See

discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/6630679

Essential Fatty Acids - A Review

Article in Current pharmaceutical biotechnology · January 2007

DOI: 10.2174/138920106779116856 · Source: PubMed

CITATIONS READS

226 897

1 author:

Undurti Das
UND Life Sciences
544 PUBLICATIONS 14,969 CITATIONS

SEE PROFILE

Some of the authors of this publication are also working on these related projects:

Diabetes mellitus View project

All content following this page was uploaded by Undurti Das on 23 March 2014.

The user has requested enhancement of the downloaded file.

 Current Pharmaceutical Biotechnology, 2006, 7, 000-000 1

Essential Fatty Acids - A Review

Undurti N. Das*

UND Life Sciences, 13800 Fairhill Road, Shaker Heights, OH 44120, USA

Abstract: Essential fatty acids (EFAs): cis-linoleic acid (LA) and α-linolenic acid (ALA) are essential for humans and
their deficiency is rare in humans due to their easy availability in diet. EFAs are metabolized to their respective long-chain
metabolites: dihomo-gamma-linolenic acid (DGLA), and arachidonic acid (AA) from LA; and eicosapentaenoic acid
(EPA) and docosahexaenoic acid (DHA) from ALA. Some of these long-chain metabolites form precursors to respective
prostaglandins (PGs), thromboxanes (TXs), and leukotrienes (LTs), lipoxins (LXs) and resolvins. EFAs and their metabo-
lites may function as endogenous angiotensin converting enzyme and HMG-CoA reductase inhibitors, nitric oxide en-
hancers, anti-hypertensives, and anti-atherosclerotic molecules. EFAs react with nitric oxide (NO) to yield respective ni-
troalkene derivatives that have cell-signaling actions via ligation and activation of peroxisome proliferator-activated re-
ceptors (PPARs). In several diseases such as obesity, hypertension, diabetes mellitus, coronary heart disease, alcoholism,
schizophrenia, Alzheimer’s disease, atherosclerosis, and cancer the metabolism of EFAs is altered. Thus, EFAs and their
derivatives have significant clinical implications.
Key Words: Essential fatty acids, linoleic acid, alpha-linolenic acid, gamma-linolenic acid, arachidonic acid, eicosapentaenoic
acid, docosahexaenoic acid, prostaglandins, lipoxins, nitric oxide, atherosclerosis, Alzheimer’s disease.

INTRODUCTION
Essential fatty acids (EFAs) are important constituents of
all cell membranes and alter membrane fluidity and thus,
determine and influence the behaviour of membrane-bound
enzymes and receptors. EFAs are essential for survival of
humans and as are not synthesized in the body; have to be
obtained in our diet [1]. EFAs are of two types as they occur
in the body, the ω-6 series derived from cis-linoleic acid
(LA, 18:2) and the ω-3 series derived from α-linolenic acid
(ALA, 18:3). There is another sequence of fatty acids de-
rived from oleic acid (OA, 18:1 ω-9), and OA is not an EFA.
The ω-9, ω-6, and ω-3 series of fatty acids are metabolized
by the same set of enzymes to their respective long-chain
metabolites. Further discussion is centered on ω-6 LA and ω-
3 A fatty acids and their metabolites, since they are the
EFAs. It is important to note that while some of the actions
and functions of EFAs require their conversion to eicosa-
noids and other products, in majority of the instances the
fatty acids themselves are active.
METABOLISM OF EFAs
EFAs are polyunsaturated fatty acids (PUFAs) since they
contain two or more double bonds. There are at least 4 inde-
pendent families of PUFAs. They include:
The “ω -3” series derived from α-linolenic acid (ALA, 18:3,
ω -3).
The “ω -6” series derived from cis-linoleic acid (LA, 18:2, ω
-6).
The “ω -9” series derived from oleic acid (OA, 18:1, ω -9).
*Address correspondence to this author at the UND Life Sciences, 13800
Fairhill Road, #321, Shaker Heights, OH 44120, USA; Tel: 216-231-5548;
Fax: 928-833-0316; E-mail: undurti@hotmail.com
The “ω -7” series derived from palmitoleic acid (PA, 16:1, ω
-7).
LA is converted to γ-linolenic acid (GLA, 18:3, n-6) by
the enzyme Δ6 desaturase (d-6-d) and GLA is elongated to
form dihomo-GLA (DGLA, 20:3, ω-6), the precursor of the
1 series of prostaglandins (PGs). DGLA can also be con-
verted to arachidonic acid (AA, 20:4, ω-6) by the enzyme Δ5
desaturase (d-5-d). AA forms the precursor of 2 series of
PGs, thromboxanes (TXs) and the 4 series of leukotrienes
(LTs). ALA is converted to eicosapentaenoic acid (EPA,
20:5, ω-3) by d-6-d and d-5-d. EPA forms the precursor of
the 3 series of PGs, TXs and the 5 series of LTs. LA, GLA,
DGLA, AA, ALA, EPA and docosahexaenoic acid (DHA,
22:6, ω-3) are all PUFAs, but only LA and ALA are EFAs
(see Fig. 1 for metabolism of EFAs). AA and EPA also are
converted to their respective LTs. PGs, TXs, and LTs are
biologically active and involved in diseases such as athero-
sclerosis, bronchial asthma, inflammatory bowel disease, and
several other inflammatory conditions. In the present discus-
sion, the term “PUFAs” is used to refer to all unsaturated
fatty acids: LA, GLA, DGLA, AA, ALA, EPA, and DHA;
and the term EFAs refers to LA and ALA. Although the
terms EFAs and PUFAs are used interchangeably for the
sake of convenience it should be understood that all EFAs
are PUFAs but all PUFAs are not EFAs. Many actions of
EFAs are also brought about by PUFAs and so EFA-
deficiency can be corrected to a large extent by PUFAs, and
hence, PUFAs are termed as “functional EFAs”. In view of
this, the terms EFAs and PUFAs are used interchangeably.
EFAs/PUFAs play a significant role in collagen vascular
diseases, hypertension, diabetes mellitus, metabolic syn-
drome X, psoriasis, eczema, atopic dermatitis, coronary heart
disease, atherosclerosis, and cancer [2-5]. This is in addition
to the role of PGs and LTs in these conditions. The molecu-
lar mechanism(s) by which various stimuli preferentially

1389-2010/06 $50.00+.00 © 2006 Bentham Science Publishers Ltd.

