There has been a dramatic surge in interest recently, amongst the public and health professionals alike, of the health effects of omega-3 fatty acids derived from fish/fish oils - consisting of docosahexaenoic acid (DHA) plus eicosapentaenoic acid (EPA). DHA is required in high levels in the brain and retina as a physiologically-essential nutrient to provide for optimal neuronal functioning (learning ability, mental development) and visual acuity, in young and old alike. DHA plus EPA are both considered to have beneficial effects in the prevention and management of cardiovascular disease plus associated risk factors as well as other chronic disorders. Whereas considerable amounts of the plant-derived omega-3 fatty acid known as a-linolenic acid (ALA) is consumed daily in North America (approximately 2 g/day), the physiologically-essential nutrient, DHA, is consumed at much smaller levels (approximately 80 mg/day) while EPA is consumed at the level of approximately 50 mg/day in a typical North American diet.
DHA plus EPA are absent from plant food sources rich in ALA (such as flax, canola oil, and walnuts). Since the metabolic conversion of ALA to DHA/EPA (combined) by metabolism is very limited in humans, the most direct way of providing DHA plus EPA for the body is via their direct consumption. Current intakes of DHA are approximately 20% of the target (300 mg/day) suggested by an expert scientific group during pregnancy and lactation. The extremely low intake of DHA in young children (e.g., approximately 19 mg DHA/day on average for 3-yr. olds in North America ) is also of particular concern. Current intakes of DHA/EPA (combined) of 130 mg/day are approximately 15% of the target (900 mg/day) officially recommended by the American Heart Association for those with coronary heart disease and 20% of the 650 mg/day advised by an expert scientific group for healthy individuals. In view of the widespread reluctance of the public to consume sufficient amounts of fish, functional foods containing DHA plus EPA will become increasingly important sources of these important nutrients in the coming years to support optimal brain/visual performance, for cardio care, and other health conditions for young and old alike.
Omega-3 fatty acids (n-3 polyunsaturated fatty acids) are dietary nutrients offering human health plus disease preventing/managing potential. Certain plant sources (and derived vegetable oils) such as flaxseed, canola oil, walnuts, etc. contain significant amounts of the plant-based omega-3 fatty acid known as a-linolenic acid (ALA, 18:3n-3). In contrast, fish/fish oils are enriched to varying degrees with the omega-3 fatty acids known as eicosapentaenoic acid (EPA, 20:5n-3) plus docosahexaenoic acid (DHA, 22:6n-3). Flaxseed and other plant-derived oils are totally lacking in DHA/EPA combined whereas DHA/EPA are found in fish/fish oils which contain very minor amounts of ALA. A typical North American diet provides approximately 2-3 g/day of ALA from mixed plant /animal sources whereas EPA and DHA are consumed at levels of approximately 50 mg and 80 mg/day, respectively, for an overall combined DHA/EPA intake per person of approximately 130-150 mg/day. The vast majority of the dietary DHA/EPA is consumed from fish /fish oil sources.
DHA is the omega-3 fatty acid that is now widely recognized as the physiologically-essential nutrient in the brain for normal functioning of neural tissue (including cognitive performance, learning ability, memory, etc) and in the retina of the eye for visual acuity. Almost all the omega-3 fatty acid found in brain tissue, where it is required for structure-function relationships, is in the form of DHA with other omega-3 fatty acids such as ALA being found only in trace amounts regardless of dietary intakes of ALA. DHA addition to infant formula containing ALA was found to improve the mental development index. In 1990, Health Canada established ALA as an essential fatty acid in the diet (at 0.5% of total dietary energy) based on considerations from previous animal studies (for the most part) that ALA can be converted into the physiologically-essential DHA for brain and retinal functioning. However, human studies during the last few years have indicated a very limited conversion efficiency from dietary ALA to DHA such that attention has been given to consideration that dietary DHA is a potentially essential dietary nutrient for many in the population who lack sufficient conversion capacity from ALA to DHA. Using deuterated ALA in controlled human trials coupled with GLC-mass spec analysis of newly formed DHA in human trials, conversion efficiencies ranging from 0 to 8% on average have been reported. Furthermore, a recent study has shown that the consumption of several grams of ALA per day failed to increase the low levels of DHA in human breast milk. These studies on the very limited conversion of ALA to DHA coupled with the recognition of DHA as a physiologically-essential nutrient for neuronal functioning has lead to the release of a number of commercial products containing DHA including infant formulae, cow's milk, omega-3 shell eggs, plus a wide variety of fortified foods containing DHA as an additive. This trend is expected to continue so that the current low intakes of DHA (in North America and elsewhere across all sectors) can be enhanced so that the nutritional gap between current intakes and targets for optimal health can be closed. In this regard, it should be noted that the average adult in North America consumes approximately 80 mg of DHA per day; whereas, the Workshop on the Essentiality of Recommended Dietary Intakes (RDIs) for omega-6 and omega-3 fatty acids as held at the NIH in Bethesda (1999) recommended that pregnant and lactating women should ensure an intake of at least 300 mg/day of DHA.
