1), respectively]. In contrast, n-3 polyunsaturated fatty acids were not associated with nonfatal myocardial infarction. CONCLUSIONS: Higher combined dietary intake of DHA and EPA, and possibly alpha-linolenic acid, may lower the risk of fatal ischemic heart disease in older adults. The association of n-3 polyunsaturated fatty acids with fatal ischemic heart disease, but not with nonfatal myocardial infarction, is consistent with possible antiarrhythmic effects of these fatty acids.     

Dietary fat and cardiovascular disease risk: quantity or quality?

When considering dietary fat quantity, there are two main factors to consider, impact on body weight and plasma lipoprotein profiles. Data supporting a major role of dietary fat quantity in determining body weight are weak and may be confounded by differences in energy density, dietary fiber, and dietary protein. With respect to plasma lipoprotein profiles, relatively consistent evidence indicates that under isoweight conditions, decreasing the total fat content of the diet causes an increase in triglyceride and decrease in high-density lipoprotein (HDL) cholesterol levels. When considering dietary fat quality, current evidence suggests that saturated fatty acids tend to increase low-density lipoprotein (LDL) cholesterol levels, whereas monounsaturated and polyunsaturated fatty acids tend to decrease LDL cholesterol levels. Long-chain omega-3 fatty acids, eicosapentaenoic acid (EPA) (20:5n-3) and docosahexaenoic acid (DHA) (22:6n-3), are associated with decreased triglyceride levels in hypertriglyceridemic patients and decreased risk of developing coronary heart disease (CHD). Dietary trans-fatty acids are associated with increased LDL cholesterol levels. Hence, a diet low in saturated and trans-fatty acids, with adequate amounts of monounsaturated and polyunsaturated fatty acids, especially long-chain omega-3 fatty acids, would be recommended to reduce the risk of developing CHD. Additionally, the current data suggest it is necessary to go beyond dietary fat, regardless of whether the emphasis is on quantity or quality, and consider lifestyle. This would include encouraging abstinence from smoking, habitual physical activity, avoidance of weight gain with age, and responsible limited alcohol intake (one drink for females and two drinks for males per day).     

Ratio of n-6 to n-3 fatty acids and bone mineral density in older adults: the Rancho Bernardo Study

BACKGROUND: Several lines of evidence suggest that n-3 fatty acids reduce the risk of some chronic diseases, including heart disease, diabetes, and cancer. Other research, mainly in animals, also suggests a role in bone health. OBJECTIVE: We aimed to investigate the association between the ratio of dietary n-6 to n-3 fatty acids and bone mineral density (BMD) in 1532 community-dwelling men and women aged 45-90 y. DESIGN: Between 1988 and 1992, dietary data were obtained through self-administered food-frequency questionnaires, and BMD was measured at the hip and spine with the use of dual-energy X-ray absorptiometry. A medical history was obtained and current medication use was validated. Age- and multiple-adjusted linear regression analyses were performed. RESULTS: There was a significant inverse association between the ratio of dietary linoleic acid to alpha-linolenic acid and BMD at the hip in 642 men, 564 women not using hormone therapy, and 326 women using hormone therapy; these results were independent of age, body mass index, and lifestyle factors. An increasing ratio of total dietary n-6 to n-3 fatty acids was also significantly and independently associated with lower BMD at the hip in all women and at the spine in women not using hormone therapy. CONCLUSIONS: A higher ratio of n-6 to n-3 fatty acids is associated with lower BMD at the hip in both sexes. These findings suggest that the relative amounts of dietary polyunsaturated fatty acids may play a vital role in preserving skeletal integrity in older age.     

Perinatal Dietary Polyunsaturated Fatty Acids in Brain Development,Role in Neurodevelopmental Disorders

n-3 and n-6 polyunsaturated fatty acids (PUFAs) are essential fatty acids that are provided by dietary intake. Growing evidence suggests that n-3 and n-6 PUFAs are paramount for brain functions. They constitute crucial elements of cellular membranes, especially in the brain. They are the precursors of several metabolites with different effects on inflammation and neuron outgrowth. Overall, long-chain PUFAs accumulate in the offspring brain during the embryonic and post-natal periods. In this review, we discuss how they accumulate in the developing brain, considering the maternal dietary supply, the polymorphisms of genes involved in their metabolism, and the differences linked to gender. We also report the mechanisms linking their bioavailability in the developing brain, their transfer from the mother to the embryo through the placenta, and their role in brain development. In addition, data on the potential role of altered bioavailability of long-chain n-3 PUFAs in the etiologies of neurodevelopmental diseases, such as autism, attention deficit and hyperactivity disorder, and schizophrenia, are reviewed.     

