Studies conducted on Greenland Eskimos, which consume large amount of fish or marine mammals rich in omega-3 fatty acids and have a low incidence of cardiovascular disease or CVD, have suggested a protective effects of such fatty acids against these disease. Results of other epidemiological studies, randomized trials and animal investigations, have also suggested that omega-3 fats, and in particular long-chain omega-3 fatty acids, eicosapentaenoic aci or EPA and docosahexaenoic acid or DHA have cardiovascular effects. These studies indicate that they have anti-inflammatory, antiatherogenic, and antiarrhythmic effects, which are considered plausible mechanisms for reducing the risk of cardiovascular disease.
Omega-3 fatty acid supplements and secondary prevention of CVD
In a study published on Archives of Internal Medicine a research team, using a meta-analysis of randomized, double-blind, placebo-controlled trials, has evaluated the preventive effect of omega-3 fatty acid supplements (omega-3 fatty acid supplements for at least 1 year, with a daily dose of EPA or DHA ranged from 0.4 to 4.8 g/d, and a follow-up period ranged from 1.0 to 4.7 years) in the secondary prevention of cardiovascular disease, i.e. among patients with a history of cardiovascular disease (not in healthy individuals).
The study involved 20485 patients, male or female aged ≥18 years, 10259 randomized to a placebo group and 10226 randomized to an intervention group. Placebo groups received vegetable oils (sunflower oil, olive oil, and corn oil), mixed fatty oil, and other “inert” or ill-defined substances (aluminum hydroxide and unspecified placebo).
The meta-analysis showed insufficient evidence of a secondary preventive effect of omega-3 fatty acid supplements against overall cardiovascular events, which include peripheral vascular disease, angina and unstable angina, transient ischemic attack and stroke, fatal and nonfatal myocardial infarction, sudden cardiac death, cardiovascular death, congestive heart failure, and nonscheduled cardiovascular interventions (i.e., coronary artery bypass surgery or angioplasty).
Moreover, no significant preventive effect was observed in subgroup analyses by the following: history of cardiovascular disease, concomitant medication use (lipid lowering agents, no lipid-lowering agents, or antiplatelet agents only), country location (Western Europe, Northern Europe, United States, or Asia), inland or coastal geographic area, methodological quality of the trial, duration of treatment, type of placebo material in the trial (oil vs nonoil), dosage of EPA or DHA, or use of fish oil supplementation only as treatment.
The study showed insufficient evidence of a secondary preventive effect of omega-3 fatty acid supplements against overall cardiovascular events among patients with a history of cardiovascular disease.
Kwak S.M., Myung S-K., Lee Y.J., Seo H.G., for the Korean Meta-analysis Study Group. Efficacy of omega-3 fatty acid supplements (eicosapentaenoic acid and docosahexaenoic acid) in the secondary prevention of cardiovascular disease. A meta-analysis of randomized, double-blind, placebo-controlled trials. Arch Intern Med 2012;172(9):686-694. doi:10.1001/archinternmed.2012.262
Omega-3 polyunsaturated fatty acids and α-linolenic acid
Like linoleic acid (omega-6 fatty acid), alpha-linolenic acid or ALA is a primary product of plant polyunsaturated fatty acid or PUFA synthesis and is the precursor of all the omega-3 polyunsaturated fatty acids.
It is produced de novo from linoleic acidonly by plants (by the chloroplasts of marine phytoplankton and land plants) in a reaction catalyzed by Δ15-desaturase, i.e. the enzyme that forms the omega-3 polyunsaturated fatty acid family from omega-6 one catalyzing the insertion of the double bond between carbon atoms 3 and 4, numbered from methyl end of the molecule.
Note: while many land plants lack the ability to synthesize omega-3 polyunsaturated fatty acids, aquatic ones and planktons in colder water produce abundant amounts of them.
Animals, lacking Δ15-desaturase, can’t synthesize alpha-linolenic acid, and all the omega-3 polyunsaturated fatty acid family de novo, and they are obliged to obtain it from plant foodstuff and/or from animals that eat them; for this reason omega-3 polyunsaturated fatty acids are considered essential fatty acids, so called EFA.
Omega-3 polyunsaturated fatty acids: from α-linolenic acid to EPA and DHA
Animals are able to elongate and desaturase dietary alpha-linolenic acid in a cascade of reactions to form very long polyunsaturated omega-3 fatty acids but terrestrial animals have limited ability to do it. The efficiency of synthesis decreases down the cascade: conversion of alpha-linolenic acid to EPA is limited (the activity of Δ6-desaturase is the rate limiting in humans) and to DHA is even more restricted than that of EPA. This metabolic pathway occurs mainly in the liver and cerebral microvasculature of the blood brain barrier, but also in the cerebral endothelium and astrocytes.
Fish and shellfish, unlike terrestrial animals, are able to convert efficiently alpha-linolenic acid, obtained from chloroplast of marine phytoplankton, in EPA and DHA (the last one is present in high concentration in many fish oils but pay attention: many fish oils are also rich in saturated fatty acids).