Considerable research activity (both epidemiological plus interventional studies) has focused on the relationship between increased omega-3 fatty acid intakes and the risk of coronary heart disease (CHD) and mortality. Interest in ALA as a cardioprotective fatty acid has arisen in part from reports on the Mediterranean diet wherein higher intakes of ALA as part of such dietary patterns have been associated with the secondary prevention of coronary heart disease. It should be noted that ALA is but one of many potential cardioprotective components of the so-called Mediterranean diet. The proposed mechanism(s) by which an ALA-enriched diet might protect against fatal coronary heart disease is proposed to be mediated by the metabolic conversion of ALA to the long-chain omega-3 fatty acids in the form of EPA plus DHA. A recent study seeing flaxseed oil rich in ALA has confirmed a moderate rise in circulating plasma lipid levels of EPA plus DPA (but not DHA); the authors suggest that this rise, although moderate, in EPA plus DPA might possibly mediate any beneficial effects towards cardiovascular health derived by the consumption of flaxseed oil. It should be noted herein that the published literature using deuterated ALA suggests conversion efficiencies of dietary ALA to EPA plus DHA (combined) ranging from 5-15% overall. Controlled studies wherein high levels of ALA had been fed in the presence of moderate or low levels of linoleic acid (LA, 18:2n-6), including the use of low-n-6:n-3 ratios, have indicated a moderate rise in EPA as well as docosapentaenoic acid (DPA, 22:5n-3) in circulating blood serum phospholipid (biomarker for status) upon increasing ALA intakes without any significant elevation in the measured levels of DHA.
The relationship between dietary intakes of ALA in relation to the incidence of fatal heart disease has been evaluated in five prospective epidemiological studies. The relative risk of fatal heart disease showed an apparent protective with higher intakes of ALA. There appeared to be a beneficial effect of ALA intakes in three trials, no effect in one, and a detrimental effect in one study. Overall, the relative risk of fatal heart disease for a high vs. low intake of ALA showed an approximate 20% lower relative risk (RR) when adjusting for various confounding factors. The clinical/interventional trials to date with increasing ALA intakes in relation to fatal coronary heart disease tend to support the aforementioned perspective studies and, overall, suggest that increasing the intake of ALA by 1.2 g/day may decrease the risk of fatal coronary heart disease by approximately 20%. Recently, a review of 9 cohort and case-control studies (analyzed by meta-analysis) have suggested that dietary ALA is associated with an increased prostate cancer risk; the authors of this study have indicated this relationship to be of concern and meritorious of further studies. However, the authors do point out in their discussion that even if the latter relationship were real, the protective effect on fatal or coronary heart disease with increasing consumption of ALA would probably outweigh the possible negative effects, especially for men with an increased risk of heart disease. It is of interest to note that a recent prospective study on a cohort of 48,000 men with no cancer history in 1986 followed for 14 years indicated that increased dietary intakes of ALA may increase the risk of advanced prostate cancer while, in contrast, increased intakes of DHA and EPA may reduce the risk of total and advanced prostate cancer. It has been pointed out that any potential relationship of increased dietary intakes of ALA and advanced prostate cancer should attempt to identify the specific food sources of ALA contributing to any such relationships since factors other than ALA in such food sources may be contributing to such apparent relationships based on epidemiological (population) studies. Two recent studies (in the year 2005) have been published from the Harvard School of Public Health on the relationship between dietary ALA intake and the risk of sudden cardiac death and coronary heart disease in women as well as a separate study evaluating the potential beneficial effects of ALA consumption in men in relation to their background dietary intake of DHA plus EPA as derived from fish. The first study on 77,000 women participating in the nurses' health study over 18 years suggested that increased dietary intakes of ALA may reduce the risk of sudden cardiac death (by up to 40%) but not other types of fatal coronary heart disease or non fatal myocardial infarctions. The second study involved 46,000 men initially free of known cardiovascular disease who were followed up over 14 years. Interestingly, the reduced risk of sudden cardiac death with higher intakes of omega-3 fatty acids did not appear to be significantly influenced by the background intake of omega-6 fatty acids or by the omega-6:omega-3 ratio in the diet. The omega-3 fatty acids from both seafood (DHA plus EPA) and plant sources (as ALA) appeared to significantly reduce the risk of coronary heart disease however the protective effects of increased ALA consumption were only observed when the intake of DHA plus EPA from seafood was low. Specifically, no apparent benefit of increasing the consumption of dietary ALA was observed of ALA for lowering the risk of non fatal myocardial infarctions and total coronary heart disease as seen when the DHA plus EPA (combined) consumption surpassed 100 mg/day; when the background intake of DHA plus EPA was below 100 mg/day, an apparent beneficial effect of increasing the consumption of ALA was exhibited.