Effect of placental function on fatty acid requirements during pregnancy

The fetus has an absolute requirement for the n-3/n-6 fatty acids and docosahexaenoic acid (22:6 n-3; DHA) in particular is essential for the development of the brain and retina. Most of the fat deposition in the fetus occurs in the last 10 weeks of pregnancy. The likely rate of DHA utilisation during late pregnancy cannot be met from dietary sources alone in a significant proportion of mothers. De novo synthesis makes up some of the shortfall but the available evidence suggests that the maternal adipose tissue makes a significant contribution to placental transport to the fetus. The placenta plays a crucial role in mobilising the maternal adipose tissue and actively concentrating and channelling the important n-3/n-6 fatty acids to the fetus via multiple mechanisms including selective uptake by the syncytiotrophoblast, intracellular metabolic channelling, and selective export to the fetal circulation. These mechanisms protect the fetus against low long-chain polyunsaturated fatty acid (LCPUFA) intakes in the last trimester of pregnancy and have the effect of reducing the maternal dietary requirement for preformed DHA at this time. As a result of these adaptations, small changes in the composition of the habitual maternal diet before pregnancy are likely to be more effective in improving LCPUFA delivery to the fetus than large dietary changes in late pregnancy. There is little evidence that DHA intake/status in the second half of pregnancy affects visual and cognitive function in the offspring, but more studies are needed, particularly in children born to vegetarian and vegan and mothers who may have very low intakes of DHA.     

Effect of different dietary triglycerides on liver fatty acids and prostaglandin synthesis by mouse peritoneal cells.

The effect of dietary triglycerides varying in fatty acid composition on the tissue fatty acids and prostaglandin synthesis was studied in mice. The dietary fats were medium-chain triglycerides (rich in C8:0 and C10:0), structured lipids (rich in 12:0), high oleic sunflower oil (rich in 18:1), corn oil (rich in n-6 polyunsaturated fatty acids), and menhaden oil (rich in n-3 polyunsaturated fatty acids) fed at 5% by weight in refined diets. The medium chain fatty acids C8 to C12 from medium-chain triglycerides and structured lipids did not accumulate in liver phospholipids. However, long-chain fatty acids from the dietary fats were incorporated into liver lipids, with n-3 polyunsaturated fatty acids replacing arachidonic acid. The synthesis of 6-keto-prostaglandin F1 alpha and prostaglandin E2 by peritoneal cells in response to intraperitoneal injection of zymosan decreased as the arachidonic acid levels were decreased. When the same dietary fats were added to the refined, fat-free diets, at 7.5 wt% levels, together with 2.5 wt% of safflower oil to provide essential fatty acids, only the long-chain fatty acids from the dietary fats were incorporated into the liver lipids. The arachidonic acid in liver lipids was enhanced after supplementation of diets with safflower oil. However, the reduction in prostaglandin synthesis by peritoneal cells in response to intraperitoneal injection of zymosan was similar to that observed when 5% fat was fed. The data suggest that dietary fats of defined composition, with or without added essential fatty acids, may be useful as alternate fat sources in parenteral nutrition in reducing inflammatory responses mediated via prostaglandins.     

n-3及n-6多不饱和脂肪酸与乳腺癌关系的Meta分析

目的 系统评价n-3多不饱和脂肪酸(n-3PUFAs)、n-6多不饱和脂肪酸(n-6PUFAs)及其比例与乳腺癌发病风险的关系。方法 系统检索Pubmed、Embase、Web of Science、知网、万方等数据库截止至2022年1月1日有关n-3及n-6多不饱和脂肪酸与乳腺癌关系的研究,对最终纳入的文献进行数据提取与质量评价,采用Stata 15.1软件进行Meta分析。结果 共纳入33项针对n-3及n-6PUFAs和乳腺癌发病风险关联的观察性流行病学研究,其中队列研究14项,病例对照研究20项,共纳入研究对象1 077 178例,患者19 207例。Meta分析结果显示:n-3多不饱和脂肪酸(OR=0.933,95%CI:0.858～1.014)、n-6多不饱和脂肪酸(OR=1.018,95%CI:0.914～1.133)与乳腺癌发病风险无统计学关联(P>0.05),而较高的n-6/n-3PUFAs比值会显著增加乳腺癌的发病风险(OR=1.166,95%CI:1.047～1.299,P=0.005)。结论 n-6/n-3多不饱和脂肪酸的比值与乳腺癌的发病风险呈正相关,提示合理的膳食脂肪摄入比可能会降低乳腺癌的患病风险。而n-3及n-6多不饱和脂肪酸与乳腺癌发病风险的单独效应关系尚不明确,仍需更多前瞻性实验流行病学证据进行支持。     

