Dietary Balance of Omega-6 and Omega-3 Fatty Acids and Coronary Heart Disease: A Short Review

Raghuveer Choudhary, Jayant Kumar, VK Chawla, Kamla, Manoj Bundella

Essential fatty acids, both n-6 and n-3 have been part of our diet since the beginning of human life. Before the agriculture revolution 10000 years ago humans consumed about equal amount of both. Over the past 150 year this balance has been upset. The current western diet is very high in n-6 (the ratio of n-6 to n-3 fatty acids is 20-30:1) because of the indiscriminate recommendation to substitute n-6 fatty acids for saturated fats to lower cholesterol concentrations.1 Over the past 100 to 150 years there has been an enormous increase in the consumption of n-6 fatty acids due to increased intake of vegetable oil from corn, sunflower seeds, safflower seeds, cotton seed and soybeans. Intake of n-3 fatty acids is much lower today because of decrease in fish consumption and production of animal feeds rich in grains containing n-6 fatty acids leading to production of meat rich in n-6 fatty acids and poor in n-3 fatty acids.2 Modern agriculture with its emphasis on production has decreased the n-3 fatty acid content in many foods: green leafy vegetables, animal meats, eggs and even fish. Studies indicate that a high intake of n-6 fatty acids shifts the physiologic state to one that is prothrombotic and proaggregatory, characterized by increase in blood viscosity, vasospasm and vasoconstriction and decreases in bleeding time. N-3 fatty acids however have anti-inflammatory, anti-thrombotic, anti-arrhythmic, hypolipidemic and vasodilatory properties. These beneficial effects of n-3 fatty acids have shown in the secondary prevention of coronary heart disease, hypertension, type-2 diabetes. Over the past 20 years many studies have been carried out on the metabolism of polyunsaturated fatty acids (PUFAs) in general and on n-3 fatty acids in particular. This review focuses on physiological effects of PUFA (n-6 and n-3 fatty acid and the effects of dietary linolenic acid (ALA) compared with long chain n-3 derivatives on coronary heart disease.

Chemistry
PUFA belongs to the class of simple lipids as they are fatty acids with two or more double bonds in cis configuration. There are two main families of PUFA: n-3 and n-6. These fatty acids family are not convertible and have different biochemical roles. Omega-3 Fatty acids are polyunsaturated, meaning they contain more than one double bond (Figure 1).

They are called omega-3 because the first double bond counting from the methyl end of the fatty acid is located at the third carbon atom. Omega 3 fatty acids include Alpha-linolenic acid (ALA), Eicosapentaenoic acid (EPA), Docosahexaenoic acid (DHA) ALA scientific abbreviation is 18:3n-3. The first part (18:3) suggests that ALA is an 18-carbon fatty acid with 3 double bonds. The second part (n-3) tells you that ALA is an omega-3 fatty acid. It is required for health, but cannot be synthesized in humans. Must be obtained from the diet. Humans can synthesize other omega-3 fatty acids from ALA. Eicosapentaenoic acid (EPA): 20:5 n-3, and Docosahexaenoic acid (DHA): 22:6 n-3 are usually referred to as marine-derived omega-3 fatty acids because they are abundant in certain species of fish. Whereas, ALA is con-sidered a plant-derived omega-3 fatty acid. Arachidonic acid is a precurser for pro-inflammatory eicosanoids. It is an omega-6 fatty acid that can come directly from the diet, or it can be manufactured from linoleic acid from the diet. EPA and DHA are the precursers for the anti-inflammatory eicosanoids. They are omega-3 fatty acids that can also come directly from the diet, or from ALA from the diet. Linoleic acid (n-6) (LA) and alpha-linolenic (n-3)(ALA) are two of the main representation compounds, known as dietary essential fatty acids (EFA) because they prevent deficiency symptoms and cannot be synthesized by humans.

Sources of PUFA
The predominant sources of n-3 fatty acids are vegetables oils and fish, vegetable oil are the major sources of ALA. In particular ALA is found in the chloroplast of green leafy vegetables, such as purslane and spinach, and in seeds of flax, linseed, walnuts and others.3 Fish is the main source of eicosapentaenoic acid (EPA) (C20:5 n-3) and of docosahexaenoic acid (C22:6 n-3) (DHA).4 Vegetables are the main source of n-6 fatty acids. The most important n-6 fatty acid LA found in large amount in western diets in corn oil, sunflower oil and soya bean oil.5 (Table 1).

