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Endocrine, Metabolic & Immune Disorders - Drug Targets, 2011, 11, 232-246
Role of 3 Longchain Polyunsaturated Fatty Acids in Reducing CardioMetabolic Risk Factors
Mahinda Y. Abeywardena* and Glen S. Patten
CSIRO Food & Nutritional Sciences, Kintore Avenue, Adelaide, SA 5000, Australia
Abstract: Cardiovascular disease is the leading cause of mortality in many economically developed nations, and its
incidence is increasing at a rapid rate in emerging economies. Diet and lifestyle issues are closely associated with a
myriad of cardiovascular disease risk factors including abnormal plasma lipids, hypertension, insulin resistance, diabetes
and obesity, suggesting that diet-based approaches may be of benefit. Omega-3 longchain-polyunsaturated fatty acids (3
LC-PUFA) are increasingly being used in the prevention and management of several cardiovascular risk factors. Both the
3 and 6 PUFA families are considered essential, as the human body is itself unable to synthesize them. The conversion
of the two precursor fatty acids - linoleic acid (18:26) and -linoleic acid (18:33) - of these two pathways to longer
(C20) PUFA is inefficient. Although there is an abundance of 6 PUFA in the food supply; in many populations the
relative intake of 3 LC-PUFA is low with health authorities advocating increased consumption. Fish oil, rich in
eicosapentaenoic (EPA, 20:53) and docosahexaenoic (DHA, 22:63) acids, has been found to cause a modest reduction
in blood pressure at a dose level of >3g/d both in untreated and treated hypertensives. Whilst a multitude of mechanisms
may contribute to the blood pressure lowering action of 3 LC-PUFA, improved vascular endothelial cell function
appears to play a central role. Recent studies which evaluated the potential benefits of fish oil in type-2 diabetes have
helped to alleviate concerns raised in some previous studies which used relatively large dose (5-8 g/d) and reported a
worsening of glycemic control. Several meta-analyses have confirmed that the most consistent action of 3 LC-PUFA in
insulin resistance and type-2 diabetes is the reduction in triglycerides. In some studies, fish oil has been found to cause a
small rise in LDL-cholesterol, but a change in the LDL particle size, from the smaller more atherogenic form to the larger,
less damaging particle size, have also been noted. 3 LC-PUFA are effective modulators of the inflammation that
accompanies several cardio-metabolic abnormalities. Taking into consideration the pleiotropic nature of their actions, it
can be concluded that dietary supplementation with 3 LC-PUFA will lead to improvements in cardio-metabolic health
parameters. These fatty acids pose only minor side effects and more importantly, do not interact adversely with the common
drug therapies used in the management and treatment of hypertension, dyslipidemia, type-2 diabetes, and obesity/
metabolic syndrome, but in some instances work synergistically, thereby providing additional cardiovascular benefits.
Keywords: Cardiovascular disease, diabetes, endothelium, hypertension, inflammation, insulin resistance, metabolic syndrome,
vasculature.
INTRODUCTION
Cardiovascular disease is the leading cause of mortality
in many economically developed nations, and accounts for
about 30% of all deaths [1, 2]. In addition, the prevalence of
this disease state is rising rapidly in the majority of the up
and coming developing countries, where two-thirds of the
world's population lives, most notably in China and India [24]. Cardiovascular disease is closely linked with a cluster of
risk factors including abnormal plasma lipids, hypertension,
insulin resistance, diabetes and obesity, which are also
becoming increasingly prevalent in today’s society [5, 6].
The combination of these abnormalities which increase the
risk of developing cardiovascular disease and diabetes has
variously been called metabolic disease, metabolic syndrome
or syndrome X [6-8]. It is also recognized that in many
instances these risk factors have strong psychophysiologic
and environmental components - i.e. diet and lifestyle
*Address correspondence to this author at the CSIRO – Food & Nutritional
Sciences, PO Box 10041, Adelaide BC, SA 5000, Australia;
Tel: +61 8 8303 8889; Fax: +61 8 8303 8899;
E-mail: [email protected]
1871-5303/11 $58.00+.00
components – therefore allowing opportunities for the
development of new strategies to curb the development of
cardiovascular disease and improve metabolic diseases [9,
10]. Accordingly, diet-based strategies to promote cardiovascular and metabolic health are becoming increasingly
popular, and recent studies have identified dietary guidelines
and potential therapeutic roles in human health for specific
dietary components [10-13]. Although a number of dietary
ingredients have been reported to offer cardiovascular health
benefits, those with strong scientific evidence for their
clinical efficacy are relatively few and include dietary fiber
[14, 15], omega-3 long-chain (C20) polyunsaturated fatty acids
(termed 3 LC-PUFA) [16, 17-20] and phytosterols [21, 22].
Recently, associative and experimental evidence supporting
polyphenols has also been generated [23-26]. Of these
ingredients, 3 LC-PUFA, particularly of marine origin, has
been thought to be the most effective due to its ability to
influence several cardiovascular risk factors [19, 27-31].
Presently, there is evidence to suggest that the two
3 LC-PUFA - EPA (eicosapentaenoic acid, 20:53) and
DHA (docosahexaenoic acid, 22:63) - exert pleiotropism
(akin to those effects which have been reported for certain
© 2011 Bentham Science Publishers
Role of 3 Longchain Polyunsaturated Fatty Acids in Reducing
Endocrine, Metabolic & Immune Disorders - Drug Targets, 2011, Vol. 11, No. 3
cardiovascular drugs) by modulating a range of diverse
target mechanisms involved in cardiovascular disease
development [32-35]. For example, benefits of 3 LC-PUFA
from fish and fish oil have been observed at different stages
of this disease process - including on plasma triglycerides
[36-37] (arising from decreased endogenous synthesis and
enhanced clearance of triglyceride-rich particles), on the size
and the density of lipoprotein particles [38], thrombosis,
inflammatory markers [39], blood pressure [29, 33], vascular
endothelium [30, 33, 40], proliferation of vascular smooth
muscle and growth of atherosclerotic plaque [33, 36, 41],
disorders of cardiac rhythm and sudden cardiac death
[16, 31, 42-45]. This review highlights some of the recent
findings that demonstrate the effects of 3 LC-PUFA
in influencing several key cardio-metabolic parameters,
including hypertension, insulin resistance and diabetes in
humans.
Essential Fatty Acids
The -3 fatty acids family represents one of the essential
fatty acid series that is required for normal human growth
and development (Fig. 1). The shorter chain 3 and 6
PUFA; -linolenic (18:33, ALA) and linoleic (18:26,
233
LA) are known as essential fatty acids as the body is unable
to produce them, and they must be obtained through the diet.
