The Journal of Nutrition

Supplement: Heart Healthy Omega-3s for FoodStearidonic Acid (SDA) as a Sustainable Choice

Mechanisms of Action of (n-3) Fatty Acids1,2

Philip C. Calder*

Institute of Human Nutrition and Human Development and Health Academic Unit, Faculty of Medicine, University of Southampton,
Southampton, UK

Abstract
(n-3) PUFA are a family of biologically active fatty acids. The simplest member of this family, a-linolenic acid, can be
converted to the more biologically active very long-chain (n-3) PUFA EPA and DHA; this process occurs by a series
of desaturation and elongation reactions, with stearidonic acid being an intermediate in the pathway. Biological activity of
a-linolenic and stearidonic acids most likely relates to their conversion to EPA. The very long-chain (n-3) PUFA have a range
of physiological roles that relate to optimal cell membrane structure and optimal cell function and responses. Thus, (n-3)
PUFA play a key role in preventing, and perhaps treating, many conditions of poor health and well-being. The multiple
actions of (n-3) PUFA appear to involve multiple mechanisms that connect the cell membrane, the cytosol, and the

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nucleus. For some actions, (n-3) PUFA appear to act via receptors or sensors, so regulating signaling processes that
influence patterns of gene expression. Some effects of (n-3) PUFA seem to involve changes in cell membrane fatty acid
composition. Changing membrane composition can in turn affect membrane order, formation of lipid rafts, intracellular
signaling processes, gene expression, and the production of both lipid and peptide mediators. Under typical Western
dietary conditions, human cells tend to have a fairly high content of the (n-6) fatty acid arachidonic acid. Increased oral
intake of EPA and DHA modifies the content of arachidonic acid as well as of EPA and DHA. Arachidonic acid is the
substrate for eicosanoids involved in physiology and pathophysiology. The eicosanoids produced from EPA frequently
have properties that are different from those that are produced from arachidonic acid. EPA and DHA are also substrates for
production of resolvins and protectins, which seem to be biologically extremely potent. Increasing the contents of EPA and
DHA in membranes modifies the pattern of production of these different lipid mediators. J. Nutr. 142: 592S599S, 2012.

Structure, Naming, and Metabolic

Relationships of (n-3) Fatty Acids
The term (n-3) is a structural descriptor for a family of PUFA (1);
(n-3) describes the position of the double bond that is closest to
the methyl terminus of the acyl chain. In all (n-3) fatty acids, this
1
Published in a supplement to The Journal of Nutrition. Presented at the
Experimental Biology 2011 satellite session, Heart Healthy Omega-3s for Food:
Stearidonic Acid (SDA) as a Sustainable Choice, held in Washington, DC, April 8,
2011.The conference was organized by the American Society for Nutrition and
was supported by an unrestricted educational grant from Solae, LLC, and
Monsanto. The coordinators for this supplement were DAnn Finley, University
of California, Davis; Richard J. Deckelbaum, Columbia University; and Eileen
Kennedy, Tufts University. Supplement Coordinator disclosures: DAnn Finley
has no relationships to disclose, Richard J. Deckelbaum has received an
honorarium from the American Society for Nutrition for editing this supplement,
Eileen Kennedy is a member of the Advisory Committee with Solae, Co.
The supplement is the responsibility of the Guest Editor to whom the Editor of
The Journal of Nutrition has delegated supervision of both technical conformity
to the published regulations of The Journal of Nutrition and general oversight of
the scientific merit of each article. The Guest Editor for this supplement is Kevin
Schalinske. Guest Editor disclosure: Kevin Schalinske has no relationships to
disclose. Publication costs for this supplement were defrayed in part by the
payment of page charges. This publication must therefore be hereby marked
advertisement in accordance with 18 USC section 1734 solely to indicate this
fact. The opinions expressed in this publication are those of the authors and are
not attributable to the sponsors or the publisher, Editor, or Editorial Board of The
Journal of Nutrition.
double bond is on carbon 3, counting the methyl carbon as
carbon number 1. As with all fatty acids, (n-3) fatty acids have
systematic and common names. They are also described by
a shorthand nomenclature that is based on the number of carbon
atoms in the acyl chain, the number of double bonds, and the
position of the first double bond relative to the methyl carbon.
The simplest (n-3) fatty acid is a-linolenic acid [18:3(n-3)].
a-Linolenic acid is synthesized from linoleic acid [18:2(n-6)] by
desaturation, catalyzed by D15-desaturase. Animals, including
humans, do not possess the D15-desaturase enzyme and so
cannot synthesize a-linolenic acid. Thus, a-linolenic acid is a
classically essential fatty acid, along with linoleic acid. Plants
can synthesize a-linolenic, acid because they possess D-15
2
Author disclosures: P. C. Calder serves on the Danone Scientific Advisory
Board on Baby Nutrition and acts as a consultant to the Danone Research Centre
for Specialised Nutrition, Mead Johnson Nutritionals, Vifor Pharma, and Amarin
Corporation. He has received speaking honoraria from Solvay Healthcare, Solvay
Pharmaceuticals, Pronova Biocare, Fresenius Kabi, B. Braun, Abbott Nutrition,
Baxter Healthcare, Nestle, and Unilever. He currently receives research funding
from Vifor Pharma and Abbott Nutrition. He is elected President of the
International Society for the Study of Fatty Acids and Lipids, an organization
that is partly supported by corporate membership fees, mainly the food and
supplements industries. He received travel funds and an honorarium from the
American Society for Nutrition for giving a presentation and writing a paper for
this symposium.
*To whom correspondence should be addressed. E-mail: pcc@soton.ac.uk.

