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Understanding Omega-3 Polyunsaturated

Fatty Acids

Philip C. Calder, PhD, DPhil 1 Abstract: Current intakes of very long-chain omega-3 fatty acids, eicosapentaenoic acid (EPA)
Parveen Yaqoob, MA, DPhil 2 and docosahexaenoic acid (DHA), are low in most individuals living in Western countries. A
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1 good natural source of these fatty acids is seafood, especially oily fish. Fish oil capsules contain
Institute of Human Nutrition,
School of Medicine, University these fatty acids also. Very long-chain omega-3 fatty acids are readily incorporated from
of Southampton, Southampton capsules into transport (blood lipids), functional (cell and tissue), and storage (adipose) pools.
General Hospital, Southampton,
UK; 2Hugh Sinclair Unit of Human
This incorporation is dose-dependent and follows a kinetic pattern that is characteristic for each
Nutrition, School of Chemistry, pool. At sufficient levels of incorporation, EPA and DHA influence the physical nature of cell
Food Biosciences and Pharmacy, membranes and membrane protein-mediated responses, lipid-mediator generation, cell signaling,
The University of Reading,
Whiteknights, Reading, UK and gene expression in many different cell types. Through these mechanisms, EPA and DHA
influence cell and tissue physiology and the way cells and tissues respond to external signals.
In most cases the effects seen are compatible with improvements in disease biomarker profiles or
health-related outcomes. As a result, very long-chain omega-3 fatty acids play a role in achieving
For personal use only.

optimal health and in protection against disease. Long-chain omega-3 fatty acids not only protect
against cardiovascular morbidity but also against mortality. In some conditions, for example
rheumatoid arthritis, they may be beneficial as therapeutic agents. On the basis of the recognized
health improvements brought about by long-chain omega-3 fatty acids, recommendations have
been made to increase their intake. The plant omega-3 fatty acid, alpha-linolenic acid (ALA), can
be converted to EPA, but conversion to DHA appears to be poor in humans. Effects of ALA on
human health-related outcomes appear to be due to conversion to EPA, and since this is limited,
moderately increased consumption of ALA may be of little benefit in improving health outcomes
compared with increased intake of preformed EPA + DHA.
Keywords: omega-3 fatty acids; fish oil; phospholipid; cell function; docosahexaenoic acid;
docosapentaenoic acid; eicosapentaenoic acid; polyunsaturated fatty acid; cardiovascular
disease

Structure, Naming, and Metabolic Relationships

of Omega-3 Fatty Acids
Fatty acids are hydrocarbon chains with a carboxyl group at one end and a methyl group
at the other. The carboxyl group is reactive and readily forms ester links with alcohol
groups, for example those on glycerol or cholesterol, in turn forming acylglycerols
Correspondence: Philip C. Calder, (eg, triacylglycerols, phospholipids) and cholesteryl esters. Fatty acids containing
PhD, DPhil,
Institute of Human Nutrition,
double bonds in the hydrocarbon chain are referred to as unsaturated fatty acids;
School of Medicine, a fatty acid containing ⱖ 2 double bonds is called a polyunsaturated fatty acid (PUFA).
University of Southampton, Fatty acids have common names and systematic names. They are also referred to by
Southampton General Hospital,
Southampton, UK. a shorthand nomenclature that denotes the number of carbon atoms in the chain, the
Tel: +44 2380 795250 number of double bonds, and the position of the first double bond relative to the methyl
Fax: +44 2380 795255
E-mail: [email protected] (ω; sometimes called n) carbon. Omega-3 fatty acids are so called because the first
double bond is on carbon number 3, counting the methyl carbon as carbon number 1.