This is in contrast to both saturated (e.g., myristic, 14:0;
palmitic, 16:0: stearic, 18:0) and mono-unsaturated (e.g.,
oleic, 18:19) fatty acids which can be synthesized de novo
from other dietary precursors.
Endogenous conversion (elongation and desaturation) of
the initial C18 PUFA precursors results in the synthesis of
longer chain counterparts such as EPA and DHA in the 3
family, and dihomo--linolenic (20:36, DGLA) and
arachidonic (20:46, AA) in the in 6 pathway. Studies in
rodents suggest that when dietary ALA is provided as the
only source of 3 PUFA it leads to tissue accumulation of
the full complement of 3 LC-PUFA, including EPA, DPA
and DHA [47]. However, the extent of accumulation of
these fatty acids, in particular DHA, is lower following
ALA diets compared to rats fed diets containing preformed
3 LC-PUFA. Guinea pigs fed diets high in ALA showed
substantial accumulation of ALA, EPA and DPA, but
relatively little increase in DHA [48]. However, recent
stable-isotope tracer studies in rats have shown synthesis
of EPA, DPA and DHA after 60 minutes post-intravenous
infusion of [U-13C]-ALA, suggesting that liver synthesis of
DIET
(e.g. seed oils, leafy vegetables)
Essential Fatty Acids
(ω9 series)
(ω6 series; LA)
9
(ω3 series; ALA)
3
6
de novo synthesis
→ →14:0 → 16:0
18:2ω6 (LA)
α18:3ω3 (ALA)
18:0
γ18:3ω6 (GLA)
18:4ω3 (SDA)
18:1ω9 (OA)
20:3ω6 (DGLA)
20:5ω3 (EPA)
20:4ω6 (AA)
22:5ω3 (DPA)
22:6ω3 (DHA)
Fig. (1). Synthesis and metabolism of different fatty acid families. The (c:d -x) nomenclature of fatty acids refers to the chain length (c),
total number of double bonds (d), and -x refers to the location of the first double bond counting from the terminal methyl end (omega
reflecting the last letter of the Greek alphabet) of the fatty acid chain. In the n nomenclature letter n is used in lieu of . Fatty acids (FAs)
typically have an even number of carbon atoms, in the range of 2-26. FAs with only single bonds between adjacent carbon atoms are referred
to as ‘saturated’, whereas those with at least one C=C double bond are called ‘unsaturated’ [46]. OA (oleic acid, 18:19); LA (linoleic acid,
18:26); ALA (-linolenic acid, 18:33); GLA (-linolenic acid, 18:36); SDA (stearidonic acid, 18:43), DGLA (di-homo--linolenic
acid, 20:36); AA (arachidonic acid, 20:46); EPA (eicosapentaenoic acid, 20:53), DPA(docoasapentaenoic acid, 22:53); DHA
(docosahexaenoic acid, 22:63). DGLA is a substrate for 1-series prostaglandins; AA is the main substrate for cyclooxygenase and
lipoxygenase enzyme complexes leading to the 2-series prostaglandins and 4-series leukotrienes; EPA results in the production of 3-series
prostaglandins and 5-series leukotrienes (33).
234 Endocrine, Metabolic & Immune Disorders - Drug Targets, 2011, Vol. 11, No. 3
3 LC-PUFA from ALA alone would be sufficient to
maintain brain DHA homeostasis [49]. Similar findings have
also been observed after infusion with EPA in the same
model [50]. Though interesting, these findings need
validation in humans because 1) rodents are known to
possess an active 6-desaturase complex resulting in high
tissue DHA content compared to several other animal
species [51] and humans and 2) very recent evidence
indicates that 3 LC-PUFA synthesis is primarily regulated
by the substrate levels for existing enzyme complexes, rather
than by changes in the expression of synthetic enzymes or
regulatory transcription factors [52]. This latter study may be
of particular relevance to the outcomes of the tracer studies
conducted by Gao et al., [49-50] where the synthesis of 3
LC PUFA was measured following direct intravenous
infusion of precursor fatty acid(s) over a 2 hour period,
resulting in an abundance of substrate fatty acid.
However, in humans the conversion of C18 precursors to
these longer chain products (C20) which act as substrates
for eicosanoids, isoprostanes and related fatty acid mediators,
is not an efficient process [53-57]. Furthermore, because the
two fatty acid pathways are mutually exclusive (i.e. 3 fatty
acid cannot become 6 fatty acid and vice versa), balanced
intakes of these fatty acids as precursors (ALA and LA) or as
their longer chain products (EPA, DHA, AA) are required.
For example, increased consumption of ALA for a period
of weeks to months leads to higher levels of EPA in plasma
and other tissues including erythrocytes, leukocytes and
platelets, but no changes in DHA have been found [47, 54,
55]. Gender differences in the fractional conversion rate
of ALA to the longer chain 3 products have also been
reported, with women being more efficient due to a regulatory effect of estrogen.
The human diet has changed considerably over the last
century, and in modern society the intake of dietary fatty
acids is predominantly of the saturated, mono and 6
polyunsaturated types along with much lower intakes of 3
LC-PUFA [58, 59]. This imbalance in the dietary intake ratio
of 6 to 3 PUFA appears to be critical for human health
and wellbeing, and consequently is thought to be a key
determinant in the development of nutrition-related chronic
diseases including cardiovascular disease, cancer, immune
disorders, diabetes and obesity. The continuously expanding
body of evidence in favor of a wide spectrum of health
benefits of 3 LC-PUFA supports this view.
Marine-Based 3 Polyunsaturated Fatty Acids
In nature, DHA and eicosapentaenoic acid (EPA,
20:53) are produced by the microalgae that are ingested by
EPA
20:5ω3
DHA
22:6ω3
Abeywardena and Patten
smaller marine creatures such as krill, and are thus found in
high concentrations (up to 3% of total fish weight) in cold
water species of oily fish such as herrings, sardines, salmon
and mackerel [60, 61]. EPA and DHA are synthesized from
the 3 precursor ALA (18:33) whereas the long chain 6
PUFA such as arachidonic acid (AA, 20:46) are
synthesized from the predominantly plant-derived precursor
LA (18:26) [62]. Certain plants also produce -linolenic
acid (ALA, 18:33), and it is found in green leafy vegetables
(small amounts) and seeds (varying levels). Commercial
crops such as soybean, canola, flax and chia contain
moderate to high amounts of ALA. Although terrestrial
plants are effective producers of C18 long PUFA, they have
limited metabolic capacity to produce EPA and DHA.