2012 American Society for Nutrition.

592S Manuscript received November 16, 2011. Initial review completed November 22, 2011. Revision accepted December 2, 2011.
First published online January 25, 2012; doi:10.3945/jn.111.155259.
desaturase. Although animals cannot synthesize a-linolenic acid,
they can metabolize it to other longer chain, more unsaturated
(n-3) fatty acids. This occurs by a series of linked desaturation
and elongation reactions that mainly take place in the liver.
a-Linolenic acid can be converted to stearidonic acid [18:4(n-3)]
by D6-desaturase and then stearidonic acid can be elongated to
eicosatetraenoic acid [20:4(n-3)] (Fig. 1). Further desaturation
by D5-desaturase yields EPA [20:5(n-3)] (Fig. 1). Conversion of
a-linolenic acid to EPA competes with the conversion of linoleic
acid to arachidonic acid [20:4(n-6)], because the same enzymes
are used. It is thought that D6-desaturase is rate limiting in this
pathway. The activities of D6-and D5-desaturases are regulated
by nutritional status, hormones, and feedback inhibition by end
products, creating a complex control network for endogenous
long-chain PUFA synthesis. EPA can be further converted via
DPA3 [22:5(n-3)] to DHA [22:6(n-3)] (Fig. 1). D6-Desaturase
participates in this conversion, which also involves limited
peroxisomal b-oxidation. a-Linolenic acid conversion to EPA,
DPA, and DHA has been studied in humans using several different
approaches that demonstrate that this conversion is generally
poor (2,3). In particular, conversion to the end product DHA
appears to be especially limited (2,3). Conversion of stearidonic
acid to EPA is superior to that of a-linolenic acid (46), probably

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because conversion of stearidonic acid does not require the ac-
tivity of the rate-limiting D6-desaturase enzyme (Fig. 1). Limited
peroxisomal b-oxidation of DHA can generate EPA and DPA, a
process termed retro-conversion. EPA, DPA, and DHA are often
collectively referred to as very long-chain (n-3) PUFA.