Dietary (n-3) polyunsaturated fatty acids remodel mouse T-cell lipid rafts

In vitro evidence indicates that (n-3) polyunsaturated fatty acids (PUFA) suppress T-cell activation in part by displacing proteins from lipid rafts, specialized regions within the plasma membrane that play an important role in T-cell signal transduction. However, the ability of (n-3) PUFA to influence membrane microdomains in vivo has not been examined to date. Therefore, we compared the effect of dietary (n-3) PUFA on raft (liquid ordered) vs. soluble (liquid disordered) microdomain phospholipid composition in mouse T cells. Mice were fed diets containing either 5 g/100 g corn oil (control) or 4 g/100 g fish oil [contains (n-3) PUFA] + 1 g/100 g corn oil for 14 d. Splenic T-cell lipid rafts were isolated by density gradient centrifugation. Raft sphingomyelin content (mol/100 mol) was decreased (P < 0.05) in T cells isolated from (n-3) PUFA-fed mice. Dietary (n-3) PUFA were selectively incorporated into T-cell raft and soluble membrane phospholipids. Phosphatidylserine and glycerophosphoethanolamine, which are highly localized to the inner cytoplasmic leaflet, were enriched to a greater extent with unsaturated fatty acids compared with sphingomyelin, phosphatidylinositol and glycerophosphocholine. These data indicate for the first time that dietary (n-3) PUFA differentially modulate T-cell raft and soluble membrane phospholipid and fatty acyl composition.     

High-linoleate and high-alpha-linolenate diets affect learning ability and natural behavior in SAMR1 mice

Semipurified diets incorporating either perilla oil [high in alpha-linolenate, 18:3(n-3)] or safflower oil [high in linoleate, 18:2(n-6)] were fed to senescence-resistant SAMR1 mouse dams and their pups. Male offspring at 15 mo were examined using behavioral tests. In the open field test, locomotor activity during a 5-min period was significantly higher in the safflower oil group than in the perilla oil group. Observations of the circadian rhythm (48 h) of spontaneous motor activity indicated that the safflower oil group was more active than the perilla oil group during the first and second dark periods. The total number of responses to positive and negative stimuli was higher in the safflower oil group than in the perilla oil group in the light and dark discrimination learning test, but the correct response ratio was lower in the safflower oil group. The difference in the (n-6)/(n-3) ratios of the diets reflected the proportions of (n-6) polyunsaturated fatty acids, rather than those of (n-3) polyunsaturated fatty acids in the brain total fatty acids, and in the proportions of (n-6) and (n-3) polyunsaturated fatty acids in the total polyunsaturated fatty acids of the brain phospholipids. These results suggest that in SAMR1 mice, the dietary alpha-linolenate/linoleate balance affects the (n-6)/(n-3) ratio of brain phospholipids, and this may modify emotional reactivity and learning ability.     

Comparative evaluation of essential fatty acid composition of mothers' milk of some urban and suburban regions of West Bengal,India

This study investigated the fatty acid composition of lipid present in breast milk of mothers residing in urban and suburban regions of West Bengal with special emphasis on n-6 and n-3 polyunsaturated fatty acids, which played a crucial role in the growth and development of neonates. Milk samples collected from 135 mothers of middle income group (average monthly income around ‘Rs 10,000/-’) were analysed by gas liquid chromatography after extraction and transmethylation to determine fatty acid composition. Information about the dietary intake of individual mothers was obtained through food frequency questionnaire. The fractions of n-6 and n-3 polyunsaturated fatty acids available in milk of urban mothers were 13.59 ± 0.94 and 3.65 ± 0.49, respectively, and in suburban mothers 12.74 ± 0.89 and 4.36 ± 0.39, respectively. The green leafy vegetables, fishes and vegetable oils were the major sources of essential fatty acids in the diet of the experimental groups of Bengali mothers. This study revealed a relationship between the alimentary habits of mothers and the concentration of essential fatty acids in breast milk of Bengali mothers.     