148 © Postgraduate Medicine, Volume 121, Issue 6, November 2009, ISSN – 0032-5481, e-ISSN – 1941-9260
71508e
 Omega-3 Fatty Acids

The simplest omega-3 fatty acid is alpha-linolenic acid (ALA) desaturation occurs at carbon atoms below carbon number 9
(18:3ω-3). Αlpha-linolenic acid is synthesized from linoleic (counting from the carboxyl carbon) and mainly occurs in the
acid (18:2ω-6) by desaturation, catalyzed by delta-15 liver. Αlpha-linolenic acid can be converted to stearidonic
desaturase (confusingly, the desaturase enzymes are named acid (18:4ω-3) by delta-6 desaturase and then stearidonic
according the first carbon carrying the newly inserted acid can be elongated to 20:4ω-3 (Figure 1). This fatty acid
double bond, counting the carboxyl carbon as carbon can be further desaturated by delta-5 desaturase to yield
number 1). Animals, including humans, do not possess the eicosapentaenoic acid (EPA) (20:5ω-3) (Figure 1). A path-
delta-15 desaturase enzyme and thus cannot synthesize way for further conversion of EPA to docosahexaenoic
ALA. Plants possess delta-15 desaturase and so are able to acid (DHA) (22:6ω-3) exists; this pathway involves
synthesize ALA. Although animals cannot synthesize ALA, addition of 2 carbons to form docosapentaenoic acid (DPA)
they can metabolize it by further desaturation and elongation; (22:5ω-3), addition of 2 further carbons to produce 24:5ω-3,

Figure 1. Pathway of alpha-linolic acid conversion to longer chain, more unsaturated omega-3 fatty acids.
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H3C COOH

-Linolenic acid (18:3-3)

6-desaturase

H 3C
COOH
For personal use only.

Stearidonic acid (18:4-3)

Elongase

H 3C
COOH
20:4-3

5-desaturase

H3C COOH

Eicosapentaenoic acid (20:5-3)

Elongase
Elongase
6-desaturase
-oxidation

H3C
COOH
Docosahexaenoic acid (22:6-3)

© Postgraduate Medicine, Volume 121, Issue 6, November 2009, ISSN – 0032-5481, e-ISSN – 1941-9260 149
 Philip C. Calder and Parveen Yaqoob

desaturation to form 24:6ω-3, and translocation of 24:6 from of very long-chain omega-3 fatty acids among adults in the
the endoplasmic reticulum to peroxisomes, where 2 carbons United Kingdom, other Northern and Eastern European
are removed by limited β-oxidation to yield DHA.1 Short- countries, North American, and Australasian countries are
term studies with isotopically labelled ALA and long-term approximately 0.15 to 0.25 g/day.4 However, the distribu-
studies using significantly increased intakes of ALA have tion of intakes is bimodal due to the presence of oily fish
demonstrated that the conversion to EPA, DPA, and DHA consumers and non-consumers, and a recent estimate of very
is poor, with very limited conversion all the way to DHA long-chain omega-3 fatty acid intake among Australian adults
being observed.2 Eicosapentaenoic acid and DPA can also gave a median intake of about 0.03 g/day, compared with a
be synthesized from DHA by retroconversion due to limited mean intake of about 0.19 mg/day.5 Intakes would be higher
peroxisomal β-oxidation. in those populations, such as the Japanese, who consume oily
fish in greater amounts and with greater regularity than in
Dietary Sources and Typical Intakes Europe, North America, and Australasia.
of Omega-3 Fatty Acids The oil obtained from oily fish flesh or lean fish livers
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Green leaves contain a significant proportion (typically (eg, cod liver) is termed “fish oil” and it has the distinctive
⬎ 50%) of their fatty acids as ALA, however green leaves are characteristic of being rich in very long-chain omega-3 fatty
not rich sources of fat. Several seeds and seed oils and some nuts acids. Because different oily fish contain different amounts
contain significant amounts of ALA. Linseeds (flaxseeds) and of omega-3 fatty acids, fish oils do as well. Eicosapentaenoic
their oil typically contain 45% to 55% of fatty acids as ALA, acid and DHA comprise about 30% of the fatty acids in a typi-
while soybean oil typically contains 5% to 10% of fatty acids cal preparation of fish oil, which means that a 1-g fish oil cap-
as ALA. Rapeseed oil and walnuts also contain ALA. Corn sule can provide about 0.3 g of EPA plus DHA. Note too that
oil, sunflower oil, and safflower oil are rich in linoleic acid it is not only the amount of omega-3 fatty acids that can vary
but contain very little ALA. Typical intakes of ALA among between fish and fish oils, but also the relative proportions
For personal use only.