FIGURE 1 The biosynthesis of (n-3) PUFA. DPA, docosapentaenoic

Dietary Sources and Typical Intakes
of a-Linolenic Acid and Very
Long-Chain (n-3) PUFA
a-Linolenic acid is a common constituent of green leaves, often
comprising over 50% of their fatty acids. However, green leaves are
not high in fat, so these are not usually a major dietary source of a-
linolenic acid. A number of different seeds and their oils and some
nuts contain considerable amounts of a-linolenic acid. Linseeds
(flaxseeds) and their oil typically contain 4555% of fatty acids as
a-linolenic acid, whereas soybean oil, rapeseed oil, and walnuts all
typically contain ~10% of fatty acids as a-linolenic acid. There is
little a-linolenic acid in corn oil, sunflower oil, or safflower oil,
which are all rich in linoleic acid. Dietary intakes of a-linolenic acid
among Western adults are typically in the range of 0.52 g/d (2,7).
The (n-6) fatty acid linoleic acid is the main PUFA in most Western
diets and is typically consumed in 5- to 20-fold greater amounts
than a-linolenic acid (2,7,8).
Fish are described as lean or fatty (oily). Lean fish, like cod,
store lipid in their liver. Oily fish, like mackerel, herring, salmon,
tuna, and sardines, store lipid in their flesh. Fish and other
seafood are much better sources of very long-chain (n-3) PUFA
than other foods (7). It is important to note though that different
types of fish contain different amounts of these fatty acids and
may have different ratios of EPA:DHA (7). This is because the
(n-3) PUFA content and type is influenced by a number of
factors, including the metabolic characteristics of the fish, their
diet, the temperature of the water in which they live, and the
season. A single lean fish meal (e.g., one serving of cod) could
provide ;0.20.3 g very long-chain (n-3) fatty acids. In contrast,
a single oily fish meal (e.g., one serving of salmon or mackerel)
3
Abbreviations used: COX, cyclooxygenase; DPA, docosapentaenoic acid; GPR,
G-protein coupled receptor; IkB, inhibitory subunit of NFkB.
acid. Reproduced with permission of (1).
could provide 1.53.5 g of these fatty acids. Because oily fish
consumption among many Western populations is typically low,
average (mean) intakes of very long-chain (n-3) fatty acids
among adults in Northern and Eastern Europe, North America,
and Australasia are low and estimated to be ;0.150.25 g/d (9).
However, the distribution of intakes is bimodal, because there
are consumers and nonconsumers of oily fish. An Australian
study estimated a median intake of very long-chain (n-3) fatty
acids of ;0.03 g/d among adults compared with a mean intake
of ;0.19 mg/d (10). Populations such as the Japanese, who
consume oily fish in greater amounts and with greater regularity
than populations in Europe, North America, and Australasia,
have higher intakes of very long-chain (n-3) PUFA.
Fish oil is obtained from oily fish flesh or lean fish livers (e.g.,
cod liver). Fish oil is rich in very long-chain (n-3) fatty acids and in a
typical fish oil, EPA and DHA comprise ;30% of the fatty acids
present. Thus, a 1-g fish oil capsule can provide ;0.3 g of EPA plus
DHA. However, the variations in the amount of (n-3) fatty acids
and the relative proportions of the individual very long-chain (n-3)
PUFA (EPA, DPA, and DHA) in fish are reflected in fish oils. As an
example, cod liver oil is richer in EPA than DHA, whereas tuna oil
is richer in DHA than EPA. Oils that are more concentrated in (n-3)
fatty acids than standard fish oils are available.
Overview of the Physiological Roles
and Corresponding Health Benefits
of (n-3) PUFA
Very long-chain (n-3) fatty acids have been demonstrated to
have a wide range of physiological roles, as summarized in Table
(n-3) Mechanisms 593S
 TABLE 1 Summary of the physiological roles and potential health benefits of very long-chain (n-3) fatty
acids

Physiological role of very

long-chain (n-3) fatty acids Potential health benefit Disease target

Regulation of blood pressure Decreased blood pressure Hypertension, CVD1

Regulation of platelet function
Regulation of blood coagulation
Regulation of plasma TG
concentrations
Regulation of vascular function
Regulation of cardiac rhythm
Regulation of heart rate
Regulation of inflammation
Regulation of immune function
Regulation of fatty acid and TG
metabolism
Regulation of bone turnover
Regulation of insulin sensitivity
Regulation of tumor cell growth
Decreased likelihood of thrombosis Thrombosis, CVD
Decreased likelihood of thrombosis Thrombosis, CVD
Decreased plasma TG concentrations Hypertriglyceridemia, CVD
Improved vascular reactivity CVD
Decreased cardiac arrhythmias CVD
Increased heart rate variability CVD
Decreased inflammation Inflammatory diseases
(arthritis, inflammatory bowel diseases,
psoriasis, lupus, asthma, cystic fibrosis,
dermatitis, neurodegeneration, etc.), CVD
Improved immune function Compromised immunity
Decreased TG synthesis and storage Weight gain, weight loss, obesity
Maintained bone mass Osteoporosis
Improved insulin sensitivity Type-2 diabetes
Decreased tumor cell growth and survival Some cancers

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Regulation of visual signaling Optimized visual signaling Poor infant visual development
(via rhodopsin) (especially preterm)
Structural component of brain Optimized brain development leading Poor infant and childhood cognitive
and central nervous system to better cognitive and learning processes processes, learning, and behavior
1
CVD, cardiovascular disease. Reproduced with permission of (1).