Evolutionary Aspects of Diet in Humans

Humans evolved on a diet that was low in saturated fat and amount of n-3 and n-6 fatty acids was quite equal. During the last 100-150 years certain nutritional changes were seen especially increase in saturated fat from grain fed cattle, an increase in trans- fatty acids from the hydrogenation of vegetables oils and increase in n-6 fatty acids ( about 30g/day) due to production of oils from vegetables seeds such as corn, safflower and cotton. Increased in meat consumption have led to increase amounts of arachidonic acid (AA) (20:4 n-6) about 0.21.0mg/day.4 Whereas the amount of ALA is only 2.92g/day6 and amounts of EPA, DHA are 48 and 72mg/day respectively. Thus decrease in the amount of n-3 fatty acids has led to an imbalance and increase in ratio of n6/n-3.

Recommended PUFA

Intake

of

In Europe, minimum requirements for essential fatty acids are based on the Report of Panel on Dietary Reference Values of the committee on medical aspects of Food Policy, in which the suggested minimum requirement of LA is at 1% of energy intake.7,8 In United States it is suggested that total PUFA intake should remain at 7% of energy and not exceeds 10% of energy intake.9

Metabolism of n-3 and n-6 Fatty Acids (Figure 2)

There are many steps in the metabolism of omega-3 and omega-6 fatty acids. The end-product of linoleic acid metabolism is AA, which is pro-inflammatory. Linoleic acid comes from sources such as corn and sunflower oil and is abundant in the typical western diet. The omega-3 fatty acids are important for cardiovascular health. These n-3 fatty acids can be obtain from the diet. Only EPA and DHA have anti-inflammatory effects. But alpha-linolenic is metabolized to EPA and DHA. The conversion is usually about 10%. Some sources of alpha-linolenic acid in the diet are flaxseed, canola oil, soy, almonds and walnuts. Good sources of EPA and DHA are fatty fish and shellfish. There is competition between linoleic acid and linolenic acid for the same series of desaturation and elongation enzymes to form their respective products. So the more of either linoleic or alpha-linolenic in the diet, the more of their respective products that will be formed, and the less of the other product that will be formed. This can affect the con-version rate of alpha-linolenic to EPA and DHA. The more linoleic acid in the diet, the less

linolenic acid will be converted, and vice versa. Increasing consumption of any of these fatty acids increases their proportion in inflammatory cell phospholipids. So when an injury or invasion occurs, a phospholipase will free these fatty acids from the cells, to make them available for eicosanoid synthesis. There is also competition between AA and EPA and DHA for the lipoxygenase and cyclooxygenase pathways. Having a higher per-centage of EPA and DHA in these cell membranes decreases the amount of AA available for synthesis of these pro-inflammatory eicosanoids. The idea behind increasing con-sumption of omega-3 is that the more omega-3 and the less omega-6 and the less inflammation. Prostaglandins, leukotrienes, and thromboxanes are eicosanoid hormones that act in the regulation of the duration and intensity of the inflammatory response. Again, the proinflammatory AA products are prostaglandin E2, leukotriene B4, and the 2 series of thromboxanes. Leukotriene B4 enhances production of tumor necrosis factor alpha, and interleukin 1 and 6. The EPA and DHA products are the 3 series prostaglandins and thromboxanes, and the five series leukotrienes.

Physiological Effects of n-6 and n-3 Fatty Acids

Linoleic acid (LA;18:2N-6) and ALA (18:3 n-3) are now regarded as nutritionally EFA. The classic symptoms of essential fatty acid deficiency includes dermatitis, growth retardation and infertility relates to the biological function of n-6 fatty acids.11 LA is a structural component in the ceramides of the water barrier of the skin; AA is a precursor of eicosanoids; n-6 fatty acids possibly play a role as second messengers in the process of signal transduction across cell membrane. The biological function of dietary n-3 fatty acids11 are to provide energy and carbon atoms ; EPA and DHA serves as a precursor for n-3 eico-sanoids increasing evidence point to a specific role of DHA from membrane function mainly in retina and neuronal tissues. Deficiencies of n-3 PUFA leads to a loss of DHA from brain and retina rods outer segment phospholipids with a compensatory replacement by 22:5 n-6. This minor changes in membrane phospholipid structure is sufficient to lead to memory loss, learning disabilities and impaired visual activity. Linoleic acid and ALA and their long chain derivatives are important components of animal and plant cell