2 Current Pharmaceutical Biotechnology, 2006, Vol. 7, No. 6
Fig. (1). Scheme showing the metabolism of essential fatty acids and co-factors that enhance the activity of Δ6 and Δ5 desaturases and elon-
gases and formation of PGs. Ethanol blocks both Δ6 and Δ5 desaturases.
(+) Indicates enhancement of the activity of the enzyme or increase in the formation of the product.
(-) Indicates either in the inhibition of the activity of the enzyme or decrease in the formation of the product.
induce the release of AA, EPA and/or DHA and convert
them to their respective products is not clear. AA, EPA and
DHA give rise to anti-inflammatory molecules lipoxins
(LXs) and resolvins that suppress inflammation. Thus, PU-
FAs form precursors to both pro- and anti-inflammatory
molecules and the balance between these mutually antago-
nistic compounds could determine the final outcome of the
disease process. Biologically active compounds formed due
to the nitration of unsaturated fatty acids called as nitrolipids
have also been identified. Nitration of linoleate by nitric ox-
ide-derived reactive species forms novel derivatives includ-
ing nitrolinoleate that stimulates smooth muscle relaxation,
blocks platelet activation, inhibits human neutrophil func-
tions and suppresses inflammation. These studies suggest
that PUFAs have important actions not only by themselves
but also by giving raise to various biologically active com-
pounds.
DIETARY SOURCES OF EFAs
The main dietary sources of EFAs are:
Undurti N. Das
LA: cereals, eggs, poultry, most vegetable oils, whole-grain
breads, baked goods, and margarine. Sunflower, saffola, and
corn oils are rich in LA [1].
ALA: Canola oil, flaxseed oil, linseed and rapeseed oils,
walnuts, and leafy green vegetables. Human milk is rich in
EFAs and GLA, DGLA, AA, EPA, and DHA. Olive oil is
rich in OA, whereas palm and coconut oils contain virtually
none. The average daily intake of EFAs, in general, is
around 7-15 g/day in Europe and USA.
GLA: Human milk contains 0.3-1.0% of its fat as GLA.
Thus, breast fed babies get significant amounts of GLA.
Evening primrose oil (EPO), borage oil, black currant oil,
and hemp seed oil contain substantial amounts of GLA. GLA
is present in EPO at concentrations of 7-14% of total fatty
acids; in borage seed oil it is 20-27%; and in black currant
seed oil at 15-20%. GLA is also found in some fungal
sources.
DGLA: Moderate amounts are found in human milk, liver,
testes, adrenals, and kidneys.
Essential Fatty Acids
AA: Human milk contains modest amounts and cow’s milk
small amounts. Meat, egg yolks, some seaweeds, and some
shrimps contain substantial amounts. Average daily intake of
AA is estimated to be in the region of 100-200 mg/day, more
than enough to account for the total daily production of vari-
ous PGs, which is estimated to be about 1 mg/day.
Adrenic acid (22:44 ω-6): The main sources of adrenic acid
are adrenals, kidneys, testes, and brain.
EPA and DHA: The major source of these two fatty acids is
marine fish. These fatty acids may be denatured and con-
verted into trans fats that are harmful to the body during
processing [6, 7]. Substantial fall in the intake of ω-3 fatty
acids: EPA and DHA could be one of the major changes in
Western nutrition in the last 50 years that contributed to the
increasing incidence of atherosclerosis, CHD, hypertension,
metabolic syndrome X, obesity, collagen vascular diseases
and cancer.
MODULATORS OF METABOLISM OF EFAs
Dietary LA and ALA are metabolized by the enzymes Δ6
and Δ5 desaturases to their respective metabolites as shown
in Fig. (1). LA, ALA, and OA are metabolized by the same
set of Δ6 and Δ5 desaturases and elongases. As a result, these
3 series compete with one another for the same set of en-
zymes, though the enzymes seem to prefer ω-3 to ω-6 and n-
6 over ω-9. Hence, under normal physiological conditions
the metabolites of ω-9 are formed only in trivial amounts in
the cells. Thus, presence of significant amounts of 20:3 ω-9
suggests that there is deficiency of ω-3 and ω-6 and is used
as an indicator of EFA deficiency. The activities of Δ6 and
Δ5 desaturases are slow in humans (Δ5 > Δ6). As a result, the
conversion of LA and ALA to their respective metabolites
may be inadequate under certain conditions. In such in-
stance, it is necessary to supplement GLA and DGLA (to
bypass Δ6 desaturase) and AA and EPA and DHA (to bypass
Δ6 and Δ5 desaturases). Generally, supplementation of AA is
not necessary since; it can be obtained from the diet. Western
diet is rich in ω-6 fatty acids compared to ω-3 fatty acids (ω-
6 to ω-3 ratio is 10:1), whereas the recommended ratio is
~1:1 [1].
Saturated fats, cholesterol, trans-fatty acids, alcohol,
adrenaline, and glucocorticoids inhibit Δ6 and Δ5 desaturases
[1, 8, 9]. Pyridoxine, zinc, nicotinic acid, and magnesium are
co-factors for normal Δ6 desaturase activity. Insulin activates
Δ6 desaturase whereas diabetics have reduced Δ6 desaturase
activity. The activity of Δ6 desaturase falls with age. Onco-
genic viruses and radiation inhibit Δ6 desaturase activity.
Total fasting, protein deficiency, and a glucose-rich diet re-
duce, whereas fat- free diet and partial caloric restriction
enhance Δ6 desaturase activity. Activity of Δ6 and Δ5 desatu-
rases are regulated by sterol regulatory element binding pro-
tein-1 (SREBP-1) and peroxisome proliferator-activated re-
ceptor-α (PPAR-α), two reciprocal transcription factors for
fatty acid metabolism, and some of their (SREBP-1 and
PPAR- α) lipogenic functions are brought about by their ac-
tion on PUFAs [10].
Activities of Δ6 and Δ5 desaturases are decreased in dia-
betes mellitus, hypertension, hyperlipidemia, and metabolic
syndrome X. Trans fats interfere with the metabolism of
Current Pharmaceutical Biotechnology, 2006, Vol. 7, No. 6 3
EFAs and promote inflammation, atherosclerosis and coro-
nary heart disease [1, 11]. The pro-inflammatory action of
trans fats is due to their ability to interfere with EFA metabo-
lism. Several PUFAs, especially EPA and DHA inhibit the
production of pro-inflammatory cytokines: interleukin-6 (IL-
6), tumor necrosis factor-α (TNF-α), IL-1, and IL-2 [1].
Saturated fatty acids and cholesterol interfere with the me-
tabolism of EFAs and thus, promote the production of pro-
inflammatory cytokines, which explains their ability to cause
atherosclerosis and coronary heart disease (CHD). Thus,
trans fats, saturated fats, and cholesterol have pro-inflamma-
tory actions whereas PUFAs possess anti-inflammatory
properties. Interference with the metabolism of EFAs by
saturated fats, cholesterol and trans fats reduces the forma-
tion of GLA, DGLA, AA, EPA, and DHA that are essential
for the formation of biologically beneficial prostacyclin
(PGI2), PGI3, lipoxins, and resolvins. Deficiency and/or ab-
sence of PGI2, PGI3, lipoxins and resolvins initiate and ac-
celerate the progression of atherosclerosis, persistence of
inflammation, CHD and failure of the healing process.
ACTIONS OF EFAS AND THEIR METABOLITES
Cell Membrane Fluidity
Cell membrane fluidity is determined by its lipid compo-
sition: increasing its content of saturated fatty acids and cho-
lesterol renders the membrane more rigid, whereas increas-
ing unsaturated fatty acids makes it more fluid. This is an
important function of lipids since the number of receptors
and their affinity to their respective hormones/growth fac-
tors/ proteins depends on the fluidity of the cell membrane.
For instance, a rigid cell membrane shows reduced number
of insulin receptors and their affinity to insulin that, in turn,
causes insulin resistance. In contrast, increase in cell mem-
brane fluidity due to its high content of unsaturated fatty
acids and reduced cholesterol, increases the number of insu-
lin receptors on the membrane and their affinity to insulin
and thus, decreases insulin resistance [1, 12, 13].
Availability of appropriate amounts of ω-3 and ω-6 fatty
acids and various growth factors is essential for the growth
of brain during the perinatal period and adolescence [1, 14,
15]. Deficiency of ω-3 EPA and DHA and ω-6 AA during
the critical period impairs brain growth and the development
of appropriate synaptic connections that, in turn, could lead
to developmental disorders of the brain and neuropsy-
chological conditions: dementia, depression, schizophrenia,
Alzheimer’s disease, and neurodegenerative diseases: Hunt-
ington’s disease, Parkinson’s disease, spinocerebellar degen-
eration, etc, and may impair memory formation and consoli-
dation.
Second Messenger Action
Growth factors and hormones activate phospholipase A2
(PLA2) leading to the release of DGLA, AA, EPA, and DHA
from the cell membrane lipid pool. Fatty acids thus released
are utilized for the formation of eicosanoids to bring about
some of their actions. For example, the tumoricidal action of
TNF-α is dependent on its ability to induce PLA2, and inhibi-
tors of PLA2 completely inhibited this action. I observed that
TNF-α-resistant tumor cells can be rendered sensitive to
4 Current Pharmaceutical Biotechnology, 2006, Vol. 7, No. 6
TNF-α by the addition of various PUFAs especially, GLA.
PUFAs enhance the activity of protein kinase C (PKC), a
well-known second messenger; activate macrophages, poly-
morphonuclear leukocytes (PMNs), modulate TH1 and TH2
balance, and increase free radical generation by these cells
[1, 16, 17].
PUFAs HAVE ANTI-BACTERIAL, ANTI-VIRAL,
ANTI-FUNGAL, AND ANTI-PARASITIC ACTIONS
Linolenic acid rapidly killed cultures of Staphylococcus
aureus, and hydrolyzed linseed oil (which contains both LA
and ALA) inactivated methicillin-resistant S. aureus. ALA
promotes adhesion of Lactobacillus casei to mucosal sur-
faces and thus, augments their growth. Lactobacilli, in turn,
suppress the growth of pathogenic bacteria like Helicobacter
pylori, Shigella flexneri, Salmonella typhimurium, Pseudo-
monas aeroginosa, Clostridium difficile, and Escherichia
coli. Kodicek [18] showed that both LA and ALA have bac-
teriostatic effect on both gram-positive and gram-negative
bacteria. Lacey and Lord [19] observed that cultures of
Staphylococcus aureus seeded on to human skin were rap-
idly killed after the skin has been covered with ALA and
suggested that it has all the attributes of an ideal anti-
bacterial agent. A variety of bacteria were found to be sensi-
tive to the growth inhibitory actions of LA and ALA in vitro
[20]. Hydrolyzed linseed oil, which contains 52% ALA and
pure ALA were found to be capable of killing methicillin-
resistant Staphylococcus aureus [21]. Both LA and AA were
reported to inactivate animal herpes, influenza, Sendai, and
Sindbis virus within minutes of contact [22]. LA adminis-
tered orally as safflower oil (which contains 76% LA) pro-
duced remission of mycosis fungoides, a rare skin disease of
viral etiology, in dogs that correlated with an increase in the
plasma levels of LA and AA [23]. AA, EPA, and DHA have
been shown to induce death of Plasmodium both in vitro and
in vivo [24]. It is interesting to note that an analog of myris-
tic acid (14:0) showed selective toxicity to African Trypano-
somes [25]. But no studies have been peformed with various
EFAs and their metabolites for such properties. It is possible
that several PUFAs alos may possess such anti-Trypano-
somal action. Furthermore, both prostaglandin E1 (PGE1) and
PGA, derived from DGLA, AA, and EPA, are known to in-
hibit viral replication and behave as anti-viral compounds
[26, 27]. These resuls suggest that EFAs/PUFAs may func-
tion as endogenous anti-viral compounds and could be of
some benefit in AIDS (acquired immunodeficiency syn-
drome) [28-30]. Thus, long-chain polyunsaturated fatty acids
(LCPUFAs) and their products have anti-bacterial, anti-
fungal, anti-viral, and anti-parasitic actions. Lymphocytes
and macrophages contain significant amounts of LCPUFAs
and release them on appropriate stimulation. In addition,
LCPUFAs stimulate NADPH-dependent superoxide produc-
tion by macrophages, neutrophils and lymphocytes that are
capable of killing the invading microorganisms [31].
It will be interesting to study whether local application or
intravenous infusions of PUFAs are of help in the treatment
of various bacterial, viral and fungal infections. Since, neu-
trophils, T cells and macrophages release PUFAs on stimula-
tion; it is possible that this could be one of the defense
mechanisms of the body to fight infections [32-34]. Recent
Undurti N. Das
studies showed that AA, EPA, and DHA could give rise to
anti-inflammatory compounds such as lipoxins (LXs) and
resolvins that are essential to limit and resolve inflammation
[1, 35]. These studies imply that a deficiency of LXs and
resolvins could lead to the perpetuation of inflammation and
tissue damage. In the light of these facts, it will be interest-
ing to study whether a sub-clinical deficiency of LCPUFAs,
decreased formation of LXs and resolvins occurs in subjects
who develop various types of infections and their complica-
tions such as sepsis. Since, LCPUFAs can inactivate envel-
oped viruses including influenza [22, 33], it is probably
worthwhile to study the effect of various fatty acids on bird
flu virus and if so, whether increased intake of these fatty
acids could reduce the risk of flu.
ACE ACTIVITY, ENDOTHELIAL NITRIC OXIDE
GENERATION, AND PUFAs
PUFAs inhibited leukocyte ACE activity [36, 37] sug-
gesting that they could function as endogenous regulators of
ACE activity, and thus regulate the formation of (angio-
tensin-II) Ang-II. PUFAs enhance nitric oxide generation
[38]. Hence, when tissue/cell concentrations of PUFAs are
low the formation of Ang-II will be high whereas that of
endothelial nitric oxide (eNO) will be low. Plasma concen-
trations of PUFA and eNO are low in hypertension, diabetes
mellitus, renal diseases, rheumatoid arthritis, lupus; psoria-
sis, eczema, atopic and non-atopic dermatitis; atherosclero-
sis, insulin resistance, obesity; dementia, schizophrenia, bi-
polar disorders, Huntington’s disease, Alzheimer’s disease;
peptic ulcer disease; and cancer [1, 5, 39-41]. Furthermore, a
25-nucelotide ACE deletion polymorphism increases ACE
activity and such individuals showed a higher risk of devel-
oping stroke, obesity, emphysema, bipolar affective disor-
ders, and cancers [42, 43]. This suggests that an altered ACE
activity and EFA metabolism plays a role in many diseases.
Transgenic rats overexpressing both human renin and
angiotensinogen genes (dTGR) develop hypertension, in-
flammation, and renal failure and showed decreased forma-
tion epoxy-eicosatrienoic acids (5,6-, 8,9-, 11,12- and 14,15-
EETs) and hydroxyeicosa-tetraenoic acids (19- and 20-
HETEs) from AA. These EETs and HETEs inhibited IL-6
and TNF-α-induced activation of NF-κB and prevented vas-
cular inflammation [44] suggesting that AA and other PU-
FAs not only regulate ACE activity and Ang-II levels but
also possess anti-inflammatory properties.
EPA and AA stimulate eNO synthesis [1, 38]. NO has
potent anti-atherosclerotic and anti-inflammatory actions.
Aspirin enhances the formation of eNO through the genera-
tion of epi-lipoxins that may explain its anti-inflammatory
action [45]. Epi-lipoxins that have potent anti-inflammatory
actions enhance the generation of NO that, in turn, prevents
the interaction between leukocytes and the vascular endothe-
lium. NO stimulates the formation of PGI2 from AA [46] and
lipoxins are derived from AA, EPA, and DHA. Aspirin in-
hibits TXA2 formation, a potent platelet aggregator and
vasoconstrictor, and enhances PGI2 formation, a platelet anti-
aggregator and vasodilator, and thus brings about its anti-
atherosclerotic actions. These results emphasize the close
interaction between PUFAs, NO synthase, and COX en-
zymes [47].
Essential Fatty Acids
PUFAs SUPPRESS PRODUCTION OF PRO-INFLAM-
MATORY CYTOKINES
ALA, DGLA, EPA, and DHA; LXs and resolvins sup-
press pro-inflammatory IL-1, IL-2, IL-6, macrophage migra-
tion inhibitory factor (MIF), HMGB1 (high mobility group
box 1) and TNF-α production by T cells and other cells [1,
48-50], and thus could function as endogenous anti-
inflammatory molecules. PGE2, PGF2α, TXA2 and LTs de-
rived from AA also modulate IL-6 and TNF-α production.
These results imply levels of IL-6 and TNF-α at the sites of
inflammation and injury may depend on the local levels of
various PUFAs and eicosanoids formed from them. In par-
ticular, the suppressive action of DHA on IL-1β and TNF-α
production by stimulated human retinal vascular endothelial
cells [51] is interesting since this suggests that it (DHA) and
possibly other PUFAs may be important to prevent athero-
sclerosis, macular degeneration, and diabetic retinopathy.
The ability of EPA and DHA to suppress the production of
pro-inflammatory cytokines and induce their anti-inflam-
matory actions are mediated by their ability to increase
PPAR-γ mRNA and protein activity [52].
IL-1, IL-6, MIF (macrophage migration inhibitory factor)
and TNF-α induce insulin resistance, have cytotoxic actions,
are neurotoxic, and produce cachexia seen in tuberculosis,
cancer, and AIDS. EPA, and other PUFAs ameliorate
cachexia induced by TNF-α in animal tumor models [53].
Lipodystrophy and insulin resistance seen with the use of
retroviral agents is due to increased levels of TNF-α and
decreased concentrations of adiponectin [54]. PUFAs de-
crease TNF-α and enhance adiponectin levels and thus, could
be of benefit to prevent/reverse insulin resistance [1, 55], and
side effects of retroviral drugs.
PUFAs DECREASE HMG-CoA REDUCTASE ACTIV-
ITY
The two sterol regulatory element-binding proteins
(SREBPs): SREBP-1 and SREBP-2, each ~1150 amino acids
in length, control the transcription of the genes for the low-
density lipoprotein (LDL) receptor and 3-hydroxy-3-methyl
glutaryl coenzyme A (HMG-CoA) synthase. The proteolytic
processing of both SREBPs is blocked by sterol overloading
and enhanced when sterols are depleted by statins, the HMG-
CoA synthesis inhibitors. [56]. Cholesterol depletion that
occurs due to the use of statins leads to proteolytic activation
of transcription factors of the SREBPs and also induces
PPAR-γ expression [57], suggesting that PPAR-γ expression
is controlled by SREBPs. Similar to statins, AA, EPA, and
DHA are useful in the treatment of hyperlipidemias, have
anti-proliferative action on tumor cells both in vitro and in
vivo, bind to DNA and regulate the expression of genes and
oncogenes. More importantly, PUFAs are also potent inhibi-
tors of the HMG-CoA reductase enzyme [58, 59]. Statins
have the ability to enhance plasma AA concentrations and
decrease the ratio of EPA to AA significantly [60].
PUFAs have inhibitory effects on SREBP-1a and
SREBP-1c [61]. In CaCo-2 cells, PUFAs decreased gene and
protein expression of SREBP-1 and FAS mRNA by interfer-
ing with LXR activity [62], and in rats PUFAs enhanced
cholesterol losses via bile acid synthesis [63]. In the intes-
tine, dietary PUFAs suppress SREBP-1c mRNA without
Current Pharmaceutical Biotechnology, 2006, Vol. 7, No. 6 5
altering expression of its target genes, fatty acid synthase,
acetyl-CoA carboxylase, or ATP citrate lyase and decreased
intestinal fatty acid synthesis by a posttranscriptional
mechanism independent of the SREBP pathway [64]. Feed-
ing mice on fish oil diet for 2 weeks decreased serum choles-
terol and triacylglycerol levels, by 50% and 60% respec-
tively, hepatic FPP (farnesyl diphosphate synthase, a SREBP
target enzyme that is subject to negative-feedback regulation
by sterols in co-ordination with HMG-CoA reductase) syn-
thase and HMG-CoA reductase mRNAs were decreased by
70% and 40% respectively. PUFAs down regulate hepatic
cholesterol synthesis by impairing the SREBP pathway [65].
PUFAs reduce SREBP-mediated gene transcription by in-
creasing intracellular cholesterol content through the hy-
drolysis of cellular sphingomyelin, and the lipid second mes-
senger ceramide, a product of sphingomyelin hydrolysis,
decreased SRE-mediated gene transcription of SREBP-1 and
SREBP-2 [66].
HMG-CoA reductase catalyzes the synthesis of me-
valonate, which is the rate-limiting step in the mevalonate
pathway. Mevalonate is the precursor of cholesterol and a
variety of isoprenoid containing compounds. These isopre-
noid precursors are necessary for the posttranslational lipid
modification (prenylation) and hence, the function of Ras
and other small GTPases. Hence, inhibition of mevalonate
pathway has the potential to disrupt the function of onco-
genic forms of Ras. This explains the ability of both statins
and PUFAs to suppress Ras activity, anti-proliferative action
and induce apoptosis of tumor cells. In addition, small
GTPases, which are prenylated products of the mevalonate
pathway, have negative control on the expression of BMPs
(bone morphogenetic proteins). In view of this, inhibition of
the mevalonate pathway by PUFAs will prevent the function
of small GTPases and enhance the expression of various
BMPs. Various BMPs are known to be essential for neuronal
growth, proliferation, and differentiation. Thus, PUFAs
modulate brain growth and development, and neuronal dif-
ferentiation. This action is in addition to their (PUFAs) abil-
ity to form an important constituent of neuronal cell mem-
branes and involvement in memory formation and consolida-
tion [14, 15], explaining the beneficial action of PUFAs in
the prevention and treatment of dementia and Alzheimer’s
disease [67-73]. The beneficial actions of PUFAs in Alz-
heimer’s disease, schizophrenia and dementia have been
attributed to the formation of anti-inflammatory compounds
such as lipoxins and resolvins, whose formation is discussed
below.
LIPOXINS, RESOLVINS, AND NEUROPROTECTIN
D1
PUFAs also give rise to LXs and resolvins. Aspirin con-
verts AA, EPA and DHA to form aspirin-triggered 15 epimer
LXs (ATLs) that are potent inhibitors of acute inflammation
[1, 47, 74, 75]. Acetylation of COX-2 by aspirin prevents the
formation of prostanoids, but the acetylated enzyme remains
active in situ to generate 15R-hydroxy-eicosatetraenoic acid
(15R-HETE) from AA that is released and converted by ac-
tivated PMNs to the 15-epimeric LXs [74, 75]. This interac-
tion between endothelial cells and PMNs leading to the for-
mation of 15R-HETE and its subsequent conversion to 15-
epimeric LXs by aspirin-acetylated COX-2 is a protective
6 Current Pharmaceutical Biotechnology, 2006, Vol. 7, No. 6 Undurti N. Das