1, where these roles are linked to certain health or clinical
benefits. They have been demonstrated to beneficially modify
a number of risk factors for cardiovascular disease. Risk factors
improved include blood pressure (11), platelet reactivity and
thrombosis (12), plasma TG concentrations (13), vascular
function (14), cardiac arrhythmias (15), heart rate variability
(15), and inflammation (16). Due to these effects, increased
intake of very long-chain (n-3) fatty acids is associated with a
reduced risk of cardiovascular morbidity and mortality (17,18).
Supplementation of at-risk patients with very long-chain (n-3)
fatty acids reduced mortality (1923). In addition, several
noncardiovascular actions of these fatty acids have been
described (Table 1), suggesting that increasing their intake could
reduce the risk of (i.e., protect against) a number of conditions
and may even be used as a treatment. As an example, very long-
chain (n-3) PUFA have been used successfully in rheumatoid
arthritis (24) and, to a lesser extent, in inflammatory bowel
diseases (25) and asthma (16). DHA has an important structural
role in the eye and brain. Consequently, ensuring a good DHA
supply early in life when the brain and eye are developing is
vitally important to optimize visual and neurological develop-
ment (26,27). Very long-chain (n-3) fatty acids may contribute
to enhanced mental development (28) and improved childhood
learning and behavior (29) and may lower the burden of
psychiatric illnesses in adults (30). There also appears to be a
role for very long-chain (n-3) PUFA, especially DHA, in
preventing neurodegenerative disease of ageing (31). The effects
of very long-chain (n-3) PUFA on health outcomes are likely to
be dose dependent, but clear dose response data have not been
identified in most cases.
Plant (n-3) PUFA that are precursors of EPA and DHA (e.g.,
a-linolenic acid and stearidonic acid) appear to share some of
the physiological and functional attributes of very long-chain
(n-3) PUFA (2,4,32,33). These actions of the plant (n-3) PUFA
594S Supplement
appear to derive from their conversion to the biologically active
EPA (2,4,32,33). Therefore, because this conversion is limited,
although greater for stearidonic acid than a-linolenic acid (4),
the biological potency of the plant (n-3) PUFA is less than that
of the very long-chain (n-3) PUFA (2).
Overview of Mechanisms of Action
of (n-3) PUFA
As outlined in the previous section, (n-3) PUFA have multiple
actions. Therefore, they are likely to act via multiple mecha-
nisms. There are 4 general mechanisms by which (n-3) PUFA
could affect cell and tissue behavior to elicit their physiological
actions: 1) (n-3) PUFA could influence metabolite and/or
hormone concentrations that in turn influence cell and tissue
behavior; 2) (n-3) PUFA could influence other factors (e.g.,
oxidiation of LDL; oxidative stress) that in turn influence cell
and tissue behavior; 3) direct effects of (n-3) PUFA on cell
behavior via surface or intracellular fatty acid receptors or
sensors; 4) effects of (n-3) PUFA on cell behavior mediated via
changes in the composition of cell membrane phospholipids.
Actions of (n-3) Fatty Acids Mediated
via Surface or Intracellular Fatty Acid
Receptors or Sensors
Involvement of PPAR
PPAR are transcription factors. They regulate gene expression
and so have a role in cell and tissue responses to the environ-
ment. PPAR act by forming a heterodimer with the retinoic-X-
receptor. The ligand for the retinoic-X-receptor is cis-9-retinoic
acid. PPARa and PPARg are the most well-understood PPAR
isoforms. PPARa is expressed mainly in the liver. It is involved in
regulating hepatic responses to the availability of certain fatty
acids, fatty acid metabolites, and other peroxisome prolifer-
ators. Genes encoding several key enzymes of b-oxidation and
lipoprotein metabolism are regulated by PPARa (34). Conse-
quently, PPARa appears to be important in partitioning fatty
acids toward hepatic oxidation (Fig. 2A). PPARg is expressed in
adipose tissue, where it regulates adipocyte differentiation and
regulates the metabolic responses of adipocytes, including
promoting insulin sensitivity. PPARg is also expressed in
inflammatory cells, where it is involved in regulating the
production of inflammatory mediators, having an antiinflam-
matory action (35) (Fig. 2B). PPAR are activated by noncovalent
binding of ligands that include (n-3) PUFA and various eicos-
anoid mediators (3640). In dendritic cells, DHA induced
PPARg (41) and a number of known PPARg target genes (42).