Similarly, humans do not possess an efficient elongation
and desaturation process to convert ALA to EPA by any
more than 5-7% [54-57] due to LA competing with ALA
at the level of the 6-desaturase which inserts additional
unsaturated bonds to these precursor fatty acids. However,
levels of up to 20% conversion have been cited [63],
dependent on baseline levels of individuals, in particular
groups of vegetarians or vegans with low baseline 3 PUFA
plasma and tissue levels [56]. Whilst both shorter-chain C18
omega-3 PUFA (e.g. ALA) and the longer (C20) 3 LCPUFA (EPA and DHA) are collectively being referred to as
3s, it is noteworthy that these two forms of PUFA vary
widely in their biological actions and bio-efficacy.
3 LC-PUFA IN CARDIO-METABOLIC DISORDERS
Hypertension
Elevated blood pressure is a major risk factor for heart
and blood vessel diseases, and leads to the development of
heart disease, heart failure, stroke, peripheral vascular
disease and renal damage. Hypertension and resulting
vascular abnormalities can increase the risk of cardiovascular
disease by 2-4 times [1]. Presently, 30% of the Australian
population aged 25 years or over has been diagnosed as
hypertensive. In the United States, about 75 million people
(one in three adults) have high blood pressure, and the most
common cause of death is directly linked to hypertension.
The World Health Organisation has recognised that high
blood pressure is a major underlying cause for the predicted
rise in cardiovascular disease in developing economies [1,
3-5]. Anti-hypertensive medications also head the list of
prescription drugs used in many economically developed
countries. Therefore, hypertension is an important public
health challenge requiring practical measures at a population
level to prevent initial development of, and subsequent
control of, high blood pressure.
COOH
COOH
Fig. (2). 3 Longchain-PUFA acids with cardiovascular protective actions. Eicosapentaenoic acid (EPA, 20:53); docosahexaenoic acid
(DHA, 22:63).
Role of 3 Longchain Polyunsaturated Fatty Acids in Reducing
Endocrine, Metabolic & Immune Disorders - Drug Targets, 2011, Vol. 11, No. 3
Though high blood pressure is easily treated by pharmaceutical means, there is significant interest in discovering
naturally occurring compounds to control this condition. The
fact that the popularity of attempts to control blood pressure
via non-pharmaceutical means is growing is evident by the
growth of the functional food / nutraceutical sector. Whilst
bioactives are unlikely to be able to match the therapeutic
efficacy of prescription medications, the present evidence
suggest that certain naturally derived preparations may be
effective in lowering blood pressure in mild to moderate
hypertensives [64, 65]. In this regard, it is noteworthy that a
5 mmHg reduction in blood pressure has been equated with a
16% decrease in cardiovascular disease. Therefore, any
strategy to lower blood pressure and minimize secondary
complications would be of considerable social and economic
benefit. A substantial body of evidence suggests 3 LC-PUFA
reduces blood pressure in its own right, and also acts synergistically when combined with other non-pharmacological
interventions such as salt reduction, exercise and body
weight reduction [27, 29, 66].
Meta-analyses of 31 placebo-controlled clinical trials
[67], and 36 trials [68] showed dose-dependent reduction in
Table 1.
blood pressure estimated at -0.66/-0.35 mmHg per g 3 fatty
acid. The extent of reductions reported has varied from 1.0/0.5 mmHg and -2.1/-1.6 mmHg to -3.0/-1.5 mmHg [68,
69]. It has also been noted that the hypotensive actions of 3
PUFA are greater in older and hypertensive patients. These
clinically significant effects have usually been achieved with
administration of 4-5 g/day of 3 LC-PUFA. Relatively few
studies have compared the effects of daily fish consumption
against fish oil supplements on blood pressure. Bao et al.,
[70] and Lara et al., [71] reported a reduction in BP
following regular consumption of fatty fish whilst several
other studies found no change [72-74]. In a recent study
Ramel et al., [75] investigated the effects of consumption of
salmon (150 g, 3 times per week yielding 2.1 g 3 LCPUFA/day), cod (150 g, 3 times per week yielding 0.39 g 3
LC-PUFA/day) and fish oil capsules that delivered 1.3g 3
LC-PUFA per day in an 8 week intervention study involving
324 overweight and obese young adults on energy-restricted
diets. The fish oil and salmon groups showed significantly
lower diastolic blood pressure than the subject group fed lean
fish (cod). Interestingly, the study indicated that the lower
baseline DHA content in erythrocyte membranes (possibly
Common Fatty Acids Arranged in Difference Classes
Trivial Name
Scientific Name
Molecular Name
Code
Lauric acid
Dodecanoic acid
12:0
Myristic acid
Tetradecanoic acid
14:0
Palmitic acid
Hexadecanoic acid
16:0
Stearic acid
Octadecanoic acid
18:0
Arachidic acid
Eicosanoic acid
20:0
Behenic acid
Docosanoic acid
22:0
Lignoceric acid
Tetracosanoic acid
24:0
Vaccenic acid
11-octadecenoic acid
18:17
Oleic acid
9-octadecenoic acid
18:19
-linolenic acid
9,12,15-octadecatrienoic acid
18:33
ALA
Stearidonic acid
6,9,12,15-octadecatetraenoic acid
18:43
SDA
Timnodonic acid
5,8,11,14,17-eicosapentaenoic acid
20:53
EPA
Clupanodonic acid
7,10,13,16,19-docosapentaenoic acid
22:53
DPA
Cervonic acid
4,7,10,13,16,19-docosahexaenoic acid
22:63
DHA
Linoleic acid
9,12-octadecadienoic acid
18:26
LA
-linolenic acid
6,9,12-octadecatrienoic acid
18:36
GLA
Arachidonic acid
5,8,11,14-eicosatetraenoic acid
20:46
AA
Osbond acid
4,7,10,13,16-docosapentaenoic acid
22:56
Saturated fatty acids
Monounsaturated fatty acids
3 polyunsaturated fatty acids
6 polyunsaturated fatty acids
(Footnote: all unsaturated FAs shown in this table are of the cis configuration).
235
236 Endocrine, Metabolic & Immune Disorders - Drug Targets, 2011, Vol. 11, No. 3
reflective of the infrequent intake of 3 LC-PUFA) was
associated with the greatest reduction in blood pressure. It is
noteworthy that not only fish oil but also fish protein may
possess anti-hypertensive properties - a fact that has been
observed in animal feeding studies [76-77]. In a human
intervention study, Erkkila et al., [78] compared the effect
of lean (white) and fatty fish following 8 week feeding on
BP of subjects with coronary heart disease undergoing
multiple drug therapy, and observed a 3.6% reduction (p<0.05)
in the group that consumed 4 meals/week lean fish. These
findings indicate that eating fish regardless of its oil content
may also render positive outcomes in coronary heart disease
patients.
EPA or DHA?