A number of review articles have appeared based on epidemiological studies from various countries indicating that higher intakes of fish/fish oils containing EPA plus DHA (combined) are associated with a reduced risk of cardiovascular disease and fatal coronary events. A very recently-published evaluation (via meta-analysis) on the basis of 11 eligible studies in 13 cohorts including 220,364 individuals with an average 11 years of follow-up indicated that fish consumption is inversely associated with fatal coronary heart disease and that mortality from coronary heart disease may be reduced by eating fish at least once per week or more (up to and including 5 servings/week). This latter meta-analysis is supportive of previous studies on omega-3 fatty acid intake as EPA plus DHA combined (where increasing intakes of DHA/EPA up to approximately 700 mg/day was associated with a reduction in cardiovascular disease-related mortality and all-caused mortality. The GISSI-Prevenzione study indicated that supplementation with DHA/EPA combined (to approximately 900 mg/day) in patients having experienced a heart attack (who were advised to consume a Mediterranean-type diet in addition to appropriate prescribed cardiovascular medications) exhibited an approximate reduction in follow-up sudden cardiac deaths as compared to placebo-treated controls. These findings have resulted in the American Heart Assocociation (in their dietary guidelines) advising at least 2 servings of fish (particularly fatty fish) per week to reduce the risk of CHD and much higher intakes of fatty fish (one serving per day) to provide for intakes of DHA/EPA combined of approximately 900 mg/day for those with coronary disease. These recommended intakes are many-fold current mean daily intakes in North American adults (at 130-150 mg/day). The aforementioned ISSFAL workshop ( Bethesda ) has recommended 650 mg of DHA/EPA combined per day (at least one third of which should be either EPA or DHA) for health and disease prevention in those without coronary heart disease.
Very recently, the group from the USDA Human Nutrition Research Centre on Aging at Tufts University has reported on relationships between dietary fatty acid (type) intake and age-related lens opacities associated with cataracts of the eye. In the female population study as part of the Nurses' Health Study cohort, higher dietary intakes of both LA (n-6) and ALA (n-3) were associated with an increased risk of age-related nuclear opacity whereas no such significant relationships were found with respect to the increased consumption of the long-chain omega-3 polyunsaturated fatty acids from fish in the form of DHA plus EPA. These authors emphasize that further study is needed to clarify the relationships between the type of fatty acid consumed and cataract risk.
Since blood levels (including serum phospholipid levels) of long-chain omega-3 fatty acids reflect the physiological status of the human body with respect to the n-3 polyunsaturates, correlations and comparative studies have been performed wherein blood levels of individual omega-3 fatty acids have been studied in relation to the risk of sudden death and fatal ischemic heart disease. In the former case, the strongest inverse relationship between blood levels of omega-3 fatty acids and those experiencing sudden death from cardiac causes was exhibited by DHA (P<0.005) followed by total long-chain omega-3 fatty acids (sum of DHA/EPA/DPA, P<0.01) and subsequently followed by EPA (P=0.06). However, the short-chain n-3 PUFA, namely ALA , showed no significant relationship in regard to the risk of sudden death from cardiac causes (P=0.28). In the Cardiovascular Health Study, a higher level of combined EPA plus DHA in plasma phospholipid was highly inversely correlated with the risk of fatal ischemic heart disease (odds ratio 0.30 with a P value of 0.01) whereas a significant but less inverse relationship was found in the case of ALA (odds ratio of 0.48 with a P value of 0.04).