membrane. When human ingest fish or fish oil, the ingested ecosapentaenoic acid (EPA;20:5 n-3) and docosahexanoic acid (DHA;22:6 n-3) particularly replace the n-6 fatty acid (especially arachidonic acid (AA;20:4n-6) in the cell membranes specially those of platelats, erythrocytes, neutrophil, monocytes and liver cells). As a result of EPA and DHA from fish or fish oil leads to Decreased production of prostaglandin E2 metabolites Decreased concentration of thromboxane A2, a potent platelet aggregator and vasoconstrictor Decreased formation of leukotriene B4, an inducer of inflammation and a powerful inducer of leucocytes chemotaxis and adherence Increased concentration of thromboxane A3 a weak platelet aggregator and vasoconstrictor Increased concentrations of prostacyclin, PGI3, leading to an overall increase in total prostacyclin by increasing PGI3 without decreasing PGI2 (both PGI2 and PGI3 are active vasodilators and inhibitors of platelet aggregation) Increased concentration of leucotriene B5 a weak inducer of inflammation and chemotactic agent.12,13 Because of increased amounts of n-6 fatty acids, the eicosanoid metabolic products from AA, specifically prostaglandins, thromboxanes, leucotrienes, hydroxy fatty acids, and lipoxins are formed in larger quantities than those formed from n-3 fatty acids, specifically EPA. The eicosanoids from AA are biologically active in small quantities and if they are formed in large quantities they contribute to the formation of thrombsis and atheromas; the development of allergic and inflammatory disorders and cell proliferation. Thus a diet rich in n-6 fatty acid shifts the physiologic state to one that is prothrombotic and proaggregatory, with increase in blood viscosity, vasospasm and vasoconstriction and decrease in bleeding time. Bleeding time is shorter in groups of patients with hypercholesterolemia,14 hyperlipoproteinemia,15 myocardial infarction, other forms of atherosclerotic disease, type-2 diabetes, obesity, and hypertriglyceridemia. Atherosclerosis is a major complication in type-2 diabetes patients. There are ethnic differences in bleeding time that appear to be related to diet. Higher the ratio of n-6 to n-3 fatty acids in platelet phospholipids, the higher is the death from cardiovascular disease (Table 2). The hypolipidemic, antithrombotic, and anti-inflammatory effects of n-3 fatty acids have been studies mainly in animal modal ( Table3).16 The investigation of EPA and DHA from fish oil leads to a more physiologic state characterized by production of prostanoid leucotriens that have anti-thrombotic, anti-chemotactic, anti-vasoconstrictive and antiinflammatory properties.17,18 Dietary n-6 and n-3 PUFA have long been recognized as being able to exert experimentally unique influence on metabolic pathways and cellular growth.19 The ingestion of very long chain PUFA (eg. EPA) enhances mitochondrial and peroxisomal fatty acid oxidation20 change in mRNAs encoding several lipogenic enzymes can be detected within hours of feeding animals diets rich in n-3 PUFA.21 These effects are sustained so long as the n-3 PUFA remains in the diet. In these cases, the fatty acids act like a hormone to control the activity or abundance of key transcription factors. The discovery some fatty acids can act as hormones that control the activity of transcription factor demonstrated that fatty acids are not merely passive energy providing molecules but are also metabolic regulators.

Effects of dietary ALA Compared with Long Chain n-3 Fatty Acid Derivatives on Physiologic Indexes
ALA, the precursor of n-3 fatty acids, can be converted to long chain n-3 PUFAs and can therefore be substituted for fish oils. The minimum intake of long chain n-3 PUFAs needed for beneficial effects depends on the intake of other fatty acids. Dietary amounts of LA as well as the ratio of LA to ALA appear to be important for the metabolism of ALA to long chain n-3 PUFAs, Indu and Ghafoorunissa22 showed that while keeping the amount of dietary LA constant 3.7gm ALA appears to have biological effects similar to those of 0.3g long chain n-3 PUFA with conversion of 11g ALA to 1g long chain n-3 PUFA. Thus a ratio of 4 (15g LA: 3.7g ALA) is appropriate for conversion. Indu and Ghafoorunissa further indicated that increasing dietary ALA increases EPA concentration in plasma phospholipids after both 3 and 6 week of intervention. Dihomo--linolenic acid (20: 3n-6) concentration were reduced but AA concentration were not altered. The reduction in the ratio of long chain n-6 PUFAs to long chain n-3 PUFAs was greater after 6 week than after 3 week. Indu and Ghafoorunisa were able to show antithrombotic effects by reducing the ratio of n-6 to n-3 fatty acids with ALA rich vegetable oil. After ALA supplementation there was an increase in long chain n-3 PUFA in plasma and platelet phospholipids and a decrease in platelet aggregation. ALA supplementation did not alter triacylglycerol concentration. As shown by others only long chain n-3 PUFAs have triacylglycerol lowering effects.23 The diet of Western countries have larger amounts of LA, which has been promoted for its cholesterol lowering effects. It is now recognized that dietary LA favours oxidative modification of LDL cholesterol24,25 increases platelet response to aggregation,26 and suppresses the immune system.27 In contrast ALA intake is associated with inhibitory effects on the clotting activity of platelets, on their response to thrombin.28,29 ALA is not equivalent in its biological effects to the long chain n-3 fatty acids found in marine oils. EPA and DHA are more rapidly incorporated into plasma and membrane lipids and produce more rapid effect than does ALA. Relatively larger reserves of LA in body fat, as are found in the diet of omnivorous in western societies, would tend to slow down the formation of long chain n-3 fatty acids from ALA. Therefore role of ALA in human nutrition becomes important in terms of long term dietary intake. One advantage of the consumption of ALA over n-3 fatty acids from fish is that the problem of insufficient vitamin E intake does not exist with high intake of ALA from plant sources.