The majority of marine oil preparations contain more
EPA than DHA. These two forms of 3 LC-PUFA have also
been shown to behave differently in relation to plasma and
tissue incorporation and in certain biological outcomes [33,
42, 79-81]. For example, EPA can serve as an alternative
substrate for cyclooxygenase and lipoxygenase whereas
DHA is not further metabolised by these enzyme systems
[82]. Differential effects between EPA and DHA have been
reported for triglyceride lowering actions with EPA being
recognized as the active fatty acid [83, 84]. EPA has also
been found to possess greater anti-platelet and antiinflammatory properties [85, 86]. More recent studies have
uncovered further differences between EPA and DHA on
cell function including phagocytosis, gene expression and
intracellular signaling pathways as well as biophysical
changes in plasma membrane [reviewed in 87].
Overall, DHA has been reported to be more effective for
cardiovascular outcomes than EPA and these include its
effects on blood pressure, heart rate and vascular function
[66, 88]. In a double-blind, placebo-controlled trial involving
mildly hyperlipidemic men, Mori et al., [80] compared the
effects of purified DHA and EPA (4g/d for 6 weeks) on
ambulatory blood pressure and heart rate. Relative to the
placebo control (olive oil), only DHA supplementation
reduced the 24-hour (-5.8/-2.0 mmHg) and daytime (awake, 3.5/-2.0) ambulatory blood pressure. In addition, DHA not
EPA was effective in slowing the heart rate (p=0.001) during
both the awake and asleep (night-time) periods. The
hypotensive action of DHA was explained by considerable
improvements in vascular reactivity via enhanced vasodilator
mechanisms and attenuation in constrictor responses in the
forearm microcirculation. However, in a later study [89]
undertaken by the same investigators of similar design but
involving type-2 diabetic patients with treated hypertension,
they failed to show any blood pressure reduction by either
DHA or EPA. Furthermore, the fish oil supplements in this
latter study adversely affected the short-term glycemic
control. As discussed by Mori [66], it is possible that the
background glycemic state and/or the concomitant use of
drug therapies may have influenced the DHA actions on
blood pressure in the study.
In relation to interaction with anti-hypertensive drugs, 3
LC-PUFA have been reported to augment the blood pressure
lowering actions of the -blocker propranolol and diuretics,
except in those hypertensives treated with angiotensin-
Abeywardena and Patten
converting enzyme (ACE) inhibitors [90-92]. Whether such
differences are related to the mode of action of individual
drugs or due to other reasons are not clear. It is interesting to
note that, unlike ACE inhibitors, the underlying mechanism
of action of both diuretics and -blockers involve membranemediated events (transporters, ion channels and receptors),
and dietary 3 LC-PUFA are effective modulators of physicochemical properties of cell membranes including composition, lipid-protein interactions and membrane fluidity.
Vasculature
It has also been recognised that a large part of the
cardiovascular benefits of 3 LC-PUFA are likely to be
mediated at the level of the vascular endothelium [30, 33, 66,
93]. This thin monolayer of cells plays a central role in
cardiovascular homeostasis and function via the production
of a range of potent autocrine and paracrine biochemical
mediators controlling the tone of vascular smooth muscle
cells [33, 77-78]. Vascular endothelium is also the site for
the inception, progression and clinical manifestations of
atherosclerosis [94-96]. Endothelium-derived vasorelaxants
include nitric oxide (NO), and endothelial-derived hyperpolarizing factor (EDHF). Vasoconstrictors include angiotensin
II, the potent endothelins, thromboxane A2/prostaglandin H2
(PGH2), prostaglandin F2 (depending on the smooth muscle
type), superoxide anion and isoprostane (Fig. 3). 3 LCPUFA has been shown to modulate a number of key lipid
mediators generated in the vascular endothelium [33]. The
endothelium is also the site of many receptors, binding
proteins, transporter and signaling processes involved in cell
growth, apoptosis and cell migration. In certain disease
states, the endothelium may also produce increased levels
of eicosanoids and free radicals and promote abnormal
contraction of blood vessels [4, 97]. There is, therefore, a
delicate interplay between the cells lining the vasculature
and the vascular smooth muscle cells, whose tone regulates
blood flow and blood pressure. A multitude of mechanisms
may contribute to the BP lowering action of 3 LC-PUFA.
These include changes in vasomotor tone through modification in vasodilatory and vasoconstrictor eicosanoids [33,
66, 94, 95], preservation of and increased production of
nitric oxide [96], enhanced release of ATP [98], modulating
endothelium-derived hyperpolarizing (EDHF) and endothelium
derive contracting factors (EDCF). Other reported actions of
3 fatty acids contributing to the decreased blood pressure
effects are regulation of renal sodium excretion, suppression
of ACE activity, changes in membrane composition and
fluidity as well as changes in the autonomic nervous system
[29, 66, 99].
Insulin Resistance
Insulin resistance is characterized by reduced responsiveness in three major target tissues - skeletal muscle, liver
and adipose tissue - to circulating insulin, thus resulting in
changes in blood glucose. The major abnormalities include
decreased insulin-stimulated uptake of glucose (skeletal
muscle), impaired insulin-mediated inhibition of gluconeogenesis in the liver, and reduced ability of insulin to arrest
lipolysis in adipocytes [100, 101]. Insulin resistance is often
associated with non-alcoholic fatty liver disease, is a major
Role of 3 Longchain Polyunsaturated Fatty Acids in Reducing
Endocrine, Metabolic & Immune Disorders - Drug Targets, 2011, Vol. 11, No. 3
237
Endothelium
Vasorelaxants
Vasoconstrictors
• A-II
• ET
• TxA2 / PGH2
• O2 / Isoprostane
• Hydroxy fatty acids
• NO
• PGF2
• EDHF
Relaxation
.
Vascular
Smooth muscle
Contraction
Dysfunctional
Normal
 vasodilatation (tissue perfusion)
 anti-thrombotic / thrombolysis
 anti-coagulant (cell surface)
 inhibit cell adhesion
 inhibit remodeling (vascular / cardiac)
 vasoconstriction
 pro-thrombotic
 pro-coagulant (cell
surface)
 promote cell adhesion
 promote VSMC growth
Fig. (3). Patho-physiological outcomes of normal and dysfunctional vascular endothelium. A diverse array of biochemical mediators are
released by the endothelium. NO, nitric oxide; PGI2, prostacyclin; EDHF, endothelium derived hyperpolarizing factor; A-II, angiotensin II;
ET, endothelin; TxA2/PGH2, thromboxaneA2/prostaglandinH2; O2, superoxide anion.
predictor for the development of type-2 diabetes and is a
defining criterion of metabolic syndrome.