mechanism to prevent local inflammation on the vessel wall
by regulating the motility of PMNs, eosinophils, and mono-
cytes [1, 74, 75]. Endothelial cells oxidize AA (and possibly
EPA and DHA) via P450 enzyme system to form 11,12-
epoxy-eicosatetraenoic acid(s) that blocks endothelial cell
activation, suggesting that COX-2 enzyme is essential for the
formation of LXs. Deficiency or absence of LXs leads to
interaction between PMN and endothelial cells as a result of
which endothelial damage occurs that results in the initiation
and progression of atherosclerosis, thrombus formation and
coronary artery disease, and persistence of inflammation.
Compounds similar to 15R-HETE and 15-epimeric LXs
are also formed from EPA and DHA. These include conver-
sion of EPA to 18R-HEPE (18R- hydroxy-eicosapentaenoic
acid), 18-HEPE, and 15R-HEPE. Activated human PMNs, in
turn, converted 18R-HEPE to 5,12,18R-triHEPE and 15R-
HEPE to 15-epi-LXA5 by 5-lipoxygenase. Both 18R-HEPE
and 5,12,18R-triHEPE inhibited LTB4-stimulated PMN tran-
sendothelial migration similar to 15-epiLXA4. 5,12,18R-
triHEPE competed with LTB4 for its receptors and inhibited
PMN infiltration, and thus, 5,12,18R-triHEPE suppresses
LT-mediated responses when present at the sites of inflam-
mation [76].
Murine brain cells transformed enzymatically DHA to
17R series of hydroxy DHAs (HDHAs) that, in turn, is con-
verted enzymatically by PMNs to di- and tri-hydroxy con-
taining docosanoids [77]. Similar small molecular weight
compounds (similar to HDHAs) are generated from AA and
EPA. Thus, 15R-hydroxy containing compounds are formed
from AA, 18R series from EPA, and 17R-hydroxy series
from DHA that have potent anti-inflammatory actions and
induce resolution of the inflammatory process and hence are
called “resolvins” (see Fig. 2). Resolvins inhibited cytokine
generation, leukocyte recruitment, leukocyte diapedesis, and
exudate formation. AA, EPA, and DHA-derived resolvins
from acetylated COX-2 are formed due to communication
between endothelial cells and PMNs. Resolvins inhibit brain
ischemia-reperfusion injury [78]. Thus, lipoxins and resolv-
ins formed from AA, EPA, and DHA have cardio-protective,
neuroprotective, and other cytoprotective actions.
Of the several 17-hydroxy-containing bioactive media-
tors derived from DHA that were termed docosatrienes and
17S series resolvins, 10,17S-dihydroxydocosatriene termed
as neuroprotectin D1 (NPD1) that reduced infiltration of
PMNs, showed anti-inflammatory and neuroprotective prop-
erties [78, 79]. NPD1 inhibited oxidative stress-induced

COOH

COOH
Aspirin/COX2 O(O)H

eicosapentaenoic acid 18R-hydro(per)oxy-EPE

COOH
COOH

OOH
OH

RvE2 5S-hydropeoxy, 18R-hydroxy-EPE

OH
OH

OH
COOH COOH
O
OH

RvE1 HO 5,6-epoxy, 18R-hydroxy-EPE

OH

Fig. (2a). Scheme showing the formation of resolvin E (RvE) derived from EPA.
In the endothelial cells, the COX-2 enzyme that has been acetylated introduces an 18R hydroperoxy-group into the EPA molecule (c.f. the
role of aspirin in the biosynthesis of the epi-lipoxins). This is reduced to the corresponding hydroxy compound before a 5S-hydroperoxy
group is introduced into the molecule by the action of 5-lipoxygenase as in the biosynthesis of leukotrienes. A further reduction step pro-
duces 15S,18R-dihydroxy-EPE or resolvin E2. Alternatively, the 5S-hydrpperoxy, 18R-hydroxy-EPE intermediates is converted to a 5,6-
epoxy fatty acids in polymorphonuclear leukocytes I humans and eventually to 5S,12R,18R-trihydroxy-6Z,8E,10E,14Z,16E-eiocsapentaenoic
acid or resolvin E1 by process similar to the formation of leukotrienes in leukocytes.
Essential Fatty Acids Current Pharmaceutical Biotechnology, 2006, Vol. 7, No. 6 7

COOH COOH
HO OH

OH
OH

HO

OH
Resolvin D 1 Resolvin D2

Fig. (2b). Structures of Resolvin D1 and D2. DHA is converted to 17R-resolvins by a similar aspirin-triggered mechanism similar to the
scheme shown in Figure 2a. In the absence of aspirin, COX-2 of endothelial cells converts DHA to 13S-hydroxy-DHA. In the presence of
aspirin, the initial product is 17R-hydroxy-DHA, which is converted to 7S-hydroperoxy, 17R-hydroxy-DHA by the action of a lipoxygenase,
and thence via an epoxy intermediate to epimeric resolvins D1 and D2. An alternative lipoxygenase-generated intermediate, 4S-hydroperoxy,
17R-hydroxy-DHA, is transformed via an epoxide to epimeric resolvins D3 and D4. 17S Resolvins of the D series are produced in cells in
the absence of aspirin by a reaction catalyzed in the first step by a lipoxygenase.

COOH
DHA

COOH
OOH 17S-hydroperoxy-DHA

COOH
O
16, 17-epoxy-docosatriene

OH
OH
17

10 COOH
neuroprotectin D1

Fig. (2c). Scheme showing the synthesis of neuroprotectin D1. Resolvins are generated in brain tissue in response to aspirin treatment, and in
addition docosatrienes termed neuroprotectins are also produced. The lipoxygenase product 17S-hydroperoxy-DHA is converted first to a
16(17)-epoxide and then to the 10, 17-dihydroxy docosatriene denoted as 10, 17 S-DT or NPD1. As with the leukotrienes, there are three
double bonds in conjugation, hence the term ‘triene’, though there are six double bonds in total.

apoptosis of human retinal pigment epithelial cells [80].
Both LXs and NPD1 enhanced wound healing [81], and
promoted brain cell survival via the induction of antiapop-
totic and neuroprotective gene-expression programs [67, 68].
Based on these findings, it is logical to propose that un-
der physiological conditions COX-1 and COX-2 enzymes
induce the formation of beneficial eicosanoids PGE1, PGI2,
and LXs, resolvins, and NPD1 to prevent inflammation.
Failure to produce adequate amounts of LXs, resolvins, and
NPD1 or interference with their action and/or a simultaneous
increase in the production of pro-inflammatory eicosanoids
and cytokines could lead to initiation and persistence of in-
flammation and tissue damage.
NITROLIPIDS
NO can react with PUFAs to yield their respective nitro-
alkene derivatives that can be detected in plasma (see Fig. 3
for the structure of some nitrolipids and their method of de-
tection by MS). These nitroalkene derivatives, termed as
nitrolipids, produce vascular relaxation, inhibit neutrophil
degranulation and superoxide formation, and inhibit platelet
activation [82-84]. Nitrolipids have endogenous PPAR-γ
ligand activity and release NO [85]. These actions of nitrol-
ipids prevent platelet aggregation, thrombus formation and
atherosclerosis, and it is possible that they also possess anti-
inflammatory actions. This implies that nitrolipids may have
a significant role in low-grade systemic inflammatory condi-
tions such as type 2 diabetes, hypertension, hyperlipidemias,
insulin resistance, and metabolic syndrome X. Since, nitrol-
ipids are present both in the plasma and urine in substantial
amounts, it will be interesting to measure their levels in these
conditions. These evidences suggest that PUFAs not only
form precursors to various eicosanoids, resolvins, LXs, and
NPD1 but also react with various other molecules and form
8 Current Pharmaceutical Biotechnology, 2006, Vol. 7, No. 6 Undurti N. Das

O O2N

HO

O NO2

HO

Two regioisomers of OA-NO2: 9- and 10-nitro-9-cis-octadecenoic acids

A.
O O2N OH O OH NO2

-O -O
202 171

B.
O OH NO2 O OH NO2

-O -O
171 211

O O2N OH O O2N OH

-O -O
202 242

C.
O OH NO2 O O2N OH

-O -O
171 242

O O2N OH O HO NO2

-O -O
202 251
O HO NO2 O O2N OH

-O -O
211 282

A= Oleic acid-NO [18:1 (OH)-NO2 ]

B= Linoleic acid-NO [18:2 (OH)-NO2 ]
C= Linolenic acid-NO [18:3 (OH)-NO2]
Some regions of the MS/MS fragmentation patterns are shown above. The 10-nitro regioisomers of 18:1(OH)-NO2 is evident by the intense peak correspond-
ing to m/z 171; Also present are fragments consistent with the 9-nitroregioisomer (m/z 202), loss of a nitro group (m/z 297) and water (m/z 326),
18:2(OH)-NO2 shows a predominant m/z 171 fragment again consistent with an oxidation product of LNO2 nitrated at 10-carbon.
Multiple regioisomers of 18:3(OH)-NO2 are present (see C above).