Western adults are 0.5 to 2 g/d.2,3 The main PUFA in most of the individual very long-chain omega-3 PUFAs (EPA,
Western diets is the omega-6 fatty acid LA (18:2ω-6), which is DPA, and DHA); for example, cod liver oil is richer in EPA
typically consumed in 5- to 20-fold greater amounts than ALA.2,3 than DHA while tuna oil is richer in DHA than EPA. Fish
Seafood is a source of the longer chain, more unsaturated liver oils contain significant amounts of fat soluble vitamins,
omega-3 PUFAs. Fish can be classified into lean fish that especially vitamins A and D. Encapsulated oil preparations
store lipid in the liver (eg, cod) or “fatty” (“oily”) fish that that contain omega-3 fatty acids in higher amounts than found
store lipid in the flesh (eg, mackerel, herring, salmon, tuna, in standard fish oils are available. In fish oil capsules, the
and sardines). Compared with other foodstuffs, fish and other fatty acids are usually present in the form of triacylglycerols.
seafood are good sources of the very long-chain omega-3 fatty It should also be mentioned that fish oils contain fairly high
acids EPA, DPA, and DHA. However, different types of fish proportions of palmitic acid (16:0) and palmitoleic acid
contain different amounts of these fatty acids and different (16:1ω-7), and contain some arachidonic acid (20:4ω-6).
ratios of EPA to DHA. This is partly dependent upon the In addition to fish oils that provide omega-3 fatty acids in
metabolic characteristics of the fish and also upon their diet, triacylglycerol form, omega-3 fatty acids are also available
water temperature, season, and other variables. Nevertheless, in the phospholipid form (eg, as krill oil) and as ethyl esters
it is clear that a single lean fish meal (eg, one serving of (eg, in the highly concentrated pharmaceutical prepara-
cod) could provide about 0.2 to 0.3 g of very long-chain tion Omacor®, also known as Lovaza® in North America).
omega-3 fatty acids, while a single oily fish meal (eg, one Clearly, capsules could make a significant contribution to
serving of salmon or mackerel) could provide 1.5 to 3 g of very long-chain omega-3 fatty acid intake. For example, an
these fatty acids. The latest estimate for fish consumption individual who consumes little or no fish could increase his
among adults in the United Kingdom is approximately 100 g or her daily very long-chain omega-3 fatty acid intake 5-fold
lean fish and approximately 50 g oily fish per week; similar (or more) by taking a single standard fish oil capsule per day.
(and in some countries even lower) intakes are expected in There are other sources of very long-chain omega-3 PUFAs.
other Northern countries and in Eastern European, North Algal oils that are particularly rich in DHA (comprising ∼45%
American, and Australasian countries.4 Lean fish intake is of total fatty acids) are used in infant formulas. Over the last
higher in Southern European countries and lean and oily fish few years there have been significant moves toward the
intake is higher than this in Japan. Average (mean) intakes enrichment of foods that are not normally rich in EPA and

150 © Postgraduate Medicine, Volume 121, Issue 6, November 2009, ISSN – 0032-5481, e-ISSN – 1941-9260
 Omega-3 Fatty Acids

DHA with those fatty acids. Two routes to such enrich- DHA intake and the EPA and DHA contents of plasma
ment have developed. The first is the addition of fish oil to phospholipids7–9 and of platelet phospholipids.10 In other stud-
products such as spreads, yogurts, or milk. The second is the ies, incorporation of EPA and DHA into blood neutrophils11
feeding of farm animals with omega-3 fatty acids, resulting and EPA into plasma phospholipids and blood mononuclear
in enrichment of meat, milk (in the case of cows, sheep, or cells12 occurred in a linear dose-response manner (Figure
goats), and eggs (in the case of chickens) with EPA and DHA. 2). In an elegant study combining dose response and time
One attraction of enriching foods like meat, spreads, eggs, course over 12 months in older men, Katan et al13 reported
yogurts, and dairy products is that consumers do not have the fatty acid compositions of serum cholesteryl esters,
to change their dietary habits in order to increase their EPA erythrocytes, and adipose tissue. This study confirmed that
and DHA intake.6 On the other hand, the level of enrichment EPA and DHA are incorporated into circulating lipid pools
that can be achieved is limited by metabolic processes in the and into erythrocytes when their intakes are increased.
animals (in the case of the animal feeding approach) or food It also demonstrated EPA and DHA incorporation into
technology, processing, and storage considerations. Thus, adipose tissue, a storage pool, when their intake is increased.
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the level of enrichment currently achievable can provide, at However, this study also clearly showed that incorporation
best, a few hundred milligrams of EPA and DHA per day, into different pools occurs at different rates and to differing
obtained from a combination of several enriched foods. Thus, extents (ie, with different efficiencies) and may not be related
a person who does not eat fish could increase his or her EPA to intake in a strictly linear fashion, at least compared with
and DHA intake by consuming such enriched foods. One the intakes studied. The study of Katan et al13 showed that
aspect of this approach that must be carefully considered is near-maximal incorporation of EPA and DHA into serum
the type of food that is used as a vehicle for delivery of EPA cholesteryl esters occurs within 30 days of beginning supple-
and DHA. It does not make sense to deliver healthy fatty mentation, whereas maximal incorporation into erythrocytes
acids within a matrix of less healthy components, and it is does not occur until sometime between 56 and 182 days.
For personal use only.