Whilst both animal studies and epidemiological studies
have suggested that 3 LC-PUFA may be effective in
reducing insulin resistance and diabetes [102], the outcomes
of the limited number of human intervention studies have
been inconsistent [101, 103]. Griffin et al., [104] in a
randomized trial of 258 subjects aged 45-70 yrs compared
the effects of varying the dietary 6 to 3 fatty acid ratio on
insulin sensitivity, lipoprotein particle size and postprandial
lipemia (the OPTLIP study), and found that dietary intervention was without effect on insulin sensitivity or postprandial lipase activities. Similar findings were reported by
Kabir et al., in diabetic women treated with fish oil [105]. In
these studies the significant outcomes of the addition of 3
LC-PUFA were the reduction of triglycerides, both fasting
and postprandial, and a shift in the LDL particle size to a
more favorable (less atherogenic) pattern. Similarly, a study
of 162 healthy adults fed two different iso-energetic diets
further supplemented with 3.6g/d of 3 LC-PUFA or olive
oil (placebo) for 3 months [106] found no improvement
in insulin sensitivity, insulin secretion, beta-cell function
or glucose tolerance. In contrast, a relatively small study
involving 12 subjects (>60 yrs) reported improved insulin
sensitivity but no change in fasting plasma glucose, as well
as a reduction in serum C-reactive protein and interleukin6 after a 8 weeks consumption of an experimental diet
consisting of 720g fatty fish weekly plus 15 ml of sardine oil
daily [107]. This study suffered from the lack of a proper
control group, and the relatively high consumption of the 3
LC-PUFA makes it difficult to compare against the relatively
modest doses used in other studies. In contrast to the fish oil
fatty acids, flax seeds rich in the shorter 3 PUFA ALA
(18:33) reduced the homeostatic model assessment of
insulin resistance (HOMA-IR) index without influencing the
inflammatory markers IL-6 or C-reactive protein in a study
involving 62 men and post-menopausal women [108].
However, it very likely that non-oil constituent (e.g. lignan)
was primarily responsible for improving the fasting plasma
glucose and HOMA-IR in the subjects.
A recent study involving overweight and obese young
adults (N=324 with an 86% completion rate) consuming an
energy-restricted diet supplemented with fish oil, lean or
fatty fish found that only fish oil intake (as capsules - 1.3 g/d
of 3 LC-PUFA) was a significant predictor of fasting insulin
and HOMA-IR. These improvements were independent from
weight loss [109]. However, the failure of the fatty fish
supplement salmon diet, despite delivering higher total
3 PUFA content (2.1 g/d as compared to 1.3 g/d from
capsules), is intriguing, and raises an interesting question
in relation to the mode of delivery of 3 LC-PUFA
and potential dietary matrix interactions, bioavailability
and bio-efficacy. In another weight loss study involving
hyperinsulinemic women, it was found that the addition of
3 LC-PUFA to a low fat/high carbohydrate weight-loss
program did not improve insulin sensitivity over weight-loss
alone [110]. However, a subsequent study by the same group
of investigators found that background inflammatory status
is an important determinant of the beneficial actions of fish
oil fatty acids [111]. In this later study, only those obese
238 Endocrine, Metabolic & Immune Disorders - Drug Targets, 2011, Vol. 11, No. 3
women with a raised inflammatory status - the top tertile for
baseline serum sialic acid concentration, but not those in the
bottom tertile - showed improvement in insulin sensitivity
following supplementation with fish oil. Inflammation is
closely linked to obesity, insulin resistance and cardiovascular disease risk. Taking note of the well documented
anti-inflammatory actions of fish oil fatty acids, it is prudent
to suggest that any benefit of 3 LC-PUFA on insulin
resistance would be indirect and secondary to blunting of the
inflammatory response. It follows that the impact of 3 LCPUFA in insulin resistance may best manifest in those
individuals with a higher inflammatory burden.
Diabetes
Conflicting results have emerged from studies where the
effects of fish oil on the glycemic control of diabetic patients
were investigated [112-114]. Several earlier studies observed
that 3 LC-PUFA supplementation worsens the glycemic
control in type 2 diabetes, since fasting plasma glucose,
meal stimulated glucose and hepatic glucose output were all
significantly elevated following dietary supplementation
[115, 116]. It has been noted that these studies have used
relatively large doses (5.5-8 g/d) of omega-3 fatty acids,
lacked proper controls and featured a low number of
subjects. Other studies using more moderate doses (1.7- 3
g/d) found no deterioration of blood glucose control [117] or
even an improvement in insulin sensitivity [118]. A metaanalysis of 26 clinical trials that involved both type 1 and
type 2 diabetic subjects [119] concluded that fish oil fatty
acids have no adverse effects on glycated hemoglobin
(HbA1c). The fasting blood glucose levels increased with
borderline significance in type-2 subjects, whilst type 1
patients treated with fish oil showed significant lowering
(-1.86 mmol/l; 95% CI, -3.1 to 0.61, p<0.05). The most
prominent and consistent response among different trials
was the dose-related triglyceride lowering action (by 30%)
of 3 LC-PUFA. Another meta-analysis of 18 randomized,
placebo-controlled trails with 3 LC-PUFA (a dose-range
of 3 to 18/g day fish oil) in type-2 diabetic subjects was
conducted by Montori & colleagues [120]. They concluded
that fish oil supplementation lowers triglycerides, raises LDLcholesterol but has no significant effect on the glycemic
control in persons with type-2 diabetics. Collectively, these
findings (which demonstrated that modest amounts of 3
LC-PUFA (1-2 g/d) pose no threat to glucose homeostasis
but may reduce overall cardiovascular risk via improvements
in lipoprotein profile and reduced inflammatory burden),
have also paved the way for recommendations by the
American Diabetes Association and the American Heart
Association for the consumption of 2-3 servings of fish per
week [19, 121, 122].
A more recent review of the effects of 3 LC-PUFA
published by the Cochrane Collaboration [123] evaluated 23
randomized control trials (1075 participants) that investigated the effects of dietary 3 LC-PUFA on cardiovascular
disease outcomes, cholesterol levels and glycemic control in
type-2 diabetic subjects. The mean dosage used in these
trials was 3.5 g/day with a mean treatment duration period of
8.9 weeks. Of the plasma lipids, triglycerides were reduced
by -0.45 mmol/L (95% CI -0.58 to -0.32, P<0.00001),
Abeywardena and Patten
VLDL-cholesterol by -0.07 mmol/L (95% CI -0.13 to 0.00,
P=0.04), total or HDL cholesterol was unaffected whilst
LDL-cholesterol were raised by 0.11 mmol/L (95% CI 0.00
to 0.22, P=0.05). However, this elevation in LDL-c was
found to be non-significant in subgroup analyses. No
statistical difference in Hb1Ac, fasting glucose, fasting
insulin or body weight was observed. In another report
published by Hartweg et al., [124], 24 trials conducted
between 1996-2008 involving 1533 participants were analyzed,
and it was concluded that, in type 2 diabetic patients, 3
fatty acid treatment does not beneficially influence any of the
flowing risk factors: HDL-cholesterol, LDL particle size,
glycemia, insulinemia, inflammatory biomarkers and BP.