Coronary Heart Diseases

The effects on long chain n-3 fatty acids (EPA and DHA) on factors involved in the pathophysiology of atherosclerosis and inflammation are shown in Table 3. In recent studies, the effects of fatty acid on gene expression have been investigated and this focus of interest has led to studies at molecular level (Table 4).

The hypolipidemic effects of n-3 fatty acids are similar to those of n-6 fatty acids, provided that they replace saturated fats in the diet. N-3 fatty acids have the added benefit of consistently lowering serum triacylglycerol concentrations, whereas the n-6 fatty acids dont and may even increase them.30 The anti-thrombotic effects of fish oil are due to decrease in platelet aggregation, a decrease in TxA2, increase in PGI2 and PGI3 production, decrease in whole blood viscosity and an increase in bleeding time.31 Because of increased amount of n-6 fatty acids in the western diet, the eicosanoid metabolic products from AA, specially PGE, Tx, LT, are formed in larger quantity than those formed from n-3 fatty acids, specifically EPA. The eicosanoids formed from AA are biologically active in small quantities and if they are formed in large amounts, they contribute to the formation of thrombosis and atheromas, the development of allergic and inflammatory disorders, and cell proliferation. Thus a diet rich in n-6 fatty acids shifts the physiologic states to one that is prothrombotic and proaggregatory, with increasing in blood viscosity, vasospasm and vasoconstriction and decrease in bleeding time. The effects of different doses of fish oil on thrombosis and bleeding time were investigated by Saynor et al.32 A dose of 1.8gm EPA/Day did not result in any prolongation in bleeding time and decreased platelet count with no adverse effect.

Prevention of Restenosis
Restenosis is a condition caused mainly by platelet aggregation, proliferation of smooth muscle cells and coronary vasospasm. The effects on n-3 supplementation on the incidence of restenosis after coronary angioplasty has been addressed in several clinical studies. Results suggest that patients undergoing coronary bypass surgery should be encouraged to consume high amounts of n-3 fatty acids.33

Conclusion
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serum lipids, bleeding time, platelets and angina. Atherosclerosis 1984;50:310. 33. Eristland J Arnesen H, Gronseth K, Field NB, Abdelnoor M: Effects of dietary supplementation with n-3 fatty acids on coronary artery bypass graft patency. Am J Cardiol 1996;77:31-36. 34. Paola Benatti, Gianfranco P, Raffaella N. Polyunsaturated Fatty Acids: Biochemical,Nutritional and Epigenetic Properties. J Am Coll Nutr 2004;23(4):281-302. 35. Artemis P Simopoulos. Essential Fatty acids in health and chronic disease. Am J Clin Nutr 1999;70(suppl):560S-9S. About the Author Dr Raghuveer Choudhary is Associate Professor, Dr Jayant Kumar is Professor, Dr VK Chawla is Professor, Mrs Kamla is Tutor, Dr Manoj Bundella is Tutor, Deptt. of Physiology, at Dr. S.N. Medical College, Jodhpur, (Rajasthan) India http://www.mims.com/India/pub/topic/Medical%20Progress/2011-08/Dietary%20Balance%20of%20Omega6%20and%20Omega-3%20Fatty%20Acids%20and%20Coronary%20Heart%20Disease%20A%20Short%20Review