important to consider the amounts of less healthy components Yaqoob et al14 reported the time-dependent incorporation of
such as total fat, saturated fat, and sugar within a product that EPA and DHA into blood mononuclear cells; incorporation
must be eaten in order for that product to deliver a particular of both fatty acids was near-maximal after 4 weeks of
amount of EPA and DHA, which may be only a few tens of supplementation (Figure 3). Upon cessation of supplemen-
milligrams per serving. tation, EPA in mononuclear cells returned to starting levels
within 8 weeks, while the cells appeared to retain DHA. The
Supplementation with Very
same observations of loss of EPA and selective retention of
Long-Chain Omega-3 Fatty Acids DHA upon cessation of fish oil supplementation have been
Alters the Fatty Acid Composition made for erthrocytes15 and platelets.16 Thus, a significant body
of Plasma, Cells, and Tissues of literature reports that EPA and DHA are incorporated into
in Humans blood, cell, and tissue lipids when their intake is increased.
Different plasma lipid pools, cells, and tissues have different
characteristic fatty acid compositions. These compositions Mechanisms of Action of Very
are influenced by the availability of different fatty acids but Long-Chain Omega-3 Fatty Acids
also by the metabolic characteristics of the particular pool, Increased cell and tissue omega-3 fatty acid content can
cell, or tissue. Modification of fatty acid profiles has been influence cell function through a variety of mechanisms as
widely reported after supplementation of the diet with fish shown in Figure 4. These include:
oil capsules; such supplementation results in the appearance
of EPA and DHA in plasma lipids, platelets, erythrocytes, • alterations in the physical properties of the membrane
leukocytes, colonic tissue, cardiac tissue, and most likely in such as membrane order (“fluidity”) and raft structure
many other cell and tissue types. The incorporation of EPA (rafts are membrane microdomains with a particular
and DHA from fish oil capsules is partly of the expense lipid and fatty acid makeup and play a role as platforms
of very long-chain omega-6 PUFAs, like arachidonic for receptor action and for the initiation of intracellular
acid, and occurs in a dose-response fashion. For example, signaling pathways), which in turn influence the activity
studies using a range of EPA + DHA intakes from 1 to 6 of membrane proteins including receptors, transporters,
g/day report near linear relationships between EPA and ion channels, and signaling enzymes.17

© Postgraduate Medicine, Volume 121, Issue 6, November 2009, ISSN – 0032-5481, e-ISSN – 1941-9260 151
 Philip C. Calder and Parveen Yaqoob

Figure 2. Dose-dependent incorporation of eicosapentaenoic acid into human plasma phospholipids and blood mononuclear cells.12

5
Change in EPA from week 0

4
(% of total fatty acids)

Plasma phospholipid

2
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Mononuclear cell
1 phospholipid

0
0 1 2 3 4

EPA intake from capsules (g/day)

Healthy young males supplemented their diet with differing amounts of an EPA-rich oil for a period of 12 weeks. Plasma and blood mononuclear cell phospholipids were
For personal use only.

isolated and their fatty acid composition determined by gas chromatography. Data are mean ± SEM from 23 or 24 subjects per group and are expressed as change in EPA
from week 0 (study entry).12
Abbreviation: EPA, eicosapentaenoic acid.