These effects were linked to decreased production of the
inflammatory cytokines TNFa and IL-6 upon endotoxin stim-
ulation (41). Thus, through activation of PPAR, (n-3) PUFA are
able to regulate metabolism and other cell and tissue responses,
including adipocyte differentiation and inflammation (Fig. 2).
This mechanism might explain some of physiological actions of
(n-3) PUFA, e.g., their ability to lower fasting plasma TG
concentrations, increase insulin sensitivity, and reduce inflam-
mation (Fig. 3).
Interaction with NFkB
NFkB is a key transcription factor involved in inducing the
expression of genes encoding a range of proteins involved in
inflammation, including several cytokines, adhesion molecules,
COX-2, and inducible NO synthase (43,44). In its inactive state,
NFkB is in the form of a trimer present in the cytosol. Activation
of NFkB occurs in response to certain extracellular signals,
including bacterial endotoxin, inflammatory cytokines, UV
irradiation, and oxidative stress. The activation of NFkB
requires that its inhibitory subunit, IkB, is phosphorylated.
This leads to dissociation of IkB from the NFkB trimer. IkB is
then degraded, while the remaining NFkB dimer translocates to
the nucleus (45). Pure EPA and DHA can inhibit the production
of a range of inflammatory proteins, including COX-2, inducible
NO synthase, TNFa, IL-1, IL-6, IL-8, and IL-12 in cultured
FIGURE 2 The PPARa and -g pathways. ACO, acyl CoA oxidase; Adipo, adiponectin; ADRP, adipose differentiation related protein; aP2,
adipocyte protein 2; ApoA, apolipoprotein A; C/EBP, CCAAT/enhancer-binding proteins; COX, cyclooxygenase; CYP4A, cytochrome P450 4A;
FABP, fatty acid binding protein; L, ligand; LPL, lipoprotein lipase; RXR, retinoic acid receptor.
endothelial cells (46,47), monocytes (48,49), macrophages (50),
and dendritic cells (41,51,52). These inhibitory effects of (n-3)
PUFA seem to involve decreased IkB phosphorylation and
decreased activation of NFkB (50,53), effects that appear to
involve a reduction in the activation of key early signaling
proteins such as mitogen-activated protein kinases (54). In
agreement with the in vitro studies, fish oil feeding to laboratory
animals also decreases NFkB activation (55) and production of
inflammatory cytokines (5658). Some studies in healthy human
volunteers involving fish oil supplementation showed decreased
production of TNFa, IL-1b, IL-6, and various growth factors by
monocytes or mononuclear cells that were stimulated with
bacterial endotoxin (5963). These findings indicate that very
long-chain (n-3) PUFA act on inflammatory processes through
inhibiting the activation of NFkB that occurs in response to
exogenous inflammatory stimuli. Although the antiinflamma-
tory effects of (n-3) PUFA on NFkB may involve actions on the
signaling process leading to its activation (54), there is also
an interaction between PPARg and NFkB (Fig. 2). Ligand-bound
(i.e., activated) PPAR interact physically with NFkB, preventing
its translocation to the nucleus (64). Thus, through binding to
PPAR, (n-3) PUFA could act to inhibit upregulation of NFkB
target genes.
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Involvement of G-protein coupled surface receptors
Some GPR can bind certain fatty acids. GPR40 and GPR120 are
both able to bind long-chain fatty acids and both these GPR
activate intracellular signaling pathways. Whereas GPR120 is
highly expressed on adipocytes and inflammatory macrophages,
GPR40 is not expressed on the latter (65). GW9508, which is an
agonist of GPR120, was found to inhibit the response of
cultured macrophages to endotoxin, and this involved mainte-
nance of cytosolic IkB and a decrease in production of TNFa and
IL-6 production, effects that are similar to those of EPA and
DHA. Thus, it appears that GPR120 is involved in antiinflam-
matory signaling. GPR120-mediated gene activation was en-
hanced by EPA and DHA. Furthermore, the ability of DHA to
inhibit responsiveness to endotoxin was abolished in GPR120
knockdown cells. These findings indicate that the inhibitory
effect of DHA (and probably also EPA) on NFkB occurs via
GPR120. Thus, there appear to be at least 2 mechanisms by
(n-3) Mechanisms 595S
FIGURE 3 Mechanisms by which (n-3) PUFA act
via PPAR to improve blood lipids and glucose
control. DPA, docosapentaenoic acid; NEFA, non-
esterified fatty acid; TAG, triglyceride.
which (n-3) PUFA inhibit NFkB activation, one involving
GPR120 and the other involving PPARg, although these may
be linked. Oh et al. (65) also demonstrated that DHA promoted
