Source: Phytochemicals: Nutrient-Gene Interactions,
Mark S. Meskin (Editor),
CRC; 1 edition (February 22, 2006)
pp 137-159
Mark S. Meskin (Editor),
CRC; 1 edition (February 22, 2006)
pp 137-159
Evolutionary Aspects of Diet, the Omega-6/Omega-3 Ratio, and Gene Expression
Artemis P. Simopoulos
Artemis P. Simopoulos
CONTENTS
- Introduction
- Evolutionary Aspects of Diet with Emphasis on Omega-6 and Omega-3 Essential Fatty Acids
- Biological Effects and Metabolic Functions of Omega-6 and Omega-3 Fatty Acids
- Clinical Intervention Studies and the Omega-6/Omega-3 EFA Balance
- Omega-3 Fatty Acids and Gene Expression
- Diet–Gene Interactions: Genetic Variation and Omega-6 and Omega-3
- Fatty Acid Intake in the Risk for Cardiovascular Disease
- Conclusions
- References
The interaction of genetics and environment, nature and nurture, is the foundation for all health and disease. In the last two decades, using the techniques of molecular biology, it has been shown that genetic factors determine susceptibility to disease and environmental factors determine which genetically susceptible individuals will be affected.1–6 Nutrition is an environmental factor of major importance. Whereas major changes have taken place in our diet over the past 10,000 years since the beginning of the Agricultural Revolution, our genes have not changed. The spontaneous mutation rate for nuclear DNA is estimated at 0.5% per million years. Therefore, over the past 10,000 years there has been time for very little change in our genes, perhaps 0.005%. In fact, our genes today are very similar to the genes of our ancestors during the Paleolithic period 40,000 years ago, at which time our genetic profile was established.7 Genetically speaking, humans today live in a nutritional environment that differs from that for which our genetic constitution was selected. Studies on the evolutionary aspects of diet indicate that major changes have taken place in our diet, particularly in the type and amount of essential fatty acids and in the antioxidant content of foods 7–11 (Table 10.1; Figure 10.1). Using the tools of molecular biology and genetics, research is defining the mechanisms by which genes influence nutrient absorption, metabolism and excretion, taste perception, and degree of satiation — and the mechanisms by which nutrients influence gene expression.
EVOLUTIONARY ASPECTS OF DIET WITH EMPHASIS ON OMEGA-6 AND OMEGA-3 ESSENTIAL FATTY ACIDS
The foods that were commonly available to pre-agricultural humans (lean meat, fish, green leafy vegetables, fruits, nuts, berries, and honey) were the foods that shaped modern humans’ genetic nutritional requirements. Cereal grains as a staple food area relatively recent addition to the human diet and represent a dramatic departure from those foods to which we are genetically programmed and adapted.12–17 Cereals did not become a part of our food supply until very recently — 10,000 years ago — with the advent of the Agricultural Revolution. Prior to the Agricultural Revolution humans ate an enormous variety of wild plants, whereas today about 17% of plant species provide 90% of the world’s food supply, with the greatest percentage contributed by cereal grains.12 Three cereals: wheat, maize, and rice together account for 75% of the world’s grain production. Human beings have become entirely dependent upon cereal grains for the greater portion of their food supply. The nutritional implications of such a high grain consumption upon human health are enormous. Cereal grains are high in carbohydrates and omega-6 fatty acids, but low in omega-3 fatty acids and in antioxidants, particularly in comparison to green leafy vegetables. Recent studies show that low-fat, high-carbohydrate diets increase insulin resistance and hyperinsulinemia, conditions that increase the risk for coronary heart disease, hypertension, diabetes, and obesity.18–21 And yet, for the 99.9% of mankind’s presence on this planet, humans rarely or never consumed cereal grains. It is only since the last 10,000 years that humans have consumed cereals. Up to that time, humans were non-cereal-eating hunter-gatherers — since the emergence of Homoerectus 1.7 million years ago. There is no evolutionary precedent in our species for grass seed consumption.7,12 Therefore, we have had little time (<500 generations) — since the beginning of the Agricultural Revolution 10,000 years ago — to adapt to a food type that now represents humanity’s major source of both calories and protein. A number of anthropological, nutritional, and genetic studies indicate that humans’ overall diet, including energy intake and energy expenditure, has changed over the past 10,000 years with major changes occurring during the past 150 years in the type and amount of fat and vitamins C and E intake 7,9,13,22,23,26,27 (Table 10.1 and Table 10.2; Figure 10.1).