Fig. (3). Nitrolipids and their detection.

novel compounds that have biological activity. It is not yet
clear whether nitrolipids have any interaction with eicosa-
noids, lipoxins, and resolvins. A study in this direction may
prove to be interesting.
ROLE OF EFAs/PUFAs IN SOME DISEASE PROC-
ESSES
Inflammation
The amount and type of PUFA(s) released in response to
inflammatory stimuli depends on the cell membrane phos-
pholipid fatty acid content. Since LA and ALA can be de-
saturated and elongated to form their long-chain metabolites,
it is reasonable to assume that dietary content EFAs is one
factor that influences the degree of inflammation and its sub-
sequent resolution. PUFAs alter the cell membrane fatty acid
composition that, in turn, modulates cell/tissue response to
infection, injury and inflammatory events. Increased dietary
intake of GLA, DGLA, and EPA/DHA substantially de-
creases inflammatory response. GLA is elongated to form
DGLA that, in turn, is converted to PGE1 and its (DGLA)
15-lipoxygenase product 15-hydroxy-8, 11, 13-eicosatrienoic
Essential Fatty Acids
acid (15-OH-20: 3, ω6), which have anti-inflammatory ac-
tions [86-88]. GLA, DGLA, AA, and EPA inhibited IL-1
and IL-2 production without conversion into their cyclo-
oxygenase pathway products [89, 90]. Cellular phospholipid
concentrations of AA, formation of LTB4, LTC4 /LTD4, 6-
keto-PGF1α (a metabolite of PGI2), and TXB2 levels, mye-
loperoxidase (MPO) activity and neutrophil accumulation
were lower, whereas the concentrations of EPA and DHA
and DGLA were higher with reduced plasma concentrations
of soluble vascular cell adhesion molecule-1 and soluble E-
selectin in experimental animals and patients that received a
combination of GLA and EPA (in the form of a mixture of
evening primrose oil and fish oil) and fish oil rich in
EPA/DHA compared to corn oil control, though no change
in the TNF-α levels between the control endotoxin-treated
rats and the fish oil and fish oil plus borage oil treated groups
was noted [91-94]. It is likely that when the cell membrane
lipid pool is rich in GLA/DGLA/EPA/DHA and contains
appropriate amounts of AA, specific activation of sPLA2 and
cPLA2 (soluble and cytosolic phospholipase A2 respectively)
in response to an inflammatory stimuli would occur that
leads to the formation of increased amounts of LXs, PGD 2
and 15deoxyΔ12-14PGJ2, eNO, GSNO, PGE1, PGI2, PGI3, and
HPETEs that dampen inflammatory process and enhance
resolution of inflammation [95, 96].
DGLA, EPA, and DHA suppress NF-κB signaling [97,
98], whereas AA activates NF- κB [99]. PUFAs serve as
endogenous ligands for PPARs and thus, suppress inflamma-
tory events [100, 101]. Oxidized PUFAs prevented LPS- or
PMA-induced activation of transcription factor NF-κB and
consequent induction of adhesion molecules, and prevented
the binding of monocytes to cultured endothelium due to the
upregulation of adhesion molecules by exposure to LPS, IL-
1α, TNF-α, or phorbol myristate acetate (PMA). The active
principle of oxidized PUFAs was found to be hydroperoxy
fatty acids [102, 103]. This ability of oxidized lipids to in-
hibit the expression of endothelial cell adhesion molecules
could be a natural mechanism whereby inflammation-
mediated oxidation of endothelial PUFAs retard unrestrained
inflammatory responses. Oxidized ω-3 fatty acids inhibit
NF-κB activation via a PPAR-α-dependent pathway.
It is generally believed that increased intake of PUFAs
may enhance lipid peroxidation, and that these oxidized
products are harmful to tissues. But, it was reported that in-
creased intake of EPA/DHA, in fact, reduces in vivo lipid
peroxidation and oxidative stress in humans [104-106].
It is now believed that the central causative event for
several of the most common diseases such as atherosclerosis,
cancer, asthma, collagen vascular diseases such as lupus,
rheumatoid arthritis, and scleroderma; CHD, hypertension,
type 2 diabetes mellitus, obesity, and neuropathological dis-
eases such as schizophrenia, stroke, Alzheimer’s, and Park-
inson’s diseases is low grade systemic inflammation [16,
107]. Hence, understanding factors that initiate, modulate,
perpetuate, and inhibit inflammation are of great signifi-
cance. Recent studies suggest that inflammation to the “nor-
mal” non-inflamed state is not merely the passive termina-
tion of inflammation but rather an actively regulated pro-
gram of resolution [108]. In this context, the interaction be-
tween pro-inflammatory cytokines and anti-inflammatory
Current Pharmaceutical Biotechnology, 2006, Vol. 7, No. 6 9
molecules such as lipoxins and resolvins and their temporal
relationship is interesting. 5S,6R,15S-trihydroxy-7,9,13-
trans-11-cis-eicosatetraenoic acid (LXA4) generated from
AA via the lipoxygenase pathway during cell-cell interaction
and aspirin-triggered 15-epi- LXA4 (ATL), an LXA4 epimer,
are endogenous anti-inflammatory lipid mediators that in-
duce resolution of inflammation acting via G-protein-
coupled receptor, LXA4 receptor [109]. These lipid media-
tors down-regulate PMN infiltration and thus, function as
“breaking signals” to stop inflammation. Both EPA and
DHA also form precursors to di- and trihydroxy-containing
lipid autacoids resolvins, docosatrienes, and neuroprotectins
(see Figs. 1 and 2 for the metabolism of EFAs and formation
of these molecules) that possess potent anti-inflammatory
actions and may serve not only to activate resolution of the
inflammatory process but may also activate the resolution
process and promote return to normalcy. Simultaneous side-
by-side lipidomic and proteomic-based approach [110] using
the standard murine model of self-resolving inflammation
revealed that the initial response (0-12 hours) of inflamma-
tion is composed of PMN influx followed monocyte infiltra-
tion and a transient exudation of serum proteins. During this
early phase also displayed formation (0-4 hours) of both
LTB4 and LXA4 from AA that showed identical kinetics. At
the same time (2 hours), unesterified AA, EPA, and DHA
was found in the inflammatory exudate presumably released
due to the involvement of calcium-insensitive iPLA2. During
this time (2 hours), S100A9, a cytosolic PMN protein that
can be secreted and exhibits potent actions on inflammatory
cell recruitment and a known AA-binding protein, was pre-
sent in the inflammatory exudate from the initiation of in-
flammation till the onset of resolution paralleling the PMN
infiltration time course and decreased by 24 hours. Serum
proteins plasminogen, fibrinogen, serum albumin, and α1 -
macroglobulin were abundant in inflammatory exudates 4
hours after the initiation of inflammation. α1-macroglobulin
binds to tissue-plasminogen activator and may also bind to
pro-inflammatory cytokines [111] present in the inflamma-
tory exudate and thus, may help to lower their effective local
concentrations and initiate the onset of resolution. The dis-
tinct events observed during the phase of resolution of in-
flammation include: (a) an increase in the levels of hapto-
globin whose purpose seems to be to prevent oxidative dam-
age, (b) activation of CD163, a scavenger receptor that has
the ability to trigger anti-inflammatory pathways [112], (c)
an increase in inflammatory exudate 10,17S-docosatriene,
(d) a remarkable rise in the concentrations of TGF-β due to
its release from macrophages, and (d) an increase in PGE2
levels at the beginning of resolution and a decline during the
active phase of resolution with an increase in the levels of
PGD2 coinciding with the decrease in PGE2 (at 24 hours).
Based on these findings it is apparent that both PGE2 and
PGD2 switch eicosanoid biosynthesis from predominantly
“pro-inflammatory” LTB4 to “anti-inflammatory” LXA4 pro-
duction that suppresses PMN infiltration at the site of in-
flammation. It is noted that some of these temporal events
could be different during TNF-α-induced inflammatory
process suggesting that the different kinetics in eicosanoid
generation may reflect the nature of the experimental models
used and/or stimulus-specific signaling pathways. Neverthe-
less, it is clear that ATLa inhibits PMN infiltration and pro-
inflammatory cytokine and chemokine release, and enhances
10 Current Pharmaceutical Biotechnology, 2006, Vol. 7, No. 6
TGF-β release, whereas resolvin E1 and 10,17S-docosatriene
activated and shortened and thus, accelerated resolution and
the healing process.
In this context, it should be noted that (a) LXA4 potently
inhibited TNF-α-induced IL-8 release [113], whose receptor
(LTA4 receptor) is induced by IL-13 and IFN-γ; (b) LXA4
and ATLa inhibited TNF-α secretion from activated T cells
[114], and LXA4 suppressed IL-12-induced responsiveness
of murine splenic dendritic cells after microbial stimulation
[115]. IL-12 production by antigen presenting cells (APCs)
is essential for the induction of IFN-γ that mediates host re-
sistance to bacterial and protozoan intracellular pathogens.
Both LXA4 and LXB4 inhibit neutrophil chemotaxis, NK
(natural killer) cell cytotoxicity, monokine and metalloprote-
inase production, TNF-α-induced superoxide anion, IL-1β,
and macrophage inflammatory protein-2 production by neu-
trophils [115]. These evidences suggest that lipoxins and
resolvins could be potent immunosuppressors.
The various anti-inflammatory products such as lipoxins
and resolvins formed from AA/EPA/DHA may explain the
beneficial actions of EPA/DHA noted in several clinical
conditions and the anti-inflammatory actions of aspirin. The
ability of EPA/DHA supplementation and aspirin use to pre-
vent CHD could be attributed to the formation of various
lipoxins and resolvins. It is possible that there may be indi-
vidual differences in their ability to form various lipoxins
and resolvins that may explain the differences in the benefits
noted with the use of EPA/DHA and aspirin that could be
attributed to the genetic differences in the expression and
activation of enzymes concerned with their synthesis and
degradation. Decreased production of lipoxins and resolvins
could be responsible for the low-grade inflammation seen in
obesity, hypertension, type 2 diabetes, metabolic syndrome
X, CHD, atherosclerosis, and persistent inflammation ob-
served in collagen vascular diseases such as lupus, rheuma-
toid arthritis and scleroderma. In contrast, immunosuppres-
sion seen in leprosy, miliary tuberculosis, some bacterial and
protozoal infections might be due to inappropriate produc-
tion of lipoxins and resolvins.
Atherosclerosis
Atherosclerosis is a disease of low-grade systemic in-
flammation [116] and is closely linked to the integrity of
endothelial cells. Healthy endothelial cells synthesize and
release adequate amounts of GLA/DGLA/EPA/DHA, NO,