It should be noted that polyunsaturated fatty acids of the ω-3 family, and of any other n-families, can be interconverted by enzymatic processed only within the same family, not among families.
EPA and DHA are primarily found in marine algae (in genetically engineered algae DHA represents approximately 50% of the total fatty acids), fish, shellfish, and marine products (particularly oil from cold-water marine fish).
Some functions of omega-3 polyunsaturated fatty acids
Omega-3 polyunsaturated fatty acid are capable of increasing high-density lipoprotein (HDL), “good cholesterol”, and of interleukin-2 levels. On the other hand, they decrease the levels of low-density lipoprotein (LDL), “bad cholesterol“, and very low density lipoprotein cholesterol (VLDL) and of interleukin-1 levels.
They are essential for the normal functioning of the brain and retina, especially in premature borns.
They are essential for growth and development throughout the life; for example if in children diet there is not enough omega-3 polyunsaturated fatty acids they may suffer dermatitis, growth retardation, neurological and visual disturbances.
C-20 polyunsaturated fatty acids, belonging to omega-3 and also omega-6 polyunsaturated fatty acid families, are the precursors eicosanoids (prostaglandins, prostacyclin, thromboxanes, and leukotrienes), potent, short-acting, local hormones.
While the omission in the diet of omega-6 polyunsaturated fatty acids results in a manifest systemic dysfunction, the deprivation of omega-3 polyunsaturated fatty acids causes dysfunction in a wide range of behavioral and physiological modalities.
Akoh C.C. and Min D.B. “Food lipids: chemistry, nutrition, and biotechnology” 3th ed. 2008
Aron H. Uber den Nahvert (On the nutritional value). Biochem Z. 1918;92:211–233 (German)
Bender D.A. “Benders’ dictionary of nutrition and food technology”. 2006, 8th Edition. Woodhead Publishing. Oxford
Bergstroem S., Danielsson H., Klenberg D. and Samuelsson B. The enzymatic conversion of essential fatty acids into prostaglandins. J Biol Chem 1964;239:PC4006-PC4008 [Full Text]
Burr G. and Burr M. A new deficiency disease produced by the rigid exclusion of fat from the diet. J Biol Chem 1929;82:345-67 [Full Text]
Chow Ching K. “Fatty acids in foods and their health implication” 3th ed. 2008
Cozzani I. e Dainese E. “Biochimica degli alimenti e della nutrizione”. Piccin Editore, 2006
Essential fatty acids or EFA are fatty acids which cannot be synthesized de novo by animals, but by plants and microorganisms, such as bacteria, fungi and molds, and whose deficiency can be reversed by dietary addition.
There are two essential fatty acids: linoleic acid or LA (18:2n-6) and α-linolenic acid or ALA (18:3n-3), polyunsaturated fatty acids (PUFAs) with 18 carbon atoms, belonging to omega-6 and omega-3 families, respectively.
Animals cannot synthesize these two fatty acids because they lack desaturases that introduce double bonds beyond the Δ9 position (carbon atoms numbered from the methyl end), namely:
Δ12-desaturase (E.C. 126.96.36.199), which catalyzes the synthesis of LA from oleic acid;
Δ15-desaturase (EC 188.8.131.52), present also in phytoplankton, which catalyzes the synthesis of ALA from linoleic acid.
Instead, animals have the enzymes needed to elongate and desaturate, though with low efficiency, the two EFA to form PUFAs with 20, 22, or 24 carbon atoms and up to 6 double bonds, such as for example dihomo-gamma-linolenic acid or DGLA (20:3n6), arachidonic acid or AA (20:4n6), eicosapentaenoic acid (EPA, 20:5n3), and docosahexaenoic acid or DHA (22:6n3).
If diet is deficient in EFA, also fatty acids synthesized from them become essential. For this reason they may be termed conditionally essential fatty acids.
It should be noted that all essential fatty acids are polyunsaturated molecules but not all polyunsaturated fatty acids are essential, such as those belonging to the omega-7 and omega-9 families.
Functions of essential fatty acids and their PUFA derivatives
The first evidence of their existence dates back to 1918, when Hans Aron suggested that dietary fat could be essential for the healthy growth of animals and that, besides its caloric contribution, there was a inherent nutritive value deriving from the presence of certain lipid molecules
In 1927, Herbert M. Evans and George Oswald Burr demonstrated that, despite the addition of vitamins A, D, and E to the diet, a deficiency of fat severely affected both growth and reproduction of experimental animals. Therefore, they suggested the presence in the fat of an essential substance they called vitamin F.
Eleven years after Aron work, in 1929, George Burr and his wife Mildred developed the hypothesis that warm-blooded animals were not able to synthesize appreciable amounts of certain fatty acids. One year later, they discovered that linoleic acid was essential for animals, and it was they who coined the term essential fatty acid.
However, EFA deficiency in humans was first described only in 1958, in infants fed a milk-based formula lacking them.