Dietary polyunsaturated fats uniquely suppress rat liver fatty acid synthase and S14 mRNA content

The objective of these studies was to demonstrate that dietary polyunsaturated, but not saturated, fatty acids decrease mRNA abundance for fatty acid synthase (FAS) and S14. A series of experiments involving adult and weanling rats was designed to examine the ability of saturated (tripalmitin), (n-9) monounsaturated (triolein), (n-6) di-unsaturated (safflower oil), and (n-3) polyenic (fish oil) fatty acids to suppress the gene expression of FAS and S14. Dietary polyunsaturated fats reduced by 75-90% the hepatic abundance of FAS and S14 mRNA. Fish oil, rich in 20- and 22-carbon polyenic fatty acids, was more effective than safflower oil, whereas tripalmitin and triolein were without effect. Polyunsaturated fats were also very effective at preventing the rise in FAS and S14 mRNA associated with weaning. The inhibitory action of polyunsaturated fat was rapidly (less than 3 h) removed by deleting the fat from the meal. Regression analysis revealed a high correlation (0.81-0.94) between FAS and S14 expression among the various dietary studies. These data support the hypothesis that dietary polyunsaturated fats uniquely regulate the gene expression of lipogenic enzymes and that the mediator is likely a specific entity derived from the long-chain polyenic fatty acids. Moreover, the high correlation between FAS and S14 expression supports the hypothesis that S14 is a member of the lipogenic protein family and has potential as a model gene for the study of FAS expression.     

Heart rate variability and fatty acid content of blood cell membranes: a dose-response study with n-3 fatty acids.

BACKGROUND: Dietary intake of long-chain n-3 polyunsaturated fatty acids (PUFA) may protect against sudden cardiac death, an event that may be predicted by measurement of heart rate variability (HRV). OBJECTIVE: The objectives of this study were to 1) examine the correlations between the content of fatty acids in blood cell membranes (platelets and granulocytes) and HRV in healthy subjects, and 2) assess the effect on HRV of dietary intervention with n-3 PUFA in different doses. DESIGN: Sixty healthy volunteers (25 women and 35 men) were randomly assigned to 3 treatment groups in a double-blind design. Subjects received a daily supplement of either 6.6 g n-3 PUFA, 2.0 g n-3 PUFA, or placebo (olive oil). A 24-h Holter recording was obtained for each subject before supplementation and after 12 wk of supplementation; the 24-h HRV was then related to the content of fatty acids in granulocytes and platelets. RESULTS: Before supplementation, positive correlations were observed in men between the content of docosahexaenoic acid in cell membranes and HRV indexes (r = 0.50, P < 0.01), whereas such correlations were not found in women. Dietary intervention revealed a dose-dependent effect of n-3 PUFA on HRV in men, whereas no effect was found in women. CONCLUSION: The study showed a beneficial effect of n-3 PUFA on HRV in healthy men, suggesting an antiarrhythmic effect of n-3 PUFA. No such effect was observed in healthy women.     

Polyunsaturated fatty acids,inflammation and immunity

Consumption of n-6 polyunsaturated fatty acids greatly exceeds that of n-3 polyunsaturated fatty acids. The n-6 polyunsaturated fatty acid arachidonic gives rise to the eicosanoid family of inflammatory mediators (prostaglandins, leukotrienes and related metabolites) and through these regulates the activities of inflammatory cells, the production of cytokines and the various balances within the immune system. Fish oil and oily fish are good sources of long chain n-3 polyunsaturated fatty acids. Consumption of these fatty acids decreases the amount of arachidonic acid in cell membranes and so available for eicosanoid production. Thus, n-3 polyunsaturated fatty acids act as arachidonic acid antagonists. Components of both natural and acquired immunity, including the production of key inflammatory cytokines, can be affected by n-3 polyunsaturated fatty acids. Although some of the effects of n-3 fatty acids may be brought about by modulation of the amount and types of eicosanoids made, it is possible that these fatty acids might elicit some of their effects by eicosanoid-independent mechanisms. Such n-3 fatty acid-induced effects may be of use as a therapy for acute and chronic inflammation, and for disorders which involve an inappropriately activated immune response.