• effects on cell signaling pathways, either through from arachidonic acid.19 Relatively recently, a new
modifying the expression, activity, or avidity of family of lipid mediators, termed resolvins and protec-
membrane receptors or modifying intracellular signal tins, synthesized from both EPA and DHA, have been
transduction mechanisms.18 As a result of these effects, described. These mediators have been demonstrated
transcription factor activation is altered and gene in cell culture and animal feeding studies to be
expression modified. Transcription factors reported potently anti-inflammatory, inflammation-resolving, and
to be modified by the presence of very long-chain immunomodulatory.21,22 Protectin D1, produced from
omega-3 PUFAs include nuclear factor κ B, peroxi- DHA, appears to have an important role in protecting
some proliferator-activated receptor-α and γ, and the tissue from excessive damage in a variety of experimental
sterol regulatory element binding proteins. situations.23
• alterations in the pattern of lipid mediators produced
(eg, eicosanoids). The different mediators have different
biological activities and potencies.19 Eicosanoids An Increased Intake of Very
produced from the omega-6 PUFA arachidonic acid Long-Chain Omega-3 Fatty Acids
have well-established roles in regulation of inflammation, is Beneficial to Health
immunity, platelet aggregation, smooth muscle Through the mechanisms of action outlined above (Figure 4)
contraction, and renal function.20 Very long-chain and the resulting modifications of cell and tissue function,
omega-3 PUFAs decrease the production of arachidonic very long-chain omega-3 fatty acids exert physiological
acid-derived eicosanoids and so can impact the actions actions. These are summarized in Table 1, where they are
regulated by those mediators.19 Furthermore, EPA is a linked to certain health or clinical benefits. A number of risk
substrate for the synthesis of alternative eicosanoids, factors for cardiovascular disease (CVD) are modified in
which are typically less potent than those produced a beneficial way by long-chain omega-3 fatty acids. These

152 © Postgraduate Medicine, Volume 121, Issue 6, November 2009, ISSN – 0032-5481, e-ISSN – 1941-9260
 Omega-3 Fatty Acids

Figure 3. Time course of incorporation of EPA and DHA into human blood mononuclear cells.14

Period of
supplementation

mononuclear cell phospholipids (%)

EPA (■) or DHA (▲) in

3
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1
For personal use only.

4 8 12 20
0

Time (weeks)
Healthy subjects supplemented their diet with fish oil capsules providing 2.1 g EPA plus 1.1 g DHA per day for a period of 12 weeks (indicated by the grey area). Blood
mononuclear cell phospholipids were isolated at 0, 4, 8, 12, and 20 weeks and their fatty acid composition determined by gas chromatography. Data are mean ± SEM from
8 subjects.14
Abbreviations: DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid.

factors include: blood pressure,24 platelet reactivity and of optimizing visual and neurological development.3,4,38,39
thrombosis,25 plasma triglyceride concentrations,26 vascular Studies have highlighted the potential for very long-chain
function,27 cardiac arrhythmias,28 and inflammation.29 As a omega-3 fatty acids in mental development,40 improving
result, increased very long-chain omega-3 fatty acid intake childhood learning and behavior,41 and reducing burden
is associated with a reduced risk of cardiovascular morbidity of psychiatric illnesses in adults,42 although these remain
and mortality.30 Indeed, supplementation studies with very controversial areas of possible action that require more
long-chain omega-3 fatty acids have demonstrated reduced robust scientific support. There may also be a role for long-
mortality.31–35 A number of other noncardiovascular actions chain omega-3 PUFAs, DHA in particular, in preventing
of these fatty acids have also been documented (Table 1), neurodegenerative diseases of aging43 and the production
suggesting that increased intake of these fatty acids could of protectins, especially protectin D1 (formerly called
be of benefit in many conditions. For example, they have neuroprotectin D1), appears to be crucial for this effect.44
been used successfully in rheumatoid arthritis36 and, in
some studies, in inflammatory bowel diseases,37 and may be Recommendations to Increase
useful in other inflammatory conditions.29 Docosahexaenoic Intake of Very Long-Chain Omega-3
acid has an important structural role in the eye and Fatty Acids
brain, and its supply early in life when these tissues are Recognizing the benefits of very long-chain omega-3
developing is known to be of vital importance in terms fatty acids has resulted in a series of recommenda-

© Postgraduate Medicine, Volume 121, Issue 6, November 2009, ISSN – 0032-5481, e-ISSN – 1941-9260 153
 Philip C. Calder and Parveen Yaqoob

Figure 4. General algorithm of the interacting mechanisms whereby very long-chain omega-3 fatty acids might influence cell function.