The numerous interventional trials (controlled human trials) as published allow an overall perspective on the relative efficacy of ALA vs. DHA/EPA (combined) in favorably modifying various risk factors for cardiovascular disease (both conventional and non-conventional). The cardiovascular-protective effects of DHA/EPA have been attributed to their ability to favorably affect several risk factors for cardiovascular disease including anti-thrombotic, anti-arrhythmic, lipid-lowering (blood triglyceride-lowering), plus endothelial/vascular and other risk factors. Direct evaluation (gram vs. gram) for ALA vs. DHA/EPA (combined) is, in general, not possible for the most part since parallel studies using identical/comparative doses have not been conducted in controlled parallel/simultaneous studies by the same research group at the same time. Nonetheless, the published literature and reviews thereof indicate that, for the most part, ALA does not offer the same beneficial effects (or even portions thereof) for most of the cardiovascular risk parameters which have been evaluated and favorably influenced with DHA/EPA. It should also be noted that, in many of the controlled human trials, higher levels of ALA (omega-3) have been employed relative to DHA/EPA (combined). In general, the anti-thrombotic effects (including inhibition of blood platelet aggregation) have been very week or non-existent when ALA is compared to DHA/EPA. This overall perspective should not be surprising upon consideration that ALA likely requires conversion to DHA/EPA via desaturation/elongation reactions if it were to provide similar cardioprotective effects to that of pre-formed DHA/EPA. As mentioned previously, the conversion efficiency of ALA to DHA/EPA is very limited in humans. Controlled human studies using deuterated ALA coupled to GC-mass spec analysis have indicated conversion efficiencies of ALA to DHA/EPA (combined) ranging from 8-30%. Whereas DHA/EPA has a well-established blood triglyceride-lowering effect with a trend towards increasing HDL-cholesterol levels, ALA has no such effects. In some isolated animal studies, there is evidence that ALA may have similar anti-arrhythmic actions as compared to DHA/EPA.
Although most risk variables for cardiovascular disease/mortality which have been evaluated to date suggest that ALA is inactive or more weakly active than DHA/EPA, measures of vascular reactivity with omega-3 fatty acids in controlled human studies is one target area where ALA (example as flaxseed oil) in some studies appears to exhibit similar beneficial effects to that of DHA/EPA (from fish oils) based on improving arterial compliance. This might possibly reflect immediate postprandial benefits on blood properties/endothelial interactions within a few an hours after consuming a meal enriched with omega-3 fatty acids (where efficient conversion of ALA to DHA/EPA in subsequent accumulation of the latter two fatty acids in membrane phospholipid may not be essential in this particular regard).
In summary and conclusion, DHA is the physiologically-essential nutrient needed in the brain and retina for cognitive functioning and visual acuity, respectively. DHA supplementation of infant formula (containing ALA ) has been found to enhance cognitive performance in term infants. Conversion efficiencies of ALA to DHA in human trials have been determined to range from 0-9%. Higher dietary intakes of ALA (increasing intakes by 1,200 mg/day) have been associated with an approximate 20% lower risk of fatal heart disease whereas higher fish intakes (up to and including 5 servings/week providing approximately 650 mg DHA/EPA combined/day) have been associated with an approximate 40% lowering of CHD mortality based on epidemiological studies. In general, stronger inverse relations between blood levels of EPA plus DHA and fatal cardiac events have been found than for ALA. Most of the favorable effects of DHA/EPA ingestion on various risk factors for cardiovascular disease (via controlled interventional trials) including blood triglyceride-lowering are not found or matched by equivalent intakes of ALA. In contrast to ALA intakes, current dietary intakes of DHA/EPA in North America appear to be very much below target intakes for optimal human health and the prevention/management of cardiovascular disease and associated risk factors.
As for saturated and monounsaturated fatty acids, the omega-6 and omega-3 polyunsaturated fatty acids (PUFA) are chemically linked to fat structures known as triglycerides in the various foods and oils that are consumed. The natural triglyceride or fat structure consists of a 3-carbon glycerol backbone onto which 3 long-chain fatty acids of varying types and structures are linked or 'esterified'. These are hydrolyzed by enzymes and digested in the small intestine thereby providing for their absorption, transport in the blood, and assimilation into cells and body tissues. Table 1 lists some common food sources of both the omega-6 and omega-3 fatty acids as found in a typical North American diet.