the translocation of the glucose transporter GLUT4 to the
surface of cultured adipocytes and that this was associated with
enhanced glucose uptake. These effects were abolished by
GPR120 knockout, suggesting that GPR120 mediates some of
the metabolic actions of DHA.
Actions of (n-3) Fatty Acids Mediated
via Changes in the Composition of Cell
Membrane Phospholipids
The roles of fatty acids in cell membrane phospholipids
Fatty acids in the phospholipids of cell membranes play important
roles in assuring the correct environment for membrane protein
function (66), maintaining membrane order (fluidity) (67), and
influencing lipid raft formation (68). Second messengers like
diacylglycerol are produced by enzyme-catalyzed hydrolysis of
membrane phospholipids; the fatty acid composition of such
second messengers, which is determined by that of the precursor
phospholipid, can influence their activity (69). In addition,
membrane phospholipids are substrates for the release of (non-
esterified) PUFA; the released PUFA can act as signaling
FIGURE 4 Overview of the mechanisms by which (n-3) PUFA can
influence cell function. Adapted with permission of (98).
596S Supplement
molecules, ligands (or precursors of ligands) for transcription
factors like PPAR, or precursors for biosynthesis of lipid
mediators, which are involved in regulation of many cell and
tissue responses. Thus, as summarized in Figure 4, changes in
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membrane phospholipid fatty acid composition can influence the
function of cells via alterations in the physical properties of the
membrane such as membrane order and raft structure; effects on
cell signaling pathways that lead to altered transcription factor
activity and changes in gene expression; and alterations in the
pattern of lipid mediators produced, with the different mediators
having different biological activities and potencies.
Cell membrane fatty acid composition is modified
by exposure to (n-3) PUFA
Different plasma lipid pools, cells, and tissues have different,
characteristic, fatty acid compositions. These compositions are
influenced by the availability of different fatty acids but also by
the metabolic characteristics of the particular pool, cell, or
tissue. Dietary supplementation with fish oil results in modifi-
cation of fatty acid profiles, with an increase in the content of
EPA and DHA in plasma lipids, platelets, erythrocytes, leuko-
cytes, colonic tissue, cardiac tissue, and liver tissue. The
incorporation of EPA and DHA occurs in a dose-response
fashion (7076) and these fatty acids often replace (n-6) PUFA
such as arachidonic acid.
(n-3) PUFA alter the production and potency
of eicosanoid and eicosanoid-like mediators
Eicosanoids produced from the (n-6) PUFA arachidonic acid
include various prostaglandins, thromboxanes, and leukotrienes.
These have well-established roles in regulation of inflammation,
immunity, platelet aggregation, smooth muscle contraction, and
renal function (77). Excess or inappropriate production of these
eicosanoids is associated with disease processes. For example,
cysteinyl-leukotrienes derived from arachidonic acid have a
recognized role in the pathology of asthma. Very long-chain
(n-3) PUFA decrease the availability of arachidonic acid as a
substrate for eicosanoid synthesis and they also inhibit arach-
idonic acid metabolism. Thus, very long-chain (n-3) PUFA
decrease production of eicosanoids from arachidonic acid and
so can affect the actions regulated by those mediators (16).
EPA is a substrate for the synthesis of alternative eicosanoids,
which have a different structure from those produced from
arachidonic acid and which are typically less potent (16). This
lower potency may be related to the generally lower ability of the
EPA-derived mediators to interact with relevant eicosanoid
receptors (78). A recent study reported that the EPA-derived
PG D3 could inhibit the action of the arachidonic acid-derived
PG D2 through the DP1 receptor (79). Interestingly, Wada et al.
(78) reported that PG D3 interacted more strongly with the DP1
receptor than did PG D2.
Relatively recently, a new family of lipid mediators, termed
resolvins, synthesized from both EPA (E-series resolvins) and
DHA (D-series resolvins) has been described; related DHA-
derived mediators called protectins have also been described. The
synthesis of resolvins and protectins involves the COX and
lipoxygenase pathways. Cell culture and animal models have
shown potent antiinflammatory, inflammation-resolving, and