Increased -3 fatty

acid supply

Altered membrane fatty acid

composition
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Altered membrane
Altered signal Altered pattern of
structure & fluidity
Altered pattern transduction gene expression
(gross; rafts; acylation)
of lipid mediator pathways via transcription
synthesis factors
For personal use only.

Altered cellular function and responses

tions to increase the intake of fi sh and, more specifi - of EPA and DHA. However, one means to achieve the
cally, very long-chain omega-3 fatty acids by various desired intake of these fatty acids that would not require
government, nongovernment, and professional bodies. dietary change is the consumption of fish oil capsules
A recommendation to maintain general good health is (or liquid); consumption of a single 1-g standard fish oil
an intake of at least 2 fish meals per week including at capsule per day would allow many consumers to meet
least one of oily fish.4 Such recommendations are based the most conservative of recommendations45 since such a
mainly upon the epidemiological evidence for decreased capsule will provide about 0.3 g EPA + DHA/day. Con-
cardiovascular morbidity and mortality with increased sumption of more capsules, more concentrated forms of
consumption of fish and upon supplementation studies encapsulated omega-3 fatty acids, or fish oil liquid would
using fish oils that investigate impact on cardiovascular allow some of the less conservative recommendations
risk factors.3,4,30 In terms of the very long-chain omega-3 to be met. Finally, as indicated above, consumption of
fatty acids, recommendations that have been made include foods specifically enriched in very long-chain omega-3
a minimal intake of 0.2 to 0.65 g/day for general good PUFAs could make a contribution toward increased intake
health,4,45,46 1.5 g/day for general good health,3 1 g/day for of these fatty acids. It should be noted that there are no
secondary prevention of myocardial infarction,47–49 and likely adverse effects of intakes of these fatty acids over
2 to 4 g/day for blood triglyceride lowering.47 In those the recommended ranges. There may be an unpleasant taste
individuals not regularly consuming oily fish, the intake and mild gastrointestinal upsets when large numbers of fish
of these fatty acids is likely to be ⬍ 0.1 g/day and perhaps oil capsules or large volumes of liquids are consumed, espe-
even much lower.5 Clearly, if individuals are not willing to cially without food. Very high intakes of these fatty acids can
change their dietary habits and eat more oily fish, then it is cause an increase in bleeding time3 but this does not occur
not likely that they can achieve the recommended intake with intakes over the recommended ranges indicated above.

154 © Postgraduate Medicine, Volume 121, Issue 6, November 2009, ISSN – 0032-5481, e-ISSN – 1941-9260
 Omega-3 Fatty Acids

Table 1. Summary of the Physiological Roles and Potential Clinical Benefits of Very Long-Chain Omega-3 Fatty Acids
Physiological Role of Very-Long Potential Clinical Benefit Target
Chain Omega-3 Fatty Acids
Regulation of blood pressure Decreased blood pressure Hypertension; CVD
Regulation of platelet function Decreased likelihood of thrombosis CVD
Regulation of blood coagulation Decreased likelihood of thrombosis Thrombosis; CVD
Regulation of plasma triglyceride Decreased plasma triglyceride concentrations Hypertriglyceridemia; CVD
concentrations
Regulation of vascular function Improved vascular reactivity CVD
Regulation of cardiac rhythm Decreased arrhythmias CVD
Regulation of inflammation Decreased inflammation Inflammatory diseases (eg, arthritis,
inflammatory bowel diseases, psoriasis,
lupus, asthma, cystic fibrosis, dermatitis,
neurodegeneration); CVD
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Regulation of immune function Improved immune function Compromised immunity

Regulation of bone turnover Maintained bone mass Osteoporosis
Regulation of insulin sensitivity Improved insulin sensitivity Type 2 diabetes
Regulation of tumor cell growth Decreased tumor cell growth and survival Some cancers
Regulation of visual signaling Optimized visual signaling Poor infant visual development
(via rhodopsin) (especially pre-term)
Structural component of brain and Optimized brain development—cognitive and Poor infant and childhood cognitive
central nervous system learning processes processes and learning

Abbreviation: CVD, cardiovascular disease.