Table 1: Dietary Sources of Omega-3 and Omega-3 Fatty Acids
Fatty Acid | Food Sources |
(i) Omega-6 Types | |
LA, linoleic acid (18:2 n-6) | Vegetable oils (corn, safflower, sunflower, soybean), animal meats |
AA, arachidonic acid (20:4 n-6) | Animal sources only (meat, eggs) |
(ii) Omega-3 Types | |
ALA , (LNA) alpha-linolenic acid (18:3 n-3) | Flaxseed, canola oil, English walnuts, specialty eggs |
EPA, eicosapentaenoic acid (20:5 n-3) | Fish, fish oils, marine sources |
DHA, docosahexaenoic acid (22:6 n-3) | Fish, fish oils, specialty egg/dairy products |
In view of the high intake of vegetable oils containing n-6 PUFA directly and via various processed food products including meats, a typical diet contains 8-15 g/day of LA (omega-6) but much lower intakes of the omega-3 types. ALA consumption ranges from approximately 1.3-2.0 g/day or approximately 0.6% of total energy intake. In contrast to the considerable intake of ALA from plant sources, the intake of fish/fish oil-derived DHA/EPA (combined) represents approximately 0.13-0.15 g/day (130-150 mg/day) which is 0.05% of total energy intake or about 1/10 of the intake of ALA. The vast majority of the DHA plus EPA as consumed in the North American diet is from fish/fish oils with much smaller amounts from selected animal sources (e.g., eggs, some meat sources) and none from plant food/oils regardless of their ALA levels. The overall ratio of omega-6:omega-3 fatty acids in the current North American diet ranges from 6:1 to approximately 10:1.
Selected food sources of a-linolenic acid (ALA) are given in Table 2. Some of the common plant oils have significant levels of ALA - e.g., 7% by weight in soybean oil, 10% in canola oil, and approximately 20% in hemp oil. Much higher amounts are found in the oils from flax, perilla (Japan and elsewhere), and chia (Argentina and elsewhere) with approximately 50-60% of the fatty acids being in the form of ALA.
Table 2: Alpha-Linolenic Acid Content of Various Foods and Oils
Source (100 g raw edible portion) | ALA (g) | Source (100 g raw edible portion) | ALA (g) |
Nuts and Seeds | Legumes | ||
Almonds | 0.4 | Beans, common (dry) | 0.6 |
Beechnuts (dried) | 1.7 | Chickpeas (dry) | 0.1 |
Butternuts (dried) | 8.7 | Cowpeas (dry) | 0.3 |
Chia seeds (dried) | 3.9 | Lentils (dry) | 0.1 |
Flaxseed | 22.8 | Lima beans (dry) | 0.2 |
Hickory nuts (dried) | 1.0 | Peas, garden (dry) | 0.2 |
Mixed nuts | 0.2 | Soybeans (dry) | 1.6 |
Peanuts | 0.003 | ||
Pecans | 0.7 | Grains | |
Soybean kernels | 1.5 | Barley, bran | 0.3 |
Walnuts, black | 3.3 | Corn, germ | 0.3 |
Walnuts, English and Persian | 6.8 | Oats, germ | 1.4 |
Rice, bran | 0.2 | ||
Vegetables | Wheat, bran | 0.2 | |
Beans, navy, sprouted (cooked) | 0.3 | Wheat, germ | 0.7 |
Beans, pinto, sprouted (cooked) | 0.3 | Wheat, hard red Winter | 0.1 |
Broccoli (raw) | 0.1 | ||
Cauliflower (raw) | 0.1 | Fruit | |
Kale (raw) | 0.2 | Avocados, California (raw) | 0.1 |
Leeks (freeze-dried) | 0.7 | Raspberries (raw) | 0.1 |
Lettuce, butterhead | 0.1 | Strawberries (raw) | 0.1 |
Lettuce, red leaf | 0.1 | ||
Mustard | 0.1 | ||
Purslane | 0.4 | ||
Radish seeds, sprouted (raw) | 0.7 | ||
Seaweed, Spirulina (dried) | 0.8 | ||
Soybeans, green (raw) | 3.2 | ||
Soybeans, mature seeds, sprouted (cooked) | 2.1 | ||
Spinach (raw) | 0.1 | ||
Data from Kris-Etherton et al. (2000)
Recently, strains of flaxseed oils have become available which contain approximately 70% by weight of the oil as ALA which is significantly higher than the 50-55% found in conventional flax oil varieties. Table 3 gives the levels of EPA plus DHA in a few selected fish and seafood.