Eaton and Konner 7 have estimated higher intakes for protein, calcium, potassium, and ascorbic acid and lower sodium intakes for the diet of the late Paleolithic period than the current U.S. and Western diets. Most of our food is calorically concentrated in comparison with wild game and the uncultivated fruits and vegetables of the Paleolithic diet. Paleolithic man consumed fewer calories and drank water, whereas today most drinks to quench thirst contain calories. Today industrialized societies are characterized by (1) an increase in energy intake and decrease in energy expenditure; (2) an increase in saturated fat, omega-6 fatty acids, and trans fatty acids, and a decrease in omega-3 fatty acid intake; (3) a decrease in complex carbohydrates and fiber; (4) an increase in cereal grains and a decrease in fruits and vegetables; and (5) a decrease in protein, antioxidants, and calcium intake7,9,22,23,24,25,26 (Table 10.1–Table 10.3). The increase in trans fatty acids is detrimental to health as shown in Table 10.4.28 In addition, trans fatty acids interfere with the desaturation and elongation of both omega-6 and omega-3 fatty acids, further decreasing the amount of arachidonic acid, eicosapentaenoic acid, and docosahexaenoic acid availability for human metabolism.29
BIOLOGICAL EFFECTS AND METABOLIC FUNCTIONS OF OMEGA-6 AND OMEGA-3 FATTY ACIDS
Food technology and agribusiness provided the economic stimulus that dominated the changes in the food supply.30,31 From per capita quantities of foods available for consumption in the U.S. national food supply in 1985, the amount of eicosapentaenoic acid (EPA) is reported to be about 50 mg per capita/day and the amount of DHA is 80 mg per capita/day. The two main sources are fish and poultry. 32 It has been estimated that the present Western diet is "deficient" in omega-3 fatty acids with a ratio of omega-6 to omega-3 of 15–20/1, instead of 1/1, as is the case with wild animals and, presumably, human beings.7–11,23,33–35 Thus, an absolute and relative change of omega-6 and omega-3 in the food supply of Western societies has occurred over the last 100 years. A balance existed between omega-6 and omega-3 for millions of years during the long evolutionary history of the genus Homo, and genetic changes occurred partly in response to these dietary influences. During evolution, omega-3 fatty acids were found in all foods consumed: meat, wild plants, eggs, fish, nuts, and berries. Recent studies by Cordain et al.36 on wild animals confirm the original observations of Crawford and Sinclair et al.33,37 However, rapid dietary changes over short periods of time as have occurred over the past 100–150 years is a totally new phenomenon in human evolution 23,26,38–40 (Table 10.5).
Mammalian cells cannot convert omega-6 to omega-3 fatty acids because they lack the converting enzyme, omega-3 desaturase. Linoleic acid (LA) and alphalinolenic acid (ALA) and their long-chain derivatives are important components of animal and plant cell membranes. These two classes of essential fatty acids (EFA) are not interconvertible, are metabolically and functionally distinct, and often have important opposing physiological functions. The balance of EFA is important for good health and normal development. When humans ingest fish or fish oil, the EPA and docosahexaenoic acid (DHA) from the diet partially replace the omega-6 fatty acids, especially arachidonic acid (AA), in the membranes of probably all cells, but especially in the membranes of platelets, erythrocytes, neutrophils, monocytes, and liver cells. 8 Whereas cellular proteins are genetically determined, the polyunsaturated fatty acid (PUFA) composition of cell membranes is to a great extent dependent on the dietary intake. AA and EPA are the parent compounds for eicosanoid production (Table 10.6, Figure 10.2).
Because of the increased amounts of omega-6 fatty acids in the Western diet, the eicosanoid metabolic products from AA, specifically prostaglandins, thromboxanes,leukotrienes, hydroxy fatty acids, and lipoxins, are formed in larger quantities than those formed from omega-3 fatty acids, specifically EPA. The eicosanoids from AA are biologically active in very small quantities, and if they are formed in large amounts, they contribute to the formation of thrombus and atheromas; to allergic and inflammatory disorders, particularly in susceptible people; and to proliferation of cells. Thus, a diet rich in omega-6 fatty acids shifts the physiological state to one that is prothrombotic and proaggregatory, with increases in blood viscosity, vasospasm,and vasoconstriction and decreases in bleeding time. Bleeding time is decreased in groups of patients with hypercholesterolemia, 41 hyperlipoproteinemia, 42 myocardial infarction, other forms of atherosclerotic disease, and diabetes (obesity and hypertriglyceridemia). Bleeding time is longer in women than in men and longer in young than in old people. There are ethnic differences in bleeding time that appear to be related to diet. Table 10.7 shows that the higher the ratio of omega-6/omega-3 fatty acids in platelet phospholipids, the higher the death rate from cardiovascular disease. 43