However, for some of the measures (e.g. inflammatory
biomarkers), the total number of trial patients was small.
This latter systematic review and meta-analysis re-confirmed
the triglyceride lowering actions and provided supporting
evidence for improvement in thrombogenesis by fish oil
fatty acids, EPA and DHA. Collectively, these findings
also mirror the earlier experiments conducted in healthy
individuals receiving 3 and 6 PUFA supplements.
It can be concluded that the benefits of 3 LC-PUFA on
glucose metabolism, insulin sensitivity and diabetes are best
viewed as an integral part of a wider strategy to improve the
overall health both in healthy and diseased patients alike [19,
121, 125] through changes in diet and lifestyle issues. The
regular consumption of 3 LC-PUFA will influence the
composition of cell membrane phospholipid fatty acids and
triacylglycerols not only of the structural tissues including
platelets, red blood cells, vasculature, heart, kidney, and
liver, but also of the adipocytes and skeletal muscle. One
should not overlook the fact that these two latter
compartments are also central to glucose homeostasis and
the inflammatory process.
Andersson et al., [126] in a study involving 32 healthy
adults found that dietary supplementation with 3.6 g/d of
EPA and DHA against background diets rich in either
saturated or monounsaturated fatty acids led to a significant
increase in 3 LC-PUFA in the skeletal muscle phospholipid
and triacylglycerols. Against the placebo control (olive oil),
the fish oil supplemented groups displayed 2.5 fold higher
proportion of total 3, with EPA being increased 5 fold
compared to the placebo group. It is noteworthy that skeletal
muscle fatty acid composition has been linked to insulin
resistance [127-130] and obesity [129, 131]. More specifically,
these abnormalities have been related to increased 16:0,
lower proportion of LC-PUFA and lower ratio of 6 polyunsaturated 20:4 (arachidonic) to 20:3 (di-homo--linolenic)
acids in skeletal muscle fatty acid pools. Impairment in
insulin sensitivity in healthy men and women by dietary
saturated and monounsaturated fatty acid types was first
demonstrated in the KANWU study [132]. As noted above,
the accumulation of 3 LC-PUFA in skeletal muscle [126]
can lead to change in membrane fluidity, lipid-protein
interactions, ion-channels, enzyme and receptor functions.
Future studies should focus on the potential modulatory
effects of 3 LC-PUFA on the insulin signaling mechanisms
metabolic outcomes of the skeletal muscle including doserelated studies. It is possible that the differential effects on
glucose homeostasis of high and moderate doses of 3 LC-
Role of 3 Longchain Polyunsaturated Fatty Acids in Reducing
Endocrine, Metabolic & Immune Disorders - Drug Targets, 2011, Vol. 11, No. 3
PUFA in type-2 diabetes may at least in part be explained at
this level.
Metabolic Syndrome
Metabolic syndrome is a condition that comprises of an
array of metabolic risk factors that seem to directly
contribute directly to the development of atherosclerotic
cardiovascular disease [6, 7, 133]. It classically refers to the
co-existence of 3 or more different abnormalities including
(i) abdominal obesity (ii) dyslipidemia (elevated triglycerides
and reduced HDL-cholesterol (iii) elevated blood pressure
and (iv) high fasting concentration of plasma glucose or
current treatment for elevated glucose. It has been recognised
that individuals with this cluster of metabolic risk factors
usually carry a high pro-inflammatory burden and manifest a
pro-thrombotic state. The dyslipidemia in metabolic syndrome
is characterized by the presence of high triglycerides, low
HDL-cholesterol, elevated apolipoprotein B (apoB) and
increased small LDL particles. Abdominal obesity and
insulin resistance have been identified as the key underlying
risk factors of metabolic syndrome whilst conditions such
as physical inactivity, aging and hormonal imbalance may
be regarded as contributory [6, 7]. The criteria for clinical
diagnosis of metabolic syndrome may also need to be
modified for some populations (e.g. particularly those of
South Asian ethnicity) where insulin resistance can occur
in the absence of frank clinical obesity, but is commonly
associated with visceral fat distribution (upper body or
abdominal obesity).
DHA
22:6ω3
Blood pressure
Plasma lipids
IR / diabetes
Inflammation
The benefits of 3 LC-PUFA in metabolic syndrome
may be exerted at several different levels both directly and
indirectly (Fig. 4). Whilst there have been some promising
results from animal studies for potential anti-obesity actions
of 3 LC-PUFA, supportive evidence in humans has been
relatively scarce. Furthermore, these trials also lack high
scientific rigor due to low sample size and short study
durations [134]. On the other hand, obesity (in particular
abdominal obesity) which contributes to metabolic syndrome
is closely associated with inflammation and altered fatty acid
metabolism - conditions where 3 LC-PUFA has been
shown to be beneficial [135-137]. In support of this, a recent
population-based prospective cohort study involving 3504
Korean male and female subjects concluded that regular
consumption of fish and 3 fatty acids significantly reduces
the future risk of metabolic syndrome in men but not in
women [138]. It is noteworthy, however, that the women
participants in this study had lower intakes of 3 LC-PUFA;
median consumptions of 29 mg (bottom decile) and 563 mg
(top decile) vs. 37 mg and 786 mg in men respectively which may have been inadequate to deliver a therapeutic
effect.
A common abnormality of insulin resistant patients with
obesity and type II diabetes is dyslipidemia, and is associated
with increased risk of cardiovascular disease [6, 139-141].
This dysregulation of lipoprotein metabolism may be
caused by overproduction of VLDL apolipoprotein (apoB)
B-100 and VLDL-apoC-III, decreased catabolism of apoB
containing particles, and increased catabolism of HDL apoACOOH
EPA
20:5ω3
COOH
• reduce BP (3-5 mmHg)
• increase vascular flow
• improve endothelial function
• favorable mediator profile
• decrease triglycerides (30%)
• improve LDL-particle size (from small to large)
• increase VLDL-apoB-100 secretion
• enhance conversion of VLDL to LDL-apoB-100
• improve insulin sensitivity
• favorably influence adipose tissue
• increase lipolysis
• decrease lipogenesis
• no adverse effect on glycemic control
• reduce pro-inflammatory cytokines
• influence adipokines
• increase adiponectin
• reduce overall inflammatory burden
Fig. (4). Potential benefits of 3 LC-PUFA in metabolic syndrome.