For personal use only.

Is There a Role for the amounts of ALA. These studies confirm that increasing
Plant-Derived Omega-3 ALA intake increases the EPA (and DPA) content of plasma
PUFA, ALA, in Human Health? lipids, platelets, leukocytes, and erythrocytes but that DHA
The foregoing discussion has centered upon the very long- content does not increase;2,50 clearly, these findings are in
chain omega-3 PUFAs, for which there is much evidence agreement with the stable isotope studies. Such studies with
for human health benefit and an increasing understanding of ALA have demonstrated some effects on cardiovascular risk
the multiple mechanisms involved, and for which a number factors and on inflammatory markers, but where these are
of recommendations for increased intake have been made. reported, they are typically weaker than the effects achieved
The major plant omega-3 PUFA, ALA, may also have human from increasing consumption of EPA + DHA, and may
health benefits either in its own right or by acting as a pre- be due to the increased appearance of EPA.53 The limited
cursor for synthesis of the longer chain more unsaturated capacity for conversion to longer chain omega-3 fatty acids,
derivatives, using the pathway shown in Figure 1. These pos- and the lack of efficacy in ameliorating cardiovascular risk
sibilities have been reviewed in some detail fairly recently.2,50 factors and inflammatory markers in humans suggests that
Studies in humans using acute ingestion of stable, isotopi- moderately increased consumption of ALA may be of little
cally labelled ALA have demonstrated some conversion to benefit in altering EPA, and particularly DHA, status or
EPA and DPA, but much more limited conversion to DHA, improving health outcomes compared with increased intake
although this may be greater in young adult women than of preformed EPA + DHA.
in men,51,52 possibly because of upregulation of the delta-6
desaturase by female sex hormones. Little is known about the Conclusion
extent of this process in infancy and childhood, in the elderly, Current intakes of very long-chain omega-3 fatty acids EPA
or during pregnancy and lactation––times when synthesis and DHA are low in most individuals living in Western
of very long-chain omega-3 PUFAs might be important or countries. A good natural source of these fatty acids is
desirable. A number of studies have examined the effect seafood, especially oily fish. Fish oil capsules contain
of chronic (ie, weeks to months) consumption of increased these fatty acids too, with a standard 1-g capsule provid-

© Postgraduate Medicine, Volume 121, Issue 6, November 2009, ISSN – 0032-5481, e-ISSN – 1941-9260 155
 Philip C. Calder and Parveen Yaqoob