Table 3: Fish and Seafood Sources of DHA plus EPA
Source (100 g portion) | DHA + EPA (g) |
Fish | |
Anchovy, European, raw | 1.449 |
Carp, cooked, dry heat | 0.451 |
Catfish, channel, farmed, cooked, dry heat | 0.177 |
Cod, Atlantic , cooked, dry heat | 0.158 |
Eel, mixed species, cooked, dry heat | 0.189 |
Flatfish (flounder and sole), cooked, dry heat | 0.501 |
Haddock, cooked, dry heat | 0.238 |
Halibut, Atlantic and Pacific, cooked, dry heat | 0.465 |
Herring, Atlantic , cooked, dry heat | 2.014 |
Mackerel, Pacific and jack, mixed species, cooked, dry heat | 1.848 |
Mullet, striped, cooked, dry heat | 0.328 |
Perch, mixed species, cooked, dry heat | 0.324 |
Pike, northern, cooked, dry heat | 0.137 |
Pollock, Atlantic , cooked, dry heat | 0.542 |
Salmon, Atlantic , farmed, cooked, dry heat | 2.147 |
Sardine, Atlantic , canned in oil, drained solids with bone | 0.982 |
Sea bass, mixed species, cooked, dry heat | 0.762 |
Shark, mixed species, raw | 0.843 |
Snapper, mixed species, cooked, dry heat | 0.321 |
Swordfish, cooked, dry heat | 0.819 |
Trout, mixed species, cooked, dry heat | 0.936 |
Tuna, skipjack, fresh, cooked, dry heat | 0.328 |
Whiting, mixed species, cooked, dry heat | 0.518 |
Crustaceans | |
Crab, Alaska king, cooked, moist heat | 0.413 |
Shrimp, mixed species, cooked, moist heat | 0.315 |
Spiny lobster, mixed species, cooked, moist heat | 0.480 |
Mollusks | |
Clam, mixed species, cooked, moist heat | 0.284 |
Conch, baked or broiled | 0.120 |
Mussel, blue, cooked, moist heat | 0.782 |
Octopus, common, cooked, moist heat | 0.314 |
Oyster, eastern, farmed, cooked, dry heat | 0.440 |
Scallop, mixed species, cooked, breaded and fried | 0.180 |
It should be noted that algal oils have recently become available as a source of DHA (free of EPA) for infant formulas and other functional food fortification. There has been a marked increase in the use of high quality liquid fish oils containing DHA plus EPA as ingredients in a wide variety of functional foods (e.g., liquid eggs). Furthermore, stable and microencapsulated forms of DHA plus EPA (with varying amounts and ratios of DHA:EPA) have been utilized in a whole plethora of processed food formulations (breads, yogurts, snack foods, etc). In view of the resistance of the North American and other populations to increase fish consumption as a source of DHA plus EPA for health despite recommendations by health care agencies and professionals, it is apparent that functional foods will became an ever-increasing source of these important nutrients in the omega-3 family.
Figure 1 gives an overview of the metabolic fate of the EFAs when consumed in the diet. The n-6 and n-3 PUFAs when consumed in the form of dietary triglyceride from various food sources undergoes digestion in the small intestine which allows for absorption, transport in the blood, and subsequent assimilation within tissues themselves through the body (including brain, retina, heart, and other tissues). As depicted in Figure 1, the EFAs can undergo cellular beta oxidation to provide cellular energy in the form of ATP as for the more common and prevalent saturated, monounsaturated fatty acids (MUFAs) and any trans fatty acids that might be present in the diet. EFAs can also undergo esterification into cellular lipids including triglyceride, cholesterol ester, and phospholipid. The essential fatty acids which are assimilated into triglyceride forms are often stored therein until required later for subsequent metabolism and functioning. As such, the EFAs will be released from the stored triglyceride forms by enzymatic/hydrolytic processes. EFAs can also be temporarily stored as esterified fatty acids to a cholesterol backbone (as cholesterol ester); the EFAs can subsequently be released from the cholesterol ester forms and utilized for subsequent metabolism as well. The EFAs which are assimilated into phospholipid are particularly important in the overall structure-function of both omega-6 and omega-3 fatty acids since these membrane forms (as phospholipids) maintain both the structural integrity and the critical functioning of cellular membranes throughout the body. Finally, and very importantly, the dietary EFAs present as linoleic acid (LA) and as alpha-linolenic acid (ALA) are activated to high-energy forms known as fatty-acyl CoA which provides for the conversion of these dietary PUFAs into their important longer-chain and more polyunsaturated products as derived by a series of desaturation plus elongation reactions which are particularly active in the liver and to a lesser extent in other tissues.