PGI2, PGI3, PGE1, and possibly, lipoxins and resolvins to
prevent platelet aggregation on their surface, prevent inap-
propriate expression of adhesion molecules, and production
of pro-inflammatory cytokines. Pro-inflammatory cytokines
IL-1, IL-2, IL-6, and TNF-α induce oxidant stress Shear
stress, hyperglycemia, clinical or sub-clinical infections, and
low-grade systemic inflammation as seen in type 2 diabetes
mellitus, hypertension, hyperlipidemia, and metabolic syn-
drome X could induce the production of pro-inflammatory
cytokines. EPA/ DHA/GLA and HDL suppress IL-6 and
TNF-α synthesis and secretion, inhibit free radical generation
and adhesion molecule expression, enhance eNO generation
and thus, prevent oxidant stress [117]. This suggests that
endothelial cell deficiency of GLA/ DGLA/EPA/DHA might
increase the production of pro-inflammatory cytokines and
Undurti N. Das
free radicals that results in the development of insulin resis-
tance; decrease in plasma and cellular HDL concentrations,
and decrease the formation of eNO, PGE1, PGI2, PGI3, LXs,
resolvins, and NPD1 that may ultimately initiate and per-
petuate atherosclerosis.
Normally a balance is maintained between pro- and anti-
inflammatory cytokines and eicosanoids, and pro- and anti-
platelet aggregation-inducing molecules such that atheroscle-
rosis is prevented. For instance, TXA2 is a platelet aggrega-
tor and vasoconstrictor; whereas PGI2 has opposite actions.
PGI2 prevents whereas TXA2 promotes atherosclerosis [118].
Both PGE2 and PGI2, formed from AA, participate in the
pathogenesis of RA (rheumatoid arthritis). PGI receptor de-
ficient (IP-/-) mice exhibited significant reduction in arthritic
scores, reduction in IL-1β and IL-6 levels in the arthritic
paws when were subjected to collagen-induced arthritis. Ad-
dition of IP agonist to cultured synovial fibroblasts enhanced
IL-6 production. In contrast, inhibition of PGE receptor sub-
type (EP2 or EP4) alone did not affect inflammatory events
in collagen-induced arthritis, whereas suppression of arthritis
occurred when both EP2 and EP4 receptors were inhibited,
suggesting that both PGE2 and PGI2 participate in RA [119].
These results emphasize the fact that the type of products
formed from various PUFAs determines the final outcome of
any physiological and pathological process.
In this context, the interaction between various PUFAs is
particularly important. In perfused vascular tissue, DGLA
and AA increased the conversion of EPA to PGI3, a vasodila-
tor and platelet anti-aggregator [120-122], whereas orally
administered EPA enhanced AA conversion to PGI2 [123]
and inhibited the activity of Δ6 and Δ5 desaturases (Δ6 > Δ5 )
which resulted in enhanced tissue levels of DGLA as a result
of decreased conversion of DGLA to AA. The enhanced
levels of DGLA could lead to an increase in the formation of
PGE1, a vasodilator and platelet anti-aggregator. This close
interaction between DGLA, AA, and EPA [124] implies that
optimal levels of DGLA, AA, EPA, and DHA need to be
present in the tissues to optimize the formation of various
beneficial eicosanoids and lipoxins and resolvins to prevent
atherosclerosis (Fig. 4).
Fetal-Alcohol Syndrome
Ethanol exposure during brain development induces neu-
rodevelopmental defects referred to as fetal-alcohol syn-
drome (FAS) that is characterized by hyperactivity, learning
and memory deficits, mental retardation, psychosis, depres-
sion, and schizophrenia. Ethanol-induced neurotoxicity, oxi-
dative stress, induction of apoptosis, excitotoxicity, interfer-
ence with the action of growth factors, and EFA metabolism
may all could be responsible for the development of FAS.
Neurons are susceptible to ethanol-induced apoptotic cell
death during synaptogenesis during brain growth spurt,
which occurs during the third trimester of pregnancy and
perinatal period.
Recent studies showed that nicotinamide enhanced neu-
ronal survival following free radical exposure and oxidative
stress [125]. The mechanism of nicotinamide-mediated neu-
roprotection has been attributed to inhibition of caspase-3
and release of cytochrome-c from mitochondria during oxy-
gen-glucose deprivation [126]. Subsequent studies showed
Essential Fatty Acids
Fig. (4). Scheme showing interaction(s) between ω-3 and ω-6 fatty acids and their effect on the formation of PGI2, PGI3, PGE1, and LXs,
resolvins and NPD1.
(-) Indicates inhibition or block in the synthesis, formation or release.
(+) Indicates enhancement in the formation or release.
It is proposed that LXs, resolvins, and NPD1 enhance the formation and/or action of PGI2, PGI3 and suppress that of TXA2 and TXA 3 thus
may prevent atherosclerosis and show their cytoprotective actions. LXs, resolvins and NPD1 suppress formation of LTs.
that nicotinamide can prevent deleterious effects of ethanol
on the developing mouse brain when given shortly after
ethanol exposure which led to the suggestion that nicotina-
mide may hold promise as preventive therapy of FAS [127].
Nicotinamide is a co-factor in the metabolism of EFAs,
which could explain the beneficial action of nicotinamide in
FAS.
EFAs are not only structural components of the brain but
also influence nerve conduction, transmitter release and ac-
tion [128]. Prostaglandins (PGs) derived from EFAs modify
nerve conduction and transmitter function. Ethanol (a) re-
duces blood linoleic acid (LA) levels; (b) blocks conversion
of LA and ALA to AA, and EPA and DHA respectively by
inhibiting Δ6 and Δ5 desaturases; and (c) enhances the con-
version of DGLA to PGE1 [128]. Ethanol enhanced IL-6 and
TNF-α production suggesting that immunological mecha-
nisms play a role in ethanol-induced diseases. Cerebral cor-
tex from chronic ethanol-fed rats showed up-regulation of
inducible nitric oxide (iNOS), COX-2, IL-1β, and activation
of transcription factors NF-κB and AP-1, effects that in-
creased both caspase-3 and apoptosis [129]. Brains of etha-
nol treated mice show raised phospholipase A2 and phos-
pholipase C activity [130] that can cause the release of AA,
EPA, and DHA from membrane phospholipids. LXs, resolv-
ins, and NPD1 formed from AA, EPA, and suppress IL-6 and
TNF-α production [47, 110]. PGs, LXs, resolvins, and NPD 1
precursor supplies are limited; therefore when ethanol con-
Current Pharmaceutical Biotechnology, 2006, Vol. 7, No. 6 11
sumption is substantial, tissue concentrations of PUFAs de-
cline leading to fall in the synthesis of various PGs, LXs,
resolvins, and NPD1. This is supported by our recent obser-
vation that in rats fed alcohol, the plasma levels of lipoxins
and resolvins is decreased whereas those of TXs and LTs are
increased (unpublished data).
DHA and other PUFAs released from the membrane in
response to neurotransmitters [131] activate RXR as PUFAs
form ligands for RXR receptor [132]. DHA deficiency re-
sults in impaired spatial learning and other abnormalities
[133]. RXR heterodimerization partners PPARs, liver X re-
ceptors, and farnesoid X receptors that are essential for regu-
lating energy and nutritional homeostasis. PUFAs being
ligands for RXR and PPARs modulate these and other regu-
latory events by binding to these nuclear receptor heterodi-
mers.
AA, DHA, EPA, and LXs, resolvins, and NPD1 have
neuroprotective actions [47, 68, 78, 80], inhibit IL-6 and
TNF-α production that are neurotoxic, and increase synthesis
of endothelial nitric oxide (eNO), a neurotransmitter. When
neurons are depleted of their PUFA content, as happens after
high alcohol intake, formation of LXs, resolvins, and NPD 1
will be suboptimal and hence, neuronal death induced by
TNF-α cannot be antagonized. This results in FAS. Thus,
nicotinamide by augmenting the action of Δ6 desaturase and
enhancing the formation of various PUFAs and their prod-
12 Current Pharmaceutical Biotechnology, 2006, Vol. 7, No. 6
ucts [134] may be able to bring about its neuroprotective
action against ethanol induced FAS.
In addition, EPA and AA protected heart against ische-
mia/reperfusion-induced injury by inhibiting caspase-3 acti-
vation and PARP-cleavage and reducing the apoptotic index
during reperfusion by increasing ERK phosphorylation and
decreasing p38 phosphorylation during reperfusion [135].
DHA promoted neuronal survival by facilitating membrane
translocation/activation of Akt. In vivo reduction of DHA by
dietary depletion increased hippocampal neuronal suscepti-
bility to apoptosis [70]. Retinal pigment epithelium and syn-
aptic membranes contain the highest content of DHA of all
cell membranes, and DHA is required for retinal pigment
epithelium functional integrity. NPD1 that is formed from
DHA upon its release from the cell membrane by the action
of phospholipase A2 counteracted H2O2/TNF-α-induced
apoptosis by upregulating anti-apoptotic proteins Bcl-2 and
Bcl-XL and decreasing pro-apoptotic Bax and Bad proteins.
In addition, NPD1 inhibited oxidative stress-induced caspase-
3 activation, IL-1β-stimulated expression of cyclo-oxygen-
ase-2 and thus, prevented oxidative stress-induced apoptosis
and inflammation [80]. EFA deficiency promotes respiratory
uncoupling [136, 137]. Mild respiratory uncoupling-a form
of mitochondrial dysfunction-increases oxidative stress and
decreases nitric oxide availability or biological action [138].
Furthermore, PUFAs modulate the activities of uncoupling
proteins [5], and under certain specific conditions PUFAs
function as anti-oxidants and prevent free radical-induced
damage to cells [139, 140]. PUFAs have the ability to modu-
late the expression, properties, and action dopamine, sero-
tonin, and acetylcholine [141-147], especially during the
perinatal period during which the growth and development
of brain is critical [14, 15]. This evidence suggests that PU-
FAs, especially EPA/DHA could be of benefit in the preven-
tion and treatment of FAS.
Metabolic Syndrome X
Metabolic syndrome X is characterized by abdominal
obesity, atheroslcerosis, insulin resistance and hyperinsu-
linemia, hyperlipidemias, essential hypertension, type 2 dia-
betes mellitus, and coronary heart disease (CHD). Plasma
levels of C-reactive protein (CRP), TNF-α, and IL-6, mark-
ers of inflammation, are elevated in subjects with obesity,
insulin resistance, essential hypertension, type 2 diabetes,
and CHD, suggesting that metabolic syndrome X is a low-
grade systemic inflammatory condition [148].
EPA, DHA, and AA, inhibit TNF-α and IL-6 production;
enhance eNO generation, inhibit 3-hydroxy-3-methylglutaryl
coenzyme A (HMG-CoA) reductase and angiotensin con-
verting enzyme activities, function as endogenous ligands for
PPARs, and modulate leptin gene expression [1, 5, 37, 58-
60, 149, 150]. Thus, PUFAs suppress inflammation, regulate
cholesterol metabolism, enhance the production of adi-