ing about 0.3 g of EPA plus DHA; more concentrated 3. British Nutrition Foundation. Briefing Paper: N-3 Fatty Acids and
Health. London: British Nutrition Foundation; 1999.
forms are also available in capsules. Very long-chain 4. Scientific Advisory Committee on Nutrition/Committee on Toxicity.
omega-3 fatty acids are readily incorporated from capsules Advice on Fish Consumption: Benefits and Risks. London: TSO; 2004.
into transport (blood lipids), functional (cell and tissue), 5. Meyer BJ, Mann NJ, Lewis JL, Milligan GC, Sinclair AJ, Howe PR.
Dietary intakes and food sources of omega-6 and omega-3 polyunsa-
and storage (adipose) pools. This incorporation is dose- turated fatty acids. Lipids. 2003;38(4):391–398.
dependent and follows a kinetic pattern that is characteristic 6. Givens DI. The role of animal nutrition in improving the nutritive value
of animal-derived foods in relation to chronic disease. Proc Nutr Soc.
for each pool. Incorporation is most rapid into blood 2005;64(3):395–402.
lipids, followed by platelets and white cells, followed by 7. Harris WS, Windsor SL, Dujovne CA. Effects of four doses of n-3 fatty
erythrocytes. At sufficient levels of incorporation, EPA acids given to hyperlipidemic patients for six months. J Am Coll Nutr.
1991;10(3):220–227.
and DHA influence the physical nature of cell membranes 8. Marsen TA, Pollok M, Oette K, Baldamus CA. Pharmacokinetics of
and membrane protein-mediated responses, lipid mediator omega-3 fatty acids during ingestion of fish oil preparations. Prost Leuk
Essent Fatty Acids. 1992;46(3):191–196.
generation, cell signaling, and gene expression in many 9. Blonk MC, Bilo HJ, Popp-Snijders C, Mulder C, Donker AJ.
different cell types. Through these mechanisms, EPA and Dose-response effects of fish oil supplementation in healthy volun-
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and tissues respond to external signals. In most cases the polyunsaturated fatty acids on blood lipids and platelet function in
effects seen are compatible with improvements in disease healthy volunteers. Clin Sci. 1983;64(1):91–99.
11. Healy DA, Wallace FA, Miles EA, Calder PC, Newsholme P. The effect
biomarker profiles or health-related outcomes. As a result, of low to moderate amounts of dietary fish oil on neutrophil lipid com-
very long-chain omega-3 fatty acids play a role in achieving position and function. Lipids. 2000;35(7):763–768.
optimal health and in protection against disease. Long-chain 12. Rees D, Miles EA, Banerjee T, et al. Dose-related effects of
eicosapentaenoic acid on innate immune function in healthy humans:
omega-3 fatty acids not only protect against cardiovascular a comparison of young and older men. Am J Clin Nutr. 2006;83(2):
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13. Katan MB, Deslypere JP, van Birgelen AP, Penders M, Zegwaard M.
for example rheumatoid arthritis, they may be beneficial as Kinetics of the incorporation of dietary fatty acids into serum choles-
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therapeutic agents although a high intake is required. On teryl esters, erythrocyte membranes and adipose tissue: an 18 month
the basis of the recognized health improvements brought controlled study. J Lipid Res. 1997;38(10):2012–2022.
14. Yaqoob P, Pala HS, Cortina-Borja M, Newsholme EA, Calder PC.
about by long-chain omega-3 fatty acids, recommendations Encapsulated fish oil enriched in α-tocopherol alters plasma
have been made to increase their intake. While this can be phospholipid and mononuclear cell fatty acid compositions but not
mononuclear cell functions. Eur J Clin Invest. 2000;30(3):260–274.
achieved through increased consumption of oily fish, for 15. Popp-Snijders C, Schouten JA, van Blitterswijk WJ, van der Veen EA.
many individuals fish oil capsules represent a viable option Changes in membrane lipid composition of human erythrocytes after
for achieving recommended intakes. The plant omega-3 dietary supplementation of (n-3) fatty acids: maintenance of membrane
fluidity. Biochim Biophys Acta. 1986;854(1):31–37.
fatty acid, ALA, can be converted to EPA but in humans 16. von Schacky C, Fischer S, Weber PC. Long term effects of dietary
conversion to DHA appears to be poor. Effects of ALA on marine omega-3 fatty acids upon plasma and cellular lipids, platelet
function, and eicosanoid formation in humans. J Clin Invest. 1985;76(4):
human health-related outcomes appear to be due to conver- 1626–1631.
sion to the EPA and since this is limited in humans, moder- 17. Calder PC, Yaqoob P. Lipid rafts—Composition, characterization and
ately increased consumption of ALA may be of little benefit controversies. J Nutr. 2007;137(3):545–547.
18. Miles EA, Calder PC. Modulation of immune function by dietary fatty
in improving health outcomes compared with increased acids. Proc Nutr Soc. 1998;57(2):277–292.
intake of preformed EPA + DHA. 19. Calder PC. The relationship between the fatty acid composition of
immune cells and their function. Prost Leuk Essent Fatty Acids. 2008;
79(3–5):101–108.
Conflict of Interest Statement 20. Nicolaou A, Kafatos G. Bioactive Lipids. Bridgewater, UK: The Oily
Philip C. Calder, PhD, DPhil discloses conflicts of interest with Press; 2004.
21. Serhan CN, Clish CB, Brannon J, Colgan SP, Gronert K, Chiang N.
Amarin Corp., Solvay Healthcare, Solvay Pharmaceuticals, Anti-inflammatory lipid signals generated from dietary n-3 fatty acids
and Vifor Pharma. Parveen Yaqoob, MA, DPhil discloses no via cyclooxygenase-2 and transcellular processing: a novel mechanism
for NSAID and n-3 PUFA therapeutic actions. J Physiol Pharmacol.
conflicts of interest. 2000;51(4 pt 1):643–654.
22. Serhan CN, Clish CB, Brannon J, Colgan SP, Chiang N, Gronert K.
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