The synthesis of omega-6 polyunsaturated fatty acids
Omega-6 polyunsaturated fatty acids are the major polyunsaturated fatty acids (PUFA) in the Western diet (about 90% of all of them in the diet), being components of most animal and vegetable fats.
Omega-6 polyunsaturated fatty acids and linoleic acid
Within the omega-6 (ω-6) family, linoleic acid is one of the most important and widespread fatty acids and the precursor of all omega-6 polyunsaturated fatty acids. It is produced de novo from oleic acid (an omega-9 fatty acid) only by plant in a reaction catalyzed by Δ12-desaturase, i.e. the enzyme that forms the omega-6 polyunsaturated fatty acid family from omega-9 one.
Δ12-desaturase catalyzes the insertion of the double bond between carbon atoms 6 and 7, numbered from the methyl end of the molecule. Linoleic acid, together with alpha-linolenic acid, is a primary product of plant polyunsaturated fatty acids synthesis.
Animals, lacking Δ12-desaturase, can’t synthesize it, and all the omega-6 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-6 polyunsaturated fatty acid are considered essential fatty acids, so called EFA (the essentiality of omega-6 polyunsaturated fatty acids, in particular just the essentiality of linoleic acid, was first reported in 1929 by Burr and Burr).
Omega-6 polyunsaturated fatty acids: from linoleic acid to arachidonic acid
Animals are able to elongate and desaturase dietary linoleic acid in a cascade of reactions to form very omega-6 polyunsaturated fatty acids. Linoleic acid is first desaturated to gamma-linolenic acid, another important ω-6 fatty acid with significant physiologic effects, in the reaction catalyzed by Δ6-desaturase. It is thought that the rate of this reaction is limiting in certain conditions like in the elderly, under certain disease states and in premature infants; for this reason, and because it is found in relatively small amounts in the diet, few oils containing it (black currant, evening primrose, and borage oils) have attracted attention.
In turn gamma-linolenic acid may be elongated to dihomo-gamma-linolenic acid by an elongase (it catalyzes the addition of two carbon atoms from glucose metabolism to lengthen the fatty acid chain) that may be further desaturated in a very limited amount to arachidonic acid, in a reaction catalyzed by another rate limiting enzyme, Δ5-desaturase. Arachidonic acid can be elongated and desaturated to adrenic acid.
It should be noted that polyunsaturated fatty acids in the omega-6 family, and in any other n-families, can be interconverted by enzymatic processes only within the same family, not among families.
C-20 polyunsaturated fatty acids belonging to omega-6 and omega-3 families are the precursors of eicosanoids (prostaglandins, prostacyclin, thromboxanes, and leukotrienes), powerful, short-acting, local hormones.
While the deprivation of omega-3polyunsaturated fatty acids causes dysfunction in a wide range of behavioral and physiological modalities, the omission in the diet of omega-6 polyunsaturated fatty acids results in manifest systemic dysfunction.
In plant seed oils omega-6 fatty acids with chain length longer than 18 carbons are present only in trace while arachidonic acid is found in all animal tissues and animal-based food products.
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.