immunomodulatory actions of resolvins (8082). For example,
resolvin E1, resolvin D1, and protectin D1 all inhibit trans-
endothelial migration of neutrophils, so preventing the infiltration
of neutrophils into sites of inflammation; resolvin D1 inhibits
IL-1b production and protectin D1 inhibits TNFa and IL-1b
production (8082). Protectin D1 appears to have an important
role in protecting tissue, including neuronal tissue, from excessive
damage in a variety of experimental situations (81) and may be
important in preventing neurodegeneration (83).
(n-3) PUFA influence formation of membrane
signaling platforms called rafts
Lipid rafts are subdomains of cell membranes. They have
a distinct, characteristic composition, being rich in sphingolipids
and cholesterol, and the side chains of the phospholipids
present are usually highly enriched in SFA compared with the
surrounding nonraft regions of the membrane (84). Many
proteins involved in signal transduction are predominantly
found in lipid rafts, which appear to act as signaling platforms
by bringing together (i.e., colocalizing) various signaling com-
ponents in response to a stimulus, so facilitating their interaction
(84). Lipid rafts are potentially modifiable by dietary (n-3) fatty
acids, but it seems that dietary PUFA are not incorporated into
raft lipids, because their low affinity to cholesterol does not
allow this to occur. However, they are incorporated into nonraft
regions and seem to influence raft formation and function from
outside of rafts. In vitro and animal studies suggest that (n-3)
PUFA modulate the structure and composition of lipid rafts in
immune cells, displacing key signaling proteins and altering
intracellular protein trafficking (8594). There is some evidence
that very long-chain (n-3) PUFA affect endothelial function
through mechanisms involving rafts (95,96), whereas exposure
of specific cancer cell lines to (n-3) PUFA results in disruption of
lipid rafts, generation of ceramide from sphingomyelin hydrol-
ysis, expulsion of key receptors, and induction of apoptosis
(68,97). This highlights that (n-3) PUFA might inhibit tumor
growth through effects on membrane rafts.
Summary and Conclusions
(n-3) PUFA are a family of biologically active fatty acids. The
simplest member of this family, a-linolenic acid, can be
converted to the more biologically active very long-chain (n-3)
PUFA EPA and DHA; this process occurs by a series of
desaturation and elongation reactions, with stearidonic acid
being an intermediate in the pathway. Biological activity of
a-linolenic and stearidonic acids most likely relates to their
conversion to EPA. The very long-chain (n-3) PUFA have a range
of physiological roles that relate to optimal cell membrane
structure and cell function and responses. Thus, (n-3) PUFA
play a key role in preventing, and perhaps in treating, many
conditions of poor health and well-being. The multiple actions
of (n-3) PUFA appear to involve multiple mechanisms that
connect the cell membrane, cytosol, and nucleus (Fig. 4). Thus,
(n-3) PUFA act via cell surface and intracellular receptors/
sensors that control cell signaling and gene expression patterns.
Some effects of (n-3) PUFA appear to be mediated by, or at least
are associated with, changes in fatty acid composition of cell
membranes. Changes in these compositions can modify mem-
brane order, lipid raft formation, cell signaling leading to altered
gene expression, and the pattern of lipid and peptide mediator
production. Under typical Western dietary conditions, human
cells are rich in the (n-6) fatty acid arachidonic acid, but the
contents of arachidonic acid and of the (n-3) fatty acids EPA and
DHA can be altered through oral administration of EPA and
DHA. Eicosanoids produced from arachidonic acid have phys-
iological and pathophysiological roles. EPA also gives rise to
eicosanoids and these may have differing properties from those
of arachidonic acid-derived eicosanoids. EPA and DHA give rise
to newly discovered resolvins and protectins that appear to be
extremely potent. Increased membrane content of EPA and
DHA (and decreased arachidonic acid content) results in a
changed pattern of production of eicosanoids and probably also
of resolvins and protectins. Thus, the (n-3) fatty acid content of
Downloaded from jn.nutrition.org by guest on June 20, 2016
human cells influences their function.
Acknowledgments
The sole author had responsibility for all parts of the manu-
script.
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