 |
Figure 1: Overview of EFA metabolism |
From the above discussions, it is apparent that some of the fatty acids which appear in the cells and tissues within the human body are derived directly from dietary sources and/or by way of endogenous synthesis within the body itself. The sources of the major physiologically-occurring fatty acids in the human body are outlined in Table 1
Table 1: Sources of major physiologically-occurring fatty acids (in human body)
Physiological Fatty Acid(s) | Dietary Source | Endogenous (in-body) synthesis |
A) Saturates | ||
16:0 | Yes | Yes (de-novo) |
18:0 | Yes | Yes (elongation from 16:0) |
B) Monounsaturates (MUFAs) | ||
cis - 18:1 n-9 | Yes | Yes (desaturation of 18:0) |
Trans - 18:1 | Yes | No |
C) Polyunsaturates (PUFAs) | ||
18:2n-6, LA | Yes | No |
18:3n-3, ALA | Yes | No |
20:4n-6, AA | Yes | Yes* |
20:5n-3, EPA | Yes | Yes ** |
22:6n-3, DHA | Yes | Yes ** |
*Requires metabolic precursor (LA) to be present
** Requires metabolic precursor ( ALA ) to be present (limited conversion from
ALA to EPA + DHA)
** Requires metabolic precursor ( ALA ) to be present (limited conversion from
ALA to EPA + DHA)
As seen in the Table 1, the saturated fatty acids (e.g., 18:0, a saturated fatty acid of 18 carbons in chain length with no double bonds) can be readily synthesized in the body from the two carbon unit known as acetate (acetyl-CoA in its active cellular form). In addition, saturated fatty acids are derived from dietary sources and can be metabolized by desaturation reactions (insertion of a double bond enzymatically) to convert it into a monounsaturated fatty acid (18:1 with one double bond in the molecule which is designated as an n-9 since the double bond is adjacent to the 9 th carbon counting from the methyl end). It is noteworthy in Table 1 that LA and ALA in the body can only be derived by dietary sources since the human body totally lacks the enzymatic capacity to synthesize these two EFAs. In contrast, plant cells do have the enzymatic machinery to synthesize LA and ALA such that many plants and derived vegetable oils are abundant sources of both LA and ALA. AA (20:4n-6) is found in small amounts in animal food sources (e.g., eggs and meats) and can also be formed by desaturation plus elongation reactions from its precursor, LA. The long-chain omega-3 fatty acids, DHA and EPA, can be formed to some degree in the human body, albeit to very limited extents as will be discussed later, and can be consumed preformed in the diet from sources rich in DHA/EPA such as fish/fish oils or functional foods which have been enriched or fortified with these important omega-3 fatty acids. Figure 2 shows the metabolic steps (desaturation plus elongation reactions) by which LA is metabolized to AA and by which ALA is metabolically converted to the long chain products including EPA and DHA, the physiologically-essential omega-3 fatty acid for brain and visual functioning.
 |
Figure 2: Desaturation, elongation, and retroconversion of omega-6 and omega-3 polyunsaturated fatty acids |
It is noted in the Figure 2 that elevations of DHA plus EPA in the human body (tissues and cells) can be readily provided for by the direct dietary consumption of DHA and EPA. Unlike LA which is present at considerable levels in most cellular lipids (particularly membrane phospholipids) throughout various tissues and cells, ALA does not usually accumulate to particularly high concentrations in cellular/tissue lipids/phospholipids even when ingested at relatively high dietary levels. This is partly due to the fact that much of the ALA which is consumed in the diet undergoes beta oxidation in the mitochondria and only a limited amount is available for the very limited conversion of ALA to EPA plus DHA. Figure 2 also indicates that dietary DHA has the potential to undergo some reverse metabolism (retroconversion) back to EPA as indicated by the dotted line in the figure.