ponectin, and decrease insulin résistance. This may explain
why and how PUFAs are useful in protection against CHD,
atheroslcerosis, and decrease blood pressure. PUFAs bind to
PPARs (similar to thiazolidinediones) and thus, enhance
adiponectin levels [151] that, in turn, improve insulin resis-
tance. Furthermore, (i) hypertension and insulin resistance
was ameliorated in experimental animals by feeding them
Undurti N. Das
with EPA- and DHA-rich oil; (ii) highly purified EPA re-
duced insulin resistance and decreased the incidence of type
2 diabetes in experimental animals; and (iii) decreased con-
centrations of EPA, DHA and AA in skeletal muscle phos-
pholipids was found to be associated with decreased insulin
sensitivity in humans [1, 152-155]. I observed that plasma
phospholipid concentrations of EPA, DHA and AA were low
in subjects with hypertension, diabetes mellitus and CHD
[156]. Metabolic syndrome X is uncommon in Greenland
Eskimos whose traditional diet is rich in EPA and DHA,
whereas South Asian Indians, who are at high risk of devel-
oping metabolic syndrome X, have significantly lower con-
centrations of AA, EPA, and DHA compared to healthy Ca-
nadians and Americans [157]. These observations suggest
that PUFAs, cytokines, and NO interact with each other and
play an important role in the pathobiology of metabolic syn-
drome X [1-3]. There is evidences to suggest that PUFAs by
their ability to influence brain growth and development, hy-
pothalamic neurons, and the secretion and actions of various
neuropeptides and their receptors and insulin receptors in
various regions of the brain during the perinatal period may
have significant impact on the development of obesity, hy-
pertension, type 2 diabetes, metabolic syndrome X, CHD,
and atherosclerosis in adult life [1-5, 73, 107].
SCHIZOPHRENIA, HUNTINGTON’S DISEASE, AND
ALZHEIMER’S DISEASE
Low-grade systemic inflammation seems to play a sig-
nificant role in the pathobiology of schizophrenia,
Huntington’s disease and Alzheimer’s disease. In patients
with schizophrenia, both circulating and cerebrospinal fluid
(CSF) concentrations of pro-inflammatory cytokines are in-
creased and the plasma phospholipid concentrations of EPA
and DHA are decreased. Supplementation of EPA (espe-
cially ethyl EPA) was reported to be of some benefit to these
patients [reviewed in 158, 159].
It was reported that diet high in DHA slowed the pro-
gression of Alzheimer's disease in mice. Specifically, DHA
cut the harmful brain plaques that mark the disease. Mice
genetically altered to develop Alzheimer's disease, when
were fed with DHA-fortified chow had 70-percent less
buildup of amyloid protein in the brain compared with con-
trol or DHA-deficient mice [67-69]. DHA protected against
damage to the "synaptic" areas and enabled mice to perform
better on memory tests. These studies indicate that increased
intake of DHA could be of benefit in people who are geneti-
cally or otherwise predisposed to develop the disease.
Huntington’s disease is an inherited neurodegenerative
disorder due to a mutation in exon 1 of the Huntingtin gene
that encodes a stretch of polyglutamine (poly Q) residues
close to the N-terminus of the Huntingtin protein. Aggre-
gated poly Q residues are toxic to the neuronal cells. Trans-
genic R6/1 mice that develop late-onset neurologic deficits
similar to the motor abnormalities of Huntington’s disease
seen in humans showed increased survival rates and de-
creased neurologic deficits when were supplemented with
PUFAs, especially ethyl EPA [41], suggesting that unsatu-
rated fatty acids may prevent or arrest poly Q aggregation.
These results suggest that PUFAs, in general, are useful in
the treatment of various neurological diseases. Some of the
Essential Fatty Acids
beneficial actions of these PUFAs in neurological diseases
could be due to the increased formation of lipoxins and re-
solvins that have neuroprotective actions. But, it is not clear
why and how a particular fatty acid is useful only in a spe-
cific neurological condition. For instance, DHA is useful in
Alzheimer’s disease whereas ethyl EPA is of benefit in
Huntington’s disease and schizophrenia. More research is
needed to understand the molecular mechanisms of action of
EPA/DHA in these neurological conditions.
CONCLUSIONS
It is evident from the preceding discussion that EFAs and
their metabolites including eicosanoids, LXs, resolvins, and
NPD1 have many biological actions and participate in sev-
eral diseases processes (Fig. 5).
Fig. (5). Scheme showing the relationship between various mediators of tissue damage/resolution and clinical conditions and the role of PU-
FAs and their metabolites in these processes.
Current Pharmaceutical Biotechnology, 2006, Vol. 7, No. 6 13
Recently it was reported that PUFAs participate in athe-
rosclerosis by modulating the expression of uncoupling pro-
tein-1 (UCP-1) in the vascular tissue. Oxidative stress is
known to play a major role in atherosclerosis. Mitochondrial
electron transport accounts for most of the reactive oxygen
species (ROS) generated. Uncoupling proteins (UCPs) (inner
mitochondrial membrane anion transporters) allow protons
to leak back into the mitochondrial matrix, thereby decreas-
ing energy available for ROS generation. Superoxide anion
activates UCPs [160], which limits further superoxide anion
generation by dissipating protonmotive force. Uncoupling
decreases glucose-induced ROS formation, and thus prevents
vascular damage in cultured endothelial cells [161]. Respira-
tory uncoupling is increased in the aortae of pigeons suscep-
tible to atherosclerosis [162]. Smooth muscle cells are a ma-
jor source of ROS in the vasculature [163]. It was reported
14 Current Pharmaceutical Biotechnology, 2006, Vol. 7, No. 6
that UCP-1 expression in aortic smooth muscle cells pro-
duced hypertension, increased high fat diet-induced athero-
sclerosis without affecting cholesterol levels, enhanced su-
peroxide anion production, and decreased the availability of
nitric oxide, suggesting that mild respiratory uncoupling due
to mitochondrial dysfunction causes atherosclerosis [164].
EFA deficiency promotes respiratory uncoupling [165-167]
and atherosclerosis [117, 168]. Atherosclerosis-free aortae
have abundant amounts of EFA linoleate, whereas fatty
streaks of early atherosclerosis are deficient in EFAs [169,
170]. Pro-inflammatory eicosanoids stimulate the formation
and the activity of adhesion molecules (integrins), and thus,
promote atherosclerosis and inflammation, whereas GLA,
DGLA, EPA, and DHA, and their products such as LXs,
resolvins, and NPD1 suppress the expression of adhesion
molecules and thus, inhibit atherosclerosis and inflammation.
LTB4, a 5-lipoxygenase (5-LO) product derived from
AA, is a potent leukocyte chemoattractant, a pro-
inflammatory molecule, and participates in atherosclerosis
through its receptors BLT-1 and BLT-2. LTB4 promotes
atherosclerosis by chemo-attracting monocytes, and enhanc-
ing the formation of foam cells [171]. It was reported that the
expression of 5-LO is elevated in symptomatic compared
with asymptomatic plaques [172], suggesting that LTB4 has
an important role in atherosclerosis.
DHA constitutes about 30 to 50% of total fatty acids in
the mammalian brain, where it is predominantly associated
with membrane phospholipids [1, 14, 173, 174]. PUFAs
serve as ligands for RXR receptor. DHA is essential for
brain growth, development, and maturation, and DHA defi-
ciency results in impaired spatial learning as well as other
abnormalities [14, 175-177], defects that are also seen in
RXRγ-deficient mice [178]. DHA reduces blood cholesterol
and enhances insulin sensitivity, actions that are also seen
with synthetic RXR ligands [179, 180], implying that DHA
brings about its actions by RXR activation. Several RXR
heterodimerization partners such as PPARs, the liver X re-
ceptors, and farnesoid X receptors are essential for regulating
energy and nutritional homeostasis. Since DHA serves as a
ligand for RXR and PPARs, it is likely that it (DHA) modu-
lates these and several other regulatory events by binding to
these nuclear receptor heterodimers.
Since several biologically active molecules are formed
from PUFAs, it is important to know the molecular triggers
that facilitate their formation and understand their actions in
various diseases. If methods to selectively enhance the syn-
thesis of desirable molecules such as LXs, resolvins, NPD1,
nitroalkenes are developed, then it may be possible to sup-
press inappropriate inflammation. Possible use of LXs and
resolvins and/or their structural analogues in the manage-
ment of asthma, metabolic syndrome X, neurodegenerative
conditions, stroke, CHD, psoriasis, collagen vascular dis-
eases, and cancer need to studied.
REFERENCES
[1] Das, U. N. (2006) Biotech. J. 1, 420-439.
[2] Das, U. N.; Mohan, I. K.; Raju, T. R. (2001) Prostaglandins Leu-
kot. Essen. Fatty Acids 65, 197-203.
[3] Das, U. N. (2004) Eur. J. Clin. Nutr. 58, 195-203.
[4] Das, U. N. (2003) Eur. J. Clin. Nutr. 57, 218-226.
Undurti N. Das
[5] Das, U. N. A Perinatal Strategy for Preventing Adult Diseases: The
Role of Long-Chain Polyunsaturated Fatty Acids. Kluwer Aca-
demic Publishers, Boston, 2002.
[6] Cantwell, M. M.; Flynn, M. A.; Cronin, D.; O’Neill, J. P.; Gibney,
M. J. (2005) J. Hum. Nutr. Diet. 18, 377-385.
[7] Lopez-Garcia, E.; Schultze, M. B.; Meigs, J. B.; Manson, J. E.;
Rifai, N.; Stampfer, M. J.; Willett, W. C.; Hu, F. B. (2005) J. Nutr.
135, 562-566.
[8] Mozaffarian, D.; Pischon, T.; Hankinson, S. E.; Rifai, N.;
Joshipura, K.; Willett, W. C.; Rimm, E. B. (2004) Am. J. Clin.
Nutr. 79, 606-612.
[9] Brenner, R. R. (1982) Prog. Lipid Res. 20, 41-48.
[10] Matsuzaka, T.; Shimano, H.; Yahagi, N.; Amemiya-Kudo, M.;
Yoshikawa, T.; Hasty, A. H.; Tamura, Y.; Osuga, J.; Okazaki, H.;
Iizuka, Y.; Takahashi, A.; Sone, H.; Gotoda, T.; Ishibashi, S.; Ya-
mada, N. (2002) J. Lipid Res. 43, 107-114.
[11] Cook, H. W. (1981) Lipids 16, 920-926.
[12] Das, U. N. (2005) Prostaglandins Leukot. Essen. Fatty Acids 72,
343-350.
[13] Coetzer, H.; Claassen, N.; van Papendorp, D. H.; Kruger, M. C.
(1994) Prostaglandins Leukot. Essen. Fatty Acids 50, 257-266.
[14] Das, U. N. (2003) Nutrition 19, 62-65.
[15] Calderon, F.; Kim. H. Y. (2004) J. Neurochem. 90, 979-988.
[16] Das, U. N. (2006) Med. Sci. Res. 12, RA99-RA111.
[17] Das, U. N. (2006) Adv. Clin. Chem. 41, 189-229.
[18] Kodicek, E. (1949) Symposia Soc. Exp. Biol. 3, 217-232.
[19] Lacey, R.W.; Lord, V.L. (1981) J. Med. Microbiol. 14, 41-49.
[20] Galbraith, H.; Miller, T.B.; Paton, A.M.; Thompson, J.K. (1971) J.
Appl. Bact. 34, 803-813.
[21] McDonald, M.I.; Graham, I.; Harvey, K.J.; Sinclair, A. (1981)
Lancet 2, 1056.