The antithrombotic aspects and the effects of different doses of fish oil on the prolongation of bleeding time were investigated by Saynor et al. 44 A dose of 1.8 g/d EPA did not result in any prolongation in bleeding time, but at 4 g/d the bleeding time increased and the platelet count decreased without any adverse effects. In human studies there has never been a case of clinical bleeding, even in patients undergoing angioplasty while they were on fish oil supplements. 45 There is substantial agreement that ingestion of fish or fish oils has the following effects: platelet aggregation to epinephrine and collagen is inhibited, thromboxane A2 production is decreased, whole blood viscosity is reduced, and erythrocyte membrane fluidity is increased.46–49 Fish oil ingestion increases the concentration of plasminogen activator and decreases the concentration of plasminogen activator inhibitor 1 (PAI-1). 50 In vitro studies have demonstrated that PAI-1 is synthesized and secreted in hepatic cells in response to insulin, and population studies indicate a strong correlation between insulinemia and PAI-1 levels. In patients with types IIb and IV hyperlipoproteinemia and in another double-blind clinical trial involving 64 men aged 35 to 40 years, ingestion of omega-3 fatty acids decreased the fibrinogen concentration. 51 Two other studies did not show a decrease in fibrinogen, but in one, a small dose of cod liver oil was used, 52 and in the other the study consisted of normal volunteers and was of short duration. A recent study noted that fish and fish oil increase fibrinolytic activity, indicating that 200 g/day of lean fish or 2 g of omega-3 EPA and DHA improve certain hematologic parameters implicated in the etiology of cardiovascular disease. 53
Ingestion of omega-3 fatty acids not only increases the production of prostaglandin I3 (PGI3), but also of PGI2 in tissue fragments from the atrium, aorta, and saphenous vein obtained at surgery in patients who received fish oil two weeks prior to surgery. 54 Omega-3 fatty acids inhibit the production of platelet-derived growth factor (PDGF) in bovine endothelial cells. 55 PDGF is a chemoattractant for smooth muscle cells and a powerful mitogen. Thus, the reduction in its production by endothelial cells, monocytes/macrophages, and platelets could inhibit both the migration and proliferation of smooth muscle cells, monocytes/macrophages, and fibroblasts in the arterial wall. Insulin increases the growth of smooth muscle cells, leading to increased risk for the development of atherosclerosis. Omega-3 fatty acids increase endothelium-derived relaxing factor (EDRF).56 EDRF (nitric oxide) facilitates relaxation in large arteries and vessels. In the presence of EPA, endothelial cells in culture increase the release of relaxing factor, indicating a direct effect of omega-3 fatty acids on the cells.
Many experimental studies have provided evidence that incorporation of alternative fatty acids into tissues may modify inflammatory and immune reactions and that omega-3 fatty acids, in particular, are potent therapeutic agents for inflammatory diseases. Supplementing the diet with omega-3 fatty acids (3.2 g EPA and 2.2 g DHA) in normal subjects increased the EPA content in neutrophils and monocytes more than sevenfold without changing the quantities of AA and DHA. The antiinflammatory effects of fish oils are partly mediated by inhibiting the 5-lipoxygenase pathway in neutrophils and monocytes and inhibiting the leukotriene B4 (LTB4)- mediated function of LTB5 (Figure 10.2). 57,58 Studies show that omega-3 fatty acids influence interleukin metabolism by decreasing IL-1B and IL-6. 59–62 Inflammation plays an important role in both the initiation of atherosclerosis and the development of atherothrombotic events. 63 An early step in the atherosclerotic process is the adhesion of monocytes to endothelial cells. Adhesion is mediated by leukocyte and vascular cell adhesion molecules (CAMs) such as selectins, integrins, vascular cell adhesion molecule 1 (VCAM-1), and intercellular adhesion molecule 1 (ICAM-1).64 The expression of E-selectin, ICAM-1 and VCAM-1, which is relatively low in normal vascular cells, is upregulated in the presence of various stimuli, including cytokines and oxidants. This increased expression promotes the adhesion of monocytes to the vessel wall. The monocytes subsequently migrate across the endothelium into the vascular intima, where they accumulate to form the initial lesions of atherosclerosis. Atherosclerotic plaques have been shown to have increased CAM expression in animal models and human studies. 65–68 A balance between the omega-6 and omega-3 fatty acids is a more physiologic state in terms of gene expression, 69 eicosanoid metabolism, and cytokine production.
Further support for the need to balance the omega-6/omega-3 EFA comes from the studies of Ge et al.70 and Kang et al.71 The study by Ge et al. clearly shows the ability of both normal rat cardiomyocytes and human breast cancer cells in culture to form all the omega-3’s from omega-6 fatty acids when fed the cDNA encoding omega-3 fatty acid desaturase obtained from the roundworm C. elegans. The omega-3 desaturase efficiently and quickly converted the omega-6 fatty acids that were fed to the cardiomyocytes in culture to the corresponding omega-3 fatty acids. Thus, omega-6 LA was converted to omega-3 ALA, and AA was converted to EPA, so that at equilibrium, the ratio of omega-6 to omega-3 PUFA was close to 1/1.71 Further studies demonstrated that the cancer cells expressing the omega-3 desaturase underwent apoptotic death, whereas the control cancer cells with a high omega-6/omega-3 ratio continued to proliferate.70 More recently, Kang et al. showed that transgenic mice expressing the C. elegans fat-1 gene encoding an omega-3 fatty acid desaturase are capable of producing omega-3 from omega-6 fatty acids, leading to enrichment of omega-3 fatty acids with reduced levels of omega-6 fatty acids in almost all organs and tissues, including muscles and milk, with no need of dietary omega-3 fatty acid supply.72 This discovery provides a unique tool and new opportunities for omega-3 research and raises the potential of production of fat-1 transgenic livestock as a new and ideal source of omega-3 fatty acids to meet the human nutritional needs.
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