239
240 Endocrine, Metabolic & Immune Disorders - Drug Targets, 2011, Vol. 11, No. 3
1 particles [142]. This can be a result of the global metabolic
effect of insulin resistance and the increase of visceral and
liver adipose tissue or fat. Fish oil may play a role in the
treatment of these abnormalities. The mechanisms of the
action of fish oils involved decreased secretion of VLDLapoB-100 secretion and enhanced conversion of VLDL to
LDL-apo-B-100 [143, 144]. However, 3 fatty acids failed
to influence the fractional catabolic rate of apoB-100
in lipoprotein fractions - VLDL, IDL and LDL. Similar
findings have been observed with type-2 diabetics. In
insulin-resistant obese men with dyslipidaemia the benefits
of cholesterol lowering statin class of drug, atorvastatin, was
further improved when combined with fish oil resulting in
decreased secretion of VLDL-apoB-100, and increased
catabolism of various LDL fractions [145]. It was interesting
to note that these benefits were not achieved with monotherapy of either atorvastatin or fish oil. However, a recent
study which focused on VLDL apoC-III kinetics found
no improvements following supplementation with 3 LCPUFA. This later study which used the same cholesterol
lowering drug atorvastatin (40 mg/d) and 3 fatty acids
(4 g/d) as in the previous investigation [127], in a group of
men with abdominal obesity, found that while fish oil
supplementation lowered the plasma triglycerides, unlike the
drug treatment, it did not alter plasma VLDL apoC-III
concentrations [146]. Combination treatment provided no
further benefits compared with the drug treatment alone.
Apolipoprotein (apo)C-III is an inhibitor of lipoprotein lipase
and of the uptake of triglycerides by the liver.
Inflammatory Markers
A chronic state of low grade inflammation appears to be
a hallmark of the individuals with metabolic syndrome, as
evidenced by abnormal circulating levels of several pro- and
anti-inflammatory cytokines (e.g. CRP, TNF, interleukinsIL-6, IL-10, IL-18) and an array of adipokines (e.g.
adiponectin, adipocyte fatty acid binding protein (A-FABP),
leptin, resistin; [147]). The role of adipokines in obesity and
diabetes has been reviewed [148-150].
The role of adipose tissue as a dynamic endocrine organ
releasing numerous biological mediators that are involved in
the regulation of insulin sensitivity and energy metabolism
has been known for some time. However, its importance as a
regulator of vascular function has only emerged relatively
recently [150-152]. Adipokines influence metabolic processes
including lipid and carbohydrate metabolism, energy balance,
insulin sensitivity and vascular endothelial cell function.
Adiponectin and A-FABP have opposing actions on
cardiovascular health, with adiponectin exerting beneficial
effects, inducing NO production, suppress endothelial cell
activation, scavenge free radicals and promoting endothelial
cell repair and A-FABP having deleterious actions on
vascular endothelial cells and atherosclerosis by promoting
vascular inflammation [152]. In fact, these two adipokines
are potential candidates for therapeutic targets for new drugs
aimed at preventing vascular disease in obesity and diabetes
[153, 154]. Two recent studies in healthy subjects reported
increased serum adiponectin levels in healthy subjects
fed diets containing a lower 6/3 ratio [155], or a salmonrich diet [71]. Conversely, there was no change in serum
Abeywardena and Patten
adiponectin following 3 PUFA supplementation in overweight and moderately obese women [156]. A more recent
study by Kondo et al., [157] reported a gender difference in
that 3 LC-PUFA supplementation (3 g/d derived from fish)
led to an increase in serum adiponectin in women (from
13.5±4.6 to 15.8±5.2 μg/ml. p<0.01), but not in men.
Differences in the serum uptake and accumulation of 3
LC-PUFA between the two sexes were noted, suggesting
that endogenous 3 content may be an important factor in
regulating serum adiponectin concentration. Although the
accumulation of 3 LC-PUFA in adipose tissue is rather
limited, fish oil fatty acids have been linked to several
processes in adipose tissue including prevention of hyperplasia and hypertrophy, induction of mitochondrial biogenesis, induction of adiponectin and reduction in adipocyte
inflammation [137, 158].
The anti-inflammatory actions of 3 LC-PUFA are
associated with reductions in oxidative stress in vivo [159,
160] and in several plasma inflammatory markers; TNF, IL6, intracellular adhesion molecule 1, high sensitive Creactive protein, hsCRP, [161-164], some of which are
closely involved in the regulation of metabolism, obesity,
insulin resistance and type-2 diabetes [165]. A recent study
investigated the association between dietary and plasma fatty
acids with several inflammatory and coagulation markers
[166]. IL-6, hsCRP, TNF, fibrinogen and homocysteine
were quantified in 374 free living healthy men and women.
Plasma 3 fatty acids were inversely associated with hsCRP,
IL-6 and TNF, and plasma 6 PUFA with CRP, IL-6 and
fibrinogen. It was also interesting to note that the most
positive association for all the markers was observed with
the 6/3 ratio of plasma fatty acids, but not with the intake
of different dietary fatty acids. Feeding of 2 g/d (3 mo) of 3
LC-PUFA to elderly patients (N=74) with chronic heart
failure led to a significant reduction in IL-6, TNF and
intercellular adhesion molecule-1 with a positive effect on
hsCRP being found only in smokers [167]. In contrast, a 3
year study of 563 men (64-76 yr) of high cardiovascular risk
found that only serum levels of IL-18 were reduced (-10.5%
vs. baseline) by increased consumption of 3 PUFA,
achieved by dietary counseling (towards a Mediterranean
diet) or via supplementation (2 g/d), and other inflammatory
markers – CRP, TNF, IL-6 - were reduced compared to
baseline values, but no differences between groups were
apparent [168]. Adiponectin also was unchanged. However
as recognised by the authors, there were several limitations
in this study including the heterogeneity of the elderly
population which carried a broad spectrum of morbidity, use
of multiple medications as well the possibility of survivor
bias as the subjects were long-term survivors from a highrisk population.
Parallel to its anti-inflammatory mechanisms, proinflammatory actions of omega-3 PUFA have also been
reported in several cell types [137]. For instance, they have
been found to up-regulate the expression of several
inflammatory mediators; serum amyloid A, TNF, and IL-6
in hepatocyte and adipocytes. Nevertheless, it has been
proposed that such increases may in fact be beneficial as
these mediators increase lipolysis and decrease lipogenesis
leading to an overall reduction in lipid deposition by 3 LCPUFA.