Some commentary on the so-called omega-6:omega-3 ratio which is readily referred to in the popular press and in the marketing of various nutritional supplements needs to be briefly addressed herein. The omega-6:omega-3 concept originates primarily in the early rodent experiments where high levels of LA (omega-6) in the diet were found to partially suppress the conversion efficiency of dietary ALA to EPA plus DHA in the body. As indicated in the previous figure, LA and ALA are metabolized to their corresponding products via common enzyme systems (including initial delta-6 desaturation). Early animal studies that used excessively high levels of dietary LA (n-6) relative to ALA (n-3), giving rise to very high omega-6:omega-3 ratios, resulted in a smaller rise in DHA/EPA levels in tissues due to the competitive inhibitory effect of LA and ALA at the level of the initial desaturation reaction. Thus, lower ratios of omega-6:omega-3 were found to provide for a somewhat better conversion efficiency of ALA to DHA/EPA as compared to higher omega-6:omega-3 ratios even when the amount of ALA was fixed at the same amount. These animal experiments have influenced subsequent dietary recommendations, such as those from Health and Welfare Canada in 1990 where they recommended that attempts should be made to reduce the omega-6:omega-3 ratio in the Canadian diet to approximately 10:1 down to 4:1. Subsequent human studies have indicated that lowering the LA(n-6):ALA(n-3) from higher levels (e.g., 27:1 down to 3:1) does allow for a somewhat moderately enhanced conversion of dietary ALA to EPA as revealed by moderately higher levels of EPA in blood samples taken from subjects given varying n-6:n-3 ratios and amounts of ALA. Thus, higher intakes of ALA and much lower ratios of LA: ALA is one strategy for moderately enhancing the conversion of ALA to EPA via the desaturation/elongation reactions presented in Figure 2. However, it is most interesting to note that numerous human studies which have lowered the n-6:n-3 ratio (as LA: ALA ) have not shown a significant rise in DHA with the lower ratios or even with higher intakes of ALA despite the moderate rise in EPA as mentioned previously. Furthermore, it is becoming apparent that the direct consumption of pre-formed DHA and EPA provides for a highly efficient elevation of these important long-chain omega-3 fatty acids in cells and tissues such that dependency on lower LA:ALA ratios becomes questionable since enrichment of the body in DHA plus EPA is then not dependent on the desaturation/elongation reactions for such enrichments. In conclusion, the omega-6:omega-3 concept, based on animal studies focusing upon LA: ALA ratios alone, needs to be reconsidered in the context of dietary/health situations where DHA plus EPA are consumed directly in their preformed state.
The omega-6 product formed from the desaturation plus elongation of LA is arachidonic acid (AA, 20:4n-6) which accumulates to very high concentrations in a wide variety of human tissues and cells. While small levels of AA in the body do have some important functions, such as in reproduction and other processes, excessively high levels of AA are considered to be potentially problematic in the development and/or progression of some chronic health conditions.
As is depicted in Figure 3, AA can be metabolized by various oxygenase enzymes (including cyclo-oxygenase and lipoxygenase systems) to form a family of varying products known as eicosanoids, prostaglandins, leukotrines and thromboxanes.
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Figure 3: Oxygenase-derived metabolites (eicosanoids) from AA (n-6) |
AA can be converted into neutrophils (white blood cells) to form leukotriene-B 4 (LTB 4 ) which is considered to be a pro-inflammatory eicosanoid associated with chronic conditions such as rheumatoid arthritis, psoriasis of the skin, and inflammatory gastrointestinal disorders. In certain cells and tissues, AA is converted into the prostaglandin form known as prostaglandin-E 2 (PGE 2) which has been associated with enhanced cell proliferation, mitogenesis, and possibly cancer promotion. In circulating blood platelets, AA is converted to thromboxine-A 2 (TXA 2) which is known as a pro-thrombotic and vaso-constrictory eicosanoid which is though to play an important role in thrombus formation and associated with fatal or non-fatal myocardial infarctions (heart attacks). High intakes of EPA plus DHA in the diet, such as from fish/fish oils, allow for the partial replacement (reduction) of AA in the aforementioned cellular systems thereby reducing the amount of AA available to form the metabolites that have been associated with various chronic disorders as mentioned. Furthermore EPA plus DHA, when present as replacement PUFAs for AA in cell membranes, can also inhibit the conversion efficiency of AA to LTB 4, PGE 2, and TXA 2, respectively. Finally, the enzyme-generated (via oxygenase activity) products of EPA plus DHA do not appear to have the potentially harmful effects in contrast to those products formed from AA via the same enzymatic pathways.
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