[22] Kohn, A.; Gitelman, J.; Inbar, M. (1980) Arch. Virol. 66, 301-307.
[23] Iwamoto, K.S.; Bennett, L.R.; Norman, A.; Villalobos, A.E.; Hut-
son, C.A. (1992) Cancer Lett. 64, 17-22.
[24] Krugloak, M.; Deharo, E.; Shalmiev, G.; Sauvain, M.; Moretti, C.;
Ginsburg, H. (1995) Exp. Parasitol. 81, 97-105.
[25] Doering, T.L.; Raper, J.; Buxbaum, L.U.; Adams, S.P.; Gordon,
J.I.; Hart, G.W.; Englund, P.T. (1991) Science 252, 1851-1854.
[26] Giron, D.J. (1982) Proc. Soc. Exp. Biol. Med. 170, 25-28.
[27] Santoro, M.G.; Benedetto, A.; Carruba, G.; Garaci, E.; Jaffe, B.M.
(1980) Science 209, 1032-1034.
[28] Das, U.N. (1985) Canadian Med. Assoc. J. 132, 900.
[29] Das, U.N. (1985) Canadian Med. Assoc. J. 132, 1350.
[30] Das, U.N. (2005) Med. Sci. Monit. 11, RA 206-RA211.
[31] Bromberg, Y.; Pick, E. (1984) Cell Immunol. 88, 213-221.
[32] Sun, C. Q.; O’Connor, C. J.; Robertson, A. (2003) FEMS Immunol.
Med. Microbiol. 36, 9-17.
[33] Das, U. N. (2006) Am. J. Clin. Nutr. 83, 390-391.
[34] Giamarellos-Bourboulis, E. J.; Mouktaroudi, M.; Adamis, T.;
Koussoulas, V.; Baziaka, F.; Perrea, D.; Karavannacos, P. E.; Gia-
marellou, H. (2004) Antimicrob. Agents Chemother. 48, 4713-
4717.
[35] Serhan, C.N.; Hong, S.; Gronert, K.; Colgan, S.P.; Devchand, P.R.;
Mirick, G.; Moussignac, R-L. (2002) J. Exp. Med. 196, 1025-1037.
[36] Das, U.N. (2005) Med. Sci. Monit. 11, RA155-RA162.
[37] Kumar, K.V.; Das, U. N. (1997) Proc. Soc. Exp. Biol. Med. 214,
374-379.
[38] Okuda, Y.; Kawashima, K.; Sawada, T.; Tsurumaru, K.; Asano,
M.; Suzuki, S.; Soma, M.; Nakajima, T.; Yamashita, K. (1997)
Biochem. Biophys. Res. Commun. 232, 487-491.
[39] Das, U. N.; Mohan, I. K.; Raju, T. R. (2001) Prostaglandins Leu-
kot. Essen. Fatty Acids 65, 197-203.
[40] Das, U. N. (1995) Prostaglandins Leukot. Essen. Fatty Acids 52,
387-391.
[41] Das, U. N.; Vaddadi, K. S. (2004) Nutrition 20, 942-947.
[42] Bunk, S. (2002) Scientist 16(24), 22-24.
[43] Moskowitz, D. W. (2002) Diabetes Tech. Therapeutics 4, 683-711.
[44] Kaergel, E.; Muller, D. N.; Honeck, H.; Theuer, J.; Shagdarsuren,
E.; Mullally, A.; Luft, F. C.; Schunck, W-H. (2002) Hypertension
40, 273-279.
[45] Gilroy, D. W. (2005) Mem. Inst. Oswaldo Cruz. 100(Suppl. 1), 49-
54.
[46] Wang, W.; Diamond, S. L. (1997) Biochem. Biophys. Res. Com-
mun. 233, 748-751.
[47] Das, U. N. (2005) Med. Sci. Monit. 11, R233-R237.
Essential Fatty Acids
[48] Kumar, G. S.; Das, U. N. (1994) Prostaglandins Leukot. Essen.
Fatty Acids 50, 331-334.
[49] Arita, M.; Bianchini, F.; Aliberti, J.; Sher, A.; Chiang, N.; Hong,
S.; Yang, R.; Petasis, N. A.; Serhan, C. N. (2005) J. Exp. Med. 201,
713-722.
[50] Dooper, M. M.; van Riel, B.; Graus, Y. M.; M’Rabet, L. (2003)
Immunology 110, 348-57.
[51] Chen, W.; Esselman, W. J.; Jump, D. B.; Busik, J. V. (2005) Invest.
Ophthalmol. Vis. Sci. 46, 4342-4347.
[52] Li, H.; Ruan, X. Z.; Powis, S. H.; Fernando, R.; Mon, W. Y.;
Wheeler, D. C.; Moohead, J. F.; Varghese, Z. (2005) Kidney Int.
67, 867-874.
[53] Beck, S. A.; Smith, K. L.; Tisdale, M. J. (1991) Cancer Res. 51,
6089-6093.
[54] Lihn, A. S.; Richelsen, B.; Pedersen, S. B.; Hangaard, S. B.;
Rathje, G. S.; Madsbad, S.; Andersen, O. (2003) Am. J. Physiol.
Endocrinol. Metab. 285, E1072-E1080.
[55] Miller, J.; Carr, A.; Emery, S.; Law, M.; Mallal, S.; Baker, D.;
Smith, D.; Kaldor, J.; Cooper, D. A. (2003) HIV Med. 4, 293-301.
[56] Sheng, Z.; Otani, H.; Brown, M. S.; Goldstein, J. L. (1995) Proc.
Natl. Acad. Sci. USA 92, 935–938.
[57] Fajas, L.; Schoonjans, K.; Gelman, L.; Kim, J. B.; Najib, J.; Martin,
G.; Fruchart, J. C.; Briggs, M.; Spiegelman, B. M.; Auwerx, J.
(1999) Mol. Cell Biol. 19, 5495-5503.
[58] El-Sohemy, A.; Archer, M. C. (1999) Lipids 34, 1037-1043.
[59] Das, U. N. (2000) Nutrition 16, 286-290.
[60] Nakamura, N.; Hamazaki, T.; Jokaji, H.; Minami, S.; Kobayashi,
M. (1998) Int. J. Clin. Lab. Res. 28, 192-195.
[61] Hannah, V. C.; Ou, J.; Luong, A.; Goldstein, J. L.; Brown, M. S.
(2001) J. Biol. Chem. 276, 4365-4372.
[62] Field, F. J.; Born, E.; Murthy, S.; Mathur, S. N. (2002) Biochem. J.
368(Pt 3), 855-864.
[63] Xu, J.; Cho, H.; O’Malley, S.; Park, J. H.; Clarke, S. D. (2002) J.
Nutr. 132, 3333-3339.
[64] Field, F. J.; Born, E.; Mathur, S. N. (2003) J. Lipid Res. 44, 1199-
1208.
[65] Le Jossic-Corcos, C.; Gonthier, C.; Zaghini, I.; Logette, E.; Shech-
ter, I.; Bournot, P. (2005) Biochem. J. 385(Pt 3), 787-794.
[66] Worgall, T. S.; Johnson, R. A.; Seo, T.; Gierens, H.; Deckelbaum,
R. J. (2002) J. Biol. Chem. 277, 3878-3885.
[67] Calon, F.; Lim, G. P.; Yang, F.; Morihara, T.; Teter, B.; Ubeda, O.;
Rostaing, P.; Triller, A.; Salem, Jr. N.; Ashe, K. H.; Frautschy, S.
A.; Cole, G. M. (2004) Neuron 43, 633-645.
[68] Lukiw, W. J.; Cui, J-G.; Marcheselli, V. L.; Bodker, M.; Botkjaer,
A.; Gotlinger, K.; Serhan, C. N.; Bazan, N. G. J. (2005) Clin. In-
vest. 115, 2774-2783.
[69] Calon, F.; Lim, G. P.; Morihara, T.; Yang, F.; Ubeda, O.; Salem, N.
Jr.; Frautschy, S. A.; Cole, G. M. (2005) Eur. J. Neurosci. 22, 617-
626.
[70] Akbar, M.; Calderon, F.; Wen, Z.; Kim, H. Y. (2005) Proc. Natl.
Acad. Sci. USA 102, 10858-10863.
[71] Hashimoto, M.; Tanabe, Y.; Fujii, Y.; Kikuta, T.; Shibata, H.;
Shido, O. (2005) J. Nutr. 135, 549-555.
[72] Aravindakshan, M.; Ghate, M.; Ranjekar, P. K.; Evans, D. R.;
Mahadik, S. P. (2003) Schizophr. Res. 62, 195-204.
[73] Das, U. N. (2004) Med. Sci. Monit. 10, HY33-HY37.
[74] Claria, J.; Serhan, C. N. (1995) Proc. Natl. Acad. Sci. USA 92,
9475-9479.
[75] Chiang, N.; Gronert, K.; Clish, C. B.; O’Brien, J. A.; Freeman, M.
W.; Serhan, C. N. (1999) J. Clin. Invest. 104, 309-316.
[76] Serhan, C. N.; Clish, C. B.; Brannon, J.; Colgan, S. P.; Chiang, N.;
Gronert, K. (2000) J. Exp. Med. 192, 1197-1204.
[77] Serhan, C. N.; Hong, S.; Gronert, K.; Colgan, S. P.; Devchand, P.
R.; Mirick, G.; Moussignac, R-L. (2002) J. Exp. Med. 196, 1025-
1037.
[78] Marcheselli, V. L.; Hong, S.; Lukiw, W. J.; Tian, X. H.; Gronet,
K.; Musto, A.; Hardy, M.; Gimenez, J. M.; Chiang, N.; Serhan, C.
N, Bazan, N. G. (2003) J. Biol. Chem. 278, 43807-43817.
[79] Hong, S.; Gronert, K.; Devchand, P. R.; Moussignac, R. L.; Serhan,
C. N. (2003) J. Biol. Chem. 278, 14677-14687.
[80] Mukherjee, P. K.; Marcheselli, V. L.; Serhan, C. N.; Bazan, N. G.
(2004) Proc. Natl. Acad. Sci. USA 101, 8491-8496.
[81] Gronert, K.; Maheshwari, N.; Khan, N.; Hasan, I. R.; Dunn, M.;
Laniado Schwartzman, M. (2005) Biol. Chem. 280, 15267-15278.
[82] Baker, P. R. S.; Lin, Y.; Schopfer, F. J.; Woodcock, S. R.; Groeger,
A. L.; Batthyany, C.; Swooney, S.; Long, M. H.; Iles, K. E.; Baker,
Current Pharmaceutical Biotechnology, 2006, Vol. 7, No. 6 15
L. M. S.; Branchaud, B. P.; Chen, Y.; Freeman, B. A. (2005) J.
Biol. Chem. 280, 42464-42475.
[83] Coles, B.; Bloodsworth, A.; Clark, S.R.; Lewis, M. J.; Cross, A. R.;
Freeman, B. A.; O’Donnell, V. B. (2002) Circ. Res. 91, 375-381.
[84] Lima, E. S.; Bonim, M. G.; Augusto, O.; Barbeiro, H. V.; Souza,
H. P.; Abdalla, D. S. P. (2005) Free Rad. Biol. Med. 39, 532-539.
[85] Wright, M.M.; Schopfer, F.J.; Baker, P.R.S.; Vidyasagar, V.; Pow-
ell, P.; Chumley, P.; Iles, K.E.; Freeman, B.A.; Agarwal, A. (2006)
Proc. Natl. Acad. Sci. USA 103, 4299-4304.
[86] Miller, C. C.; McCreedy, C. A.; Jones, A. D.; Ziboh, V. A. (1988)
Prostaglandins 35, 917-938.
[87] Tate, G.; Mandell, B. F.; Laposata, M.; Ohliger, D.; Baker, D. G.;
Schumacher, H. R.; Zurier, R. B. (1989) J. Rheumatol. 16, 729-
734.
[88] Heitmann, J.; Iversen, L.; Kragballe, K.; Ziboh, V. A. (1995) Exp.
Dermatol. 4, 74-78.
[89] Santoli, D.; Zurier, R. B. (1989) J. Immunol. 143, 1303-1309.
[90] DeLuca, P.; Rossetti, R. G.; Alavian, C.; Karim, P.; Zurier, R. B.
(1999) J. Invest. Med. 47, 246-250.
[91] Mancuso, P.; Whelan, J.; DeMichele, S. J.; Snider, C. C.; Guszcza,
J. A.; Karlstad, M. D. (1997) Crit. Care Med. 25, 1198-1206.
[92] Palombo, J. D.; DeMichele, S. J.; Boyce, P. J.; Lydon, E. E.; Liu, J.
W.; Huang, Y. S.; Forse, R. A.; Mizgerd, J. P.; Bistrian, B. R.
(1999) Crit. Care Med. 27, 1908-1915.
[93] Barham, J. B.; Edens, M. B.; Fonteh, A. N.; Johnson, M. M.;
Easter, L.; Chilton, F. H. (2000) J. Nutr. 130, 1925-1931.
[94] Thies, F.; Miles, E. A.; Nebe-von-Caron, G.; Powell, J. R.; Hurst,
T. L.; Newsholme, E. A.; Calder, P. C. (2001) Lipids 36, 1183-
1193.
[95] Kambe, T.; Murakami, M.; Kudo, I. (1999) FEBS Lett. 453, 81-84.
[96] Gilroy, D. W.; Newson, J.; Sawmynaden, P.; Willoughby, D. A.;
Croxtall, J. D. (2004) FASEB J. 18, 489-498.
[97] Lo, C. J.; Chiu, K. C.; Fu, M.; Lo, R.; Helton, S. (1999) J. Surg. 82,
216-221.
[98] Borghaei, H.; Borghaei, R. C.; Ni, X.; Pease, E.; Thornton, R.;
Mochan, E. (1997) Inflamm. Res. 46(Suppl. 2), S177-178.
[99] Camandola, S.; Leonarduzzi, G.; Musso, T.; Varesio, L.; Carini, R.;
Scavazza, A.; Chiarpotto, E.; Baeuerle, P. A.; Poli, G. (1996) Bio-
chem. Biophys. Res. Commun. 229, 643-647.
[100] Li, H.; Ruan, X. Z.; Powis, S. H.; Fernando, R.; Mon, W. Y.;
Wheeler, D. C.; Moorhead, J. F.; Varghese, Z. (2005) Kidney Int.
67, 867-874.
[101] Kliewer, S. A.; Sundseth, S. S.; Jones, S. A.; Brown, P. J.; Wisely,
G. B.; Koble, C. S.; Devchand, P.; Wahli, W.; Willson, T. M.; Len-
hard, J. M.; Lehmann, J. M. (1997) Proc. Natl. Acad. Sci. USA 94,
4318-4323.
[102] Sethi, S.; Eastman, A. Y.; Eaton, J. W. (1996) J. Lab. Clin. Med.
128, 27-38.
[103] Mishra, A.; Chaudhary, A.; Sethi, S. (2004) Arterioscler. Thromb.
Vasc. Biol. 24, 1621-1627.
[104] Mori, T. A.; Woodman, R. J.; Burke, V.; Puddey, I. B.; Croft, K.
D.; Beilin, L. J. (2003) Free Radic. Biol. Med. 35, 772-781.
[105] Mori, T. A.; Puddey, I. B.; Burke, V.; Croft, K. D.; Dunstan, D.
W.; Rivera, J. H.; Beilin, L. (2000) J. Redox. Rep. 5, 45-46.
[106] Barden, A. E.; Mori, T. A.; Dunstan, J. A.; Taylor, A. L.; Thornton,
C. A.; Croft, K. D.; Beilin, L. J.; Prescott, S. L. (2004) Free Radic.
Res. 38, 233-239.
[107] Das, U.N. (2005) Nutrition 21, 762-773.
[108] Levy, B.D.; Clish, C.B.; Schmidt, B.; Gronert, K.; Serhan, C.N.
(2001) Nature Immunol. 2, 612-
[109] Devchand, P.R.; Arita, M.; Hong, S.; Bannenberg, G.L.; Mous-
signac, R-L.; Gronert, K.; Serhan, C.N. (2003) FASEB J. 17, 652-
[110] Bannenberg, G.L.; Chiang, N.; Ariel, A.; Arita, M.; Tjonahen, E.;
Gotlinger, K.H.; Hong, S.; Serhan, C.N. (2005) J. Immunol. 174,
4345-4355.
[111] LaMarre, J.; Wollenberg, G.K.; Gonias, S.L.; Hayes, M.A. (1991)
Lab. Invest. 65, 3-
[112] Philippidis, P.; Mason, J.C.; Evans, B.J.; Nadra, I.; Taylor, K.M.;
Haskard, D.O.; Landis, R.C. (2004) Circ. Res. 94, 119-
[113] Gronert, K.; Gewirtz, A.; Madara, J.L.; Serhan, C.N. (1998) J. Exp.
Med. 187, 1285-1294.
[114] Ariel, A.; Chiang, N.; Arita, M.; Petasis, N.A.; Serhan, C.N. (2003)
J. Immunol. 170, 6266-6272.
[115] Aliberti, J.; Hieny, S.; Reis, E.; Sousa, C.; Serhan, N.C.; Sher, A.
(2002) Nature Immunol. 3, 76-82.
 16 Current Pharmaceutical Biotechnology, 2006, Vol. 7, No. 6 Undurti N. Das