Role of 3 Longchain Polyunsaturated Fatty Acids in Reducing
Endocrine, Metabolic & Immune Disorders - Drug Targets, 2011, Vol. 11, No. 3
Safety, Demand and Supply
A dose of up to 3 g/d of marine based 3 LC-PUFA is
considered safe, and carries the GRAS (Generally
Recommended as Safe) ruling by the US Food and Drug
Administration (FDA). A qualified health claim for fish oil
has also been granted by the FDA [19]. The reported
common side effects after ingestion of fish oil fatty acids
include gastrointestinal upsets, fishy aftertaste, increased
tendency for bleeding, worsening glycemia, and the potential
for a modest rise in LDL-cholesterol. Such effects are dosedependent and at moderate intakes have been found to be
infrequent. While many preparations of fish oil supplements
containing varying degrees of EPA and DHA and
combinations thereof are available in the market place, the
only dietary 3 LC-PUFA supplement which has been
approved by the FDA is Lovaza (3 LC-PUFA acid ethyl
esters; GlaxoSmithKline) which contains 465 mg of EPA
and 375 mg DHA per 1 g capsule (840 mg total 3 LCPUFA/g capsule). A FDA warning of potential bleeding
complications with the co-administration of anticoagulants
has been included in the product label for Lovaza [28].
The demand for marine based 3 LC-PUFA has grown
steadily over the recent years and the market is predicted to
increase as the potential health benefits ranging from
positive outcomes in fetal and early childhood growth and
development to anti-inflammatory actions and benefits for
neuropsychiatric disorders (cognition, Alzheimer’s disease,
mood and depression) are being confirmed through robust
clinical trails. The myriad of benefits of these 3 fatty acids
on cardiovascular disease has been established, and the
guidelines issued by the American Heart Association (AHA)
specifies the consumption of at least 2 servings of fatty fish,
high in EPA and DHA per week. For the secondary
prevention of coronary artery disease, the AHA recommends
an intake of 1 g/d of EPA and DHA via daily consumption of
fish, or alternatively via use of fish oil supplements.
Not only is the amount of fish needed to be consumed to
meet this recommendation impractical for many people, the
concerns over potentially harmful environmental pollutants
(mercury, polychlorinated biphenols, dioxins) that have been
detected in the marine food chain and in many commercial
fish supplies means that the recommended intakes of seafood
may not be a viable option. Furthermore, the continued
decline of wild fish stocks and sustainability issues
which influence the supply and demand chain and thus
affordability, are also key factors that affect the overall
intake of 3 LC-PUFA. In addition, there are those who are
unable to consume seafood due to allergies, personal dislike
and lack of availability. The agri-business sector has
recognised the supply and demand issues facing 3
LC-PUFA which are currently obtained from marine or
algal sources. Therefore, alternative approaches are being
investigated and recent genetic engineering developments
suggest that higher land plants crops may become a major
source of future 3 LC-PUFA [169]. A genetically modified
soybean oil high (16-28%) in stearidonic acid (18:43,
SDA; Fig. 1) has been reported to increase the 3 index in
humans through conversion of SDA to EPA [170, 171].
Nevertheless, the extent of increase in EPA reported was
small with no conversion of SDA to DHA despite intakes of
241
3.66 - 4.2 g/d of SDA. Whilst no adverse effects were noted
after SDA supplementation, there was no change in any of
the basal plasma lipid parameters. It is expected that better
health outcomes may be achieved by novel plant based oils
containing 3 LC-PUFA (C20). In this regard, the synthesis
of both EPA and DHA in several land crop plants has
been achieved by transfer of genes from microorganisms
[172-174]. It is highly likely that future supplies of 3 LCPUFA may soon be derived not only from marine-based raw
materials, but also from land based crops such as soybean,
cottonseed and rapeseed.
SUMMARY
It is clear that 3 LC-PUFA, EPA and DHA, possess an
array of biological actions that can lead to an improvement
in cardio-metabolic health. When provided by diet, these
fatty acids are absorbed readily and are preferentially
incorporated into membrane phospholipids and cellular
triacylglycerol pools. These features - the ability to partition
into and remain as integral components - in different cellular
pools are also crucial determinants of their biological actions,
as evident by their reported modulation of membrane fluidity,
cell signaling including G-protein coupled receptors, altered
eicosanoid production, enzyme activities, drug-receptors and
ion channels as well as nuclear receptors and altered gene
expression.
A considerable body of evidence suggests that 3 LC
PUFA lowers blood pressure and promotes vascular health in
humans. In this regard, DHA has been found to be more
effective than EPA. The observed effects of blood pressure
lowering are small (3-5 mmHg) and dose-dependent, and
the extent of reduction appears to vary with the degree
of hypertension. However, relatively high doses (>3 g/d)
of fish oil are needed to achieve hypotensive action, and
tend to suggest that at the wider population level, the use of
3 LC-PUFA for the management of hypertension may be
of limited value. Nevertheless, the finding that fish oil
potentiates the action of several anti-hypertensive therapies
is encouraging, and should be viewed not only for the
increased efficacy of drug-therapy but also for the other
multitude of intrinsic cardio-vascular health benefits
extended by EPA and DHA.
Whilst there has been some concern in the past over the
consumption of large doses of 3 PUFA (5-8 g/d) in type-2
diabetics, more recent studies have confirmed that moderate
doses (1-2 g/d) have no adverse outcomes on glucose
homeostasis in such patients. Several meta-analyses have
confirmed that the most consistent action of fish oil fatty
acids in insulin resistance and type-2 diabetes is the
reduction in triglycerides. Additional benefits of 3 PUFA
that would contribute to a reduction in overall cardiovascular
risk have also been observed and include changes in LDL
particle size, from the smaller more atherogenic form to
larger particles which are less likely to be incorporated into
plaques, improvements in inflammatory profile and vascular
health. For these reasons, although any direct improvement
of glycemic control is absent, 3 LC-PUFA should still be
included as a part of the overall diet and lifestyle strategies
designed to address insulin resistance and type-2 diabetes. In
242 Endocrine, Metabolic & Immune Disorders - Drug Targets, 2011, Vol. 11, No. 3
healthy subjects, fish oil has been found to reduce insulin
response to oral glucose supplementation without affecting
the glycemic response. Further studies are warranted to
assess whether or not such actions will indeed manifest as
true prevention of the development of insulin resistance and
metabolic syndrome.
A chronic state of low-grade inflammation appears to be
a hallmark of the individuals with metabolic syndrome,
as evidenced by abnormal circulating levels of several
pro- and anti-inflammatory cytokines. 3 LC-PUFA are
effective modulators of inflammation resulting in reduction
in several plasma inflammatory markers - particularly TNF,
IL-6, intracellular adhesion molecule-1 and high sensitive Creactive protein, hsCRP. Taking into consideration the
pleiotropic nature of their actions, it can be concluded
that dietary supplementation with 3 LC-PUFA will lead to
improvements in cardio-metabolic health parameters. It is
also important to note that most of the common pharmacotherapies currently being used to control hypertension,
dyslipidemia, type-2 diabetes, and obesity/metabolic syndrome
do not interact adversely with these fatty acids, but in some
instances work synergistically, thereby providing additional
cardiovascular benefits.
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