And in 1964, thanks to the research by Van Dorp et al. and Bergstroem et al., one of their biological functions, that is, being precursor for the synthesis of prostaglandins, was discovered.
Now, it is clear that EFA and derived PUFAs play many important roles, some of which are listed below.
They are fundamental components of biological membranes, modulating, for example, their fluidity, particularly DHA.
They are essential for the proper development and functioning of the nervous system, particularly AA and DHA.
They are involved in the regulation of genes encoding lipolytic and lipogenic enzymes. In fact they are strong inducers of fatty acid oxidation, as well as inhibitors of their synthesis and that of triglycerides, at least in animal models, by acting, for example, as:
activators of the peroxisome proliferator-activated receptor α or PPAR-α, which stimulates, among other things, the transcription of genes encoding lipolytic enzymes as well as mitochondrial and peroxisomal β-oxidation enzymes, and inhibits the transcription of genes encoding for enzymes involved in lipogenesis;
inhibitors of sterol responsive element binding protein-1c (SREBP-1c) gene transcription, a hepatic transcription factor required for liver fatty acid and triglyceride synthesis induced by insulin.
Note: PUFA also increase SREBP 1c mRNA degradation as well as SREBP-1 protein degradation.
They are precursors of signaling molecules, with autocrine and paracrine action, which act as mediators in many cellular processes. Eicosanoids, a group of oxygenated, 20 carbon fatty acids, are probably the most studied. They derive from linoleic acid, dihomo-gamma-linolenic acid, arachidonic acid, and EPA, and include prostaglandins, thromboxanes, leukotrienes, lipoxins, and epoxyeicosatrienoic acids.
They are essential, especially LA present in sphingolipids of the stratum corneum of the skin, for the formation of the barrier against water loss from the skin itself.
They have a crucial role in the prevention of many diseases, particularly coronary heart disease or CHD, acting as antihypertensive, antithrombotic, and triglyceride–lowering agents (increasing in the latter case mitochondrial β-oxidation).
Linoleic acid is present in fair amount also in animal products such as chicken eggs or lard, but only because it is present in their feed.
It should be noted that some of the major sources of LA such as walnuts, flax seed oil, soybean oil, and canola oil are also rich sources of α-linolenic acid (see below).
In seed oils, omega-6 fatty acids with a chain length longer than 18 carbon atoms, such as DGLA and arachidonic acid, are present only in traces. Instead, AA is found in all animal tissues and animal-based foods.
α-Linolenic acid is produced by plants, also cold water vegetation such as algae and phytoplankton.
In the human diet, some of the richest sources are:
flax seed oil, ~ 550 mg/g
rapeseed oil, ~ 85 mg/g
soybean oil, ~ 75 mg/g
Other foods rich in ALA are nuts, ~ 70 mg/g, and soybeans, ~ 10 mg/g.
EPA and DHA are mainly found in marine algae, and in engineered algae DHA can represent about 50% of the total fatty acids. In the human diet, EPA and DHA derive from fish, shellfish and fish oil, particularly that derived from cold-water fatty fish.
The high consumption of animal products derived from animals, such as chickens, cattle and pigs, raised on corn-based feed. In addition to this, omega-3 fatty acid content, of some species of farmed fish is lower than their wild counterparts, again because of the feed used.
Many evidences, like lower rates of incidence of cancer, autoimmunity and coronary heart disease in populations whose diet has a high ratio of omega-3 to omega-6fatty acids, such as Eskimos, Japanese and others who consume a large amount of seafood, suggest that the change of this ratio has affected human physiology adversely, promoting, together with other factors such as smoking and a sedentary lifestyle, the development of the main classes of diseases.
Note: Japanese are the only people with an omega-3/omega-6 ratio of 1/2-4.
Recommended dietary intake of essential fatty acids
Hereinafter, the recommended dietary intake for omega-3 and omega-6fatty acids for healthy adults, according to the recommendation of some of the major scientific societies and international organizations, and, as you will see, there is no common position.
Omega-3 fatty acids WHO recommends a dietary intake of omega-3-fatty acids between 0.5 and 2% of energy/day, with 300-500 mg of EPA/DHA per day, and 0.8-1.1 g per day of α-linolenic acid.
Academy of Nutrition and Dietetics recommends a dietary intake of 500 mg of EPA/DHA per day.
European Food Safety recommends a dietary intake of 250 mg of EPA/DHA per day.
American Heart Association and American Diabetes Association recommend to eat fish at least twice a week, particularly fatty fish.
American Heart Association recommends to include oils and foods rich in α-linolenic acid.
Omega-6 fatty acids In the past, dietary recommendations for omega-6 fatty acid intakes, and so especially linoleic acid, were focused on the prevention of their deficiency, while currently they are focused on the determination of the optimal intake to reduce the risk of chronic diseases, with special attention to CHD.
Currently, most scientific societies recommend a daily intake of linoleic acid between 5 and 10% of energy/day. This daily intake seems able to reduce the risk of CHD and coronary heart disease deaths compared to lower intakes.