[116] Mullenix, P. S.; Andersen, C. A.; Starnes, B. W. (2005) Ann. Vasc. Polyunsaturated fatty acids of marine origin induce adiponectin in
Surg. 19, 130-138. mice fed a high-fat diet. Diabetologia 2006 Jan 6, 1-4.
[117] Das, U. N. (2005) Prostaglandins Leukot. Essen. Fatty Acids 72, [152] Huang, Y-J.; Fang, V. S.; Chou, Y-C.; Kwok, C-F.; Ho, L-T.
173-179. (1997) Metabolism 46, 1252-1258.
[118] Kobayashi, T.; Tahara, Y.; Matsumoto, M Iguchi, M.; Sano, H.; [153] Mori, Y.; Murakawa, Y.; Katoh, S.; Hata, S.; Yokoyama, J.; Ta-
Murayama, T.; Arai, H.; Oida, H.; Kobayashi, T. Y.; Yamashita, J. jima, N.; Ikeda, Y.; Nobukata, H.; Ishikawa, T.; Shibutani, Y.
K.; Katagiri, H.; Majima, M.; Yokode, M.; Kita, T.; Narumiya, S. (1997) Metabolism 46, 1458-1464.
(2004) J. Clin. Invest. 114, 784-794. [154] Nobukata, H.; Ishikawa, T.; Obata, M.; Shibutani, Y. (2000) Me-
[119] Honda, T.; Segi-Nishida, E.; Miyachi, Y.; Narumiya, S. (2006) J. tabolism 49, 912-919.
Exp. Med. 203, 325-335. [155] Borkman, M.; Storlien, L. H.; Pan, D. A Jenkins, A. B.; Chisholm,
[120] Juan, H.; Sametz, W. (1985) Prostaglandins Leukot. Med. 19, 79- D. J.; Campbell, L. V. (1993) N. Engl. J. Med. 328, 238-244.
86. [156] Das, U. N. (1995) Prostaglandins Leukot. Essen. Fatty Acids 52,
[121] Bordet, J. C.; Guichardant, M.; Lagarde, M. (1988) Biochim. Bi- 387-391.
ophys. Acta 958, 460-468. [157] Das, U. N.; Kumar, K. V.; Ramesh, G. (1994) Prostaglandins
[122] Bordet, J. C.; Guichardant, M.; Lagarde, M. (1986) Biochem. Bi- Leukot. Essen. Fatty Acids 50, 253-255.
ophys. Res. Commun. 135, 403-410. [158] Aravindakshan, M.; Ghate, M.; Ranjekar, P. K.; Evans, D. R.;
[123] Hamazaki, T.; Hirai, A.; Terano, T.; Sajiki, J.; Kondo, S.; Fujita, Mahadik, S. P. (2003) Schizophr. Res. 62, 195-204.
T.; Tamura, Y.; Kumagai, A. (1982) Prostaglandins 23, 557-567. [159] Das, U. N. (2004) Med. Sci. Monit. 10, HY33-HY37.
[124] Das, U. N. (2000) Prostaglandins Leukot. Essen. Fatty Acids 63, [160] Echtay, K. S.; Roussel, D.; St-Pierre, J.; Jekabsons, M. B.; Cade-
351-362. nas, S.; Stuart, J. A.; Harper, J. A.; Roebuck, S. J.; Morrison, A.;
[125] Mukherjee, S.K.; Klaidman, L.K.; Yasharel, R.; Adams, J.D. Jr. Pickering, S.; Clapham, J. C.; Brand, M. D. (2002) Nature 415, 96-
(1997) Eur. J. Pharmacol. 330, 27-34. 99.
[126] Chong, Z.Z.; Lin, S.H.; Maise, K. (2004) J. Cereb. Blood Flow [161] Nishikawa, T.; Edelstein, D.; Du, X. L.; Tamagishi, S.; Matsumura,
Metab. 24, 728-743. T.; Kaneda, Y.; Yorek, M. A.; Beebe, D.; Oates, P. J.; Hammes, H.
[127] Ieraci, A.; Herrera, D.G. (2006) PloS Med. 3, e101. P.; Giardino, I.; Brownlee, M. (2000) Nature 404, 787-790.
[128] Horrobin, D.F. (1987) Alcohol Clin. Exp. Res. 11, 2-9. [162] Santerre, R. F.; Nicolosi, R. J.; Smith, S. C. (1974) Exp. Mol.
[129] Valles, S.L.; Blanco, A.M.; Pascual, M.; Guerri, C. (2004) Brain Pathol. 20, 397-406.
Pathol. 14, 365-371. [163] Droge, W. (2002) Physiol. Rev. 82, 47-95.
[130] Das, U.N. (2002) Lancet 360, 490. [164] Bernal-Mizrachi, C.; Gates, A. C.; Weng, S.; Imamura, T.; Knut-
[131] Garcia, M.C.; Kim, H.Y. (1997) Brain Res. 768, 43-48. sen, R. H.; DeSantis, P.; Coleman, T.; Townsend, R. R.; Muglia, L.
[132] Mata de Urquiza, A.; Liu, S.; Sjoberg, M.; Zetterstrom, R.H.; J.; Semenkovich, C. F. (2005) Nature 435, 502-506.
Griffiths, W.; Sjovall, J.; Perlmann, T. (2000) Science 290, 2140- [165] Klein, P. D.; Johnson, R. M. (1954) J. Biol. Chem. 211, 103-110.
2144. [166] Hayashida, T.; Portman, O. W. (1960) Proc. Soc. Exp. Biol. Med.
[133] Gamoh, S.; Hashimoto, M.; Hossain, S.; Masumura, S. (2001) Clin. 103, 656-659.
Exp. Pharmacol. Physiol. 28, 266-270. [167] Cha, S. H.; Fukushima, A.; Sakuma, K.; Kagawa, Y. (2001) J.
[134] Saareks, V.; Mucha, I.; Sievi, E.; Riutta, A. (1999) Pharmacol. Nutr. 131, 2636-2642.
Toxicol. 84, 274-280. [168] Cornwell, D. G.; Panganamala, R. V. (1981) Prog. Lipid Res. 20,
[135] Engelbrecht, A.M.; Engelbrecht, P.; Genade, S.; Niesler, C.; Page, 365-376.
C.; Smuts, M.; Lochner, A. (2005) J. Mol. Cell Cardiol. 39, 940- [169] Smith, E. B. (1962) Biochem. J. 84, 49.
954. [170] Smith, E. B. (1962) Lancet 2, 530-534.
[136] Klein, P.D.; Johnson, R.M. (1954) J. Biol. Chem. 211, 103-110. [171] Subbarao, K.; Jala, V. R.; Mathias, S.; Suttles, J.; Zacharias, W.;
[137] Hayashida, T.; Portman, O.W. (1960) Proc. Soc. Exp. Biol. Med. Ahamed, J.; Ali, H.; Tseng, M. T.; Haribabu, B. (2004) Arterio-
103, 656-659. scler. Thromb. Vasc. Biol. 24, 369-3675.
[138] Bernal-Mizrachi, C.; Gates, A.C.; Weng, S.; Imamura, T.; Knutsen, [172] Cipollone, F.; Mezzetti, A.; Fazia, M. L.; Cuccurullo, C.; Iezzi, A.;
R.H.; DeSantis, P.; Coleman, T.; Townsend, R.R.; Muglia, L.J.; Ucchino, S.; Spigonardo, F.; Bucci, M.; Cuccurullo, F.; Prescott, S.
Semenkovich, C.F. (2005) Nature 435, 502-506. M.; Stafforini, D. M. (2005) Arterioscler. Thromb. Vasc. Biol. 25,
[139] Suresh, Y.; Das, U.N. (2003) Nutrition 19, 93-114. 1665-1670.
[140] Suresh, Y.; Das, U.N. (2003) Nutrition 19, 213-228. [173] Connor, W. E.; Neuringer, M.; Reisbick, S. (1992) Nutr. Rev. 50(Pt
[141] Piomelli, D.; Pilon, C.; Giros, B.; Sokoloff, P.; Martres, M.P.; 2), 21-29.
Schwartz, J.C. (1991) Nature 353, 164-167. [174] Connor, W. E.; Neuringer, M.; Reisbick, S. (1991) World Rev.
[142] Zhang, L.; Reith, M.E. (1996) Eur. J. Pharmacol. 315, 345-354. Nutr. Diet. 66, 118-132.
[143] Blanchet, F.; Gauchy, C.; Perez, S.; Glowinski, J.; Kemel, M.L. [175] Lim, S. Y.; Hoshiba, J.; Moriguchi, T.; Salem, N. Jr. (2005) Pedi-
(1999) Synapse 31, 140-150. atr. Res. 58, 741-748.
[144] de La Presa Owens, S.; Innis, S.M. (1999) J. Nutr. 129, 2088-2093. [176] Lim, S. Y.; Hoshiba, J.; Salem, N. Jr. (2005) J. Neurochem. 95,
[145] de La Presa Owens, S.; Innis, S.M. (2000) Pediatr. Res. 48, 125- 848-857.
130. [177] Garcia-Calatayud, S.; Redondo, C.; Martin, E.; Ruiz, J. I.; Garcia-
[146] Innis, S.M.; de La Presa Owens, S. (2001) J. Nutr. 131, 118-122. Fuentes, M.; Sanjurjo, P. (2005) Pediatr. Res. 57(5 Pt 1), 719-723.
[147] Kuperstein, F.; Yakubov, E.; Dinerman, P. (2005) J. Neurochem. [178] Chiang, M. Y.; Misner, D.; Kempermann, G.; Schikorski, T.;
95, 1550-1562. Giguere, V.; Sucov, H. M.; Gage, F. H.; Stevens, C. F.; Evans, R.
[148] Das, U.N. (2002) Exp. Biol. Med. 227, 989-997. M. (1998) Neuron 21, 1353-1361.
[149] Peyron-Caso, E.; Taverna, M.; Guerre-Millo, M.; Veronese, A.; [179] Argmann, C. A.; Sawyez, C. G.; McNeil, C. J.; Hegele, R. A.;
Pacher, N.; Slama, G.; Rizkalla, S. W. (2002) J. Nutr. 132, 2235- Huff, M. W. (2003) Arterioscler. Thromb. Vasc. Biol. 23, 475-482.
2240. [180] Kim, H. I.; Cha, J. Y.; Kim, S. Y.; Kim, J. W.; Roh, K. J.; Seong, J.
[150] Reseland, J. E.; Haugen, F.; Hollung, K.; Solvoll, K.; Halvorsen, K.; Lee, N. T.; Choi, K. Y.; Kim, K. S.; Ahn, Y. H. (2002) Diabe-
B.; Brude, I. R.; Nenseter, M. S.; Christiansen, E. N.; Drevon, C. tes 51, 676-685.
A. (2001) J. Lipid Res. 42, 743-750.
[151] Flachs, P.; Mohamed-Ali, V.; Horakova, O.; Rossmeisl, M.;
Hosseinzadeh-Attar, M. J.; Hensler, M.; Ruzickova, J.; Kopecky, J.

View publication stats