Omega-3 fatty acids

Transcription

Omega-3 fatty acids

Christian A. Drevon
Omega-3 fatty acids
- metabolism and mechanisms of action of essential fatty acids
xxxx_0 Omega-3 Möllers_orig.indd 1
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CONTENTS
1.Introduction
2.Dietary sources of omega-3 fatty acids
3.Essential fatty acids
i. Chemistry, origin, metabolism
4.Development and growth
i. Essentiality
ii. Foetal development
iii. Premature infants
5.Mechanisms of action of omega-3 fatty acids
i. Eicosanoids
ii. Substrate specificity
iii. Membrane fluidity
iv. Lipid peroxidation
v. Acylation of proteins
vi. Gene interactions
6. Omega-3 fatty acids and lipoproteins
i. VLDL and chylomicrons
ii. Cholesterol and LDL
iii. High density lipoprotein (HDL)
7. Omega-3 fatty acids and vascular changes
8. Omega-3 fatty acids and diseases
i. Cardiovascular diseases
a. Atherosclerosis
b. Arrhythmias
c. Human studies
I. Epidemiological studies
II. Clinical trials
ii. Cancer
iii. Inflammatory diseases
a. Rhematoid arthritis / joints
b. Psoriasis
c. Atopic dermatitis
d. Inflammatory bowel diseases
e. Asthma and allergy
f. Diabetes
g. Obesity
9. Omega-3 fatty acids and central nervous system
i. Depression
ii. Schizophrenia
iii. Alzheimer’s and Parkinson’s disease
iv. Attention deficit hyperactivity disorder (ADHD)
10.Safety of intake
i. Bleedings
ii. Lipid peroxidation
iii. Inflammations
iv. Diabetes
v. Body weight
vi. Contaminants
11.Diagnostics
12.Conclusions and recommended intake
13.References
14.Abbreviations
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26
34
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Christian A. Drevon is a Medical Doctor and Professor in nutrition at the
Faculty of Medicine in the University of Oslo. Professor Drevon has been
an active researcher within the fields of medicine and nutrition for over
35 years, and has more than 240 articles published in international journals and books. His research spans the areas of molecular nutrition with
special focus on fatty acids, including omega-3 fatty acid, and fat-soluble
vitamins. Moreover, he has been actively studying diet in relation to
obesity, diabetes, cardiovascular disease, metabolism, genetics and fetal
development. He has also been a very active communicator of modern
nutrition to the public via talks, interviews, consultant for the industry
and he has had columns in some of the largest Norwegian newspapers
(VG and Aftenposten).
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1. Introduction
Lipids are important nutrients, providing 25-45% of dietary energy
in most affluent societies, whereas certain isolated low-technology
populations may consume as little as 9-12% of energy as lipids (1,
2). Lipids are important for use, storage and transport of energy,
for insulation (thermal and electrical) and for mechanical protection. In addition, lipids provide polyunsaturated fatty acids (PUFA)
that are essential nutrients of importance for several cellular
functions in the body (3-5) including ligands for transcription
factors, precursors of signal molecules and building blocks in all
cells of the body. It is well known that a given type of nutrients
may have several biological effects. Retinol, vitamin D and calcium
are all examples of well-characterized essential nutrients with a
variety of roles in several different tissues and organs. Retinol is,
for example, essential for visual function, fertility, defence against
infections, regulation of growth during foetal development, for
maintenance of epithelial tissues and differentiation of cells (6).
Still, the mechanism of action of retinol can be described by
functioning as a chromophore and as ligand for transcription
factors (7). Vitamin D and calcium also have several different
biological effects as messengers, building blocks and metabolic
regulators in many tissues and cell types.
Many nutritional factors play important roles in the development of several diseases. Coronary heart diseases, stroke, high
blood pressure, overweight, gallstone, several types of cancer,
some types of birth defects and inflammatory diseases, are all
related to dietary factors. Excess intake of saturated fat, trans fat
and cholesterol represent the most well established dietary risk
factors for development of cardiovascular diseases (11), whereas very long-chain omega-3 fatty acids and monounsaturated
fatty acids may provide beneficial effects (12-14). Fish and other
marine animals, and oils from these sources are rich in omega-3 fatty
acids, and they have been important ingredients of the human
diet for many populations during thousands of years. In addition,
several thousand studies of epidemiological as well as experimental types have been performed using cod liver oil or fish oil, mostly
demonstrating beneficial effects on health. These facts provide
good evidence that dietary intake of omega-3 fatty acids from
marine animals is healthy as well as very safe. Although concern
about pollutants in food products of marine origin has been expressed, there seem to be markedly more advantages than harmful effects of consuming marine foods. This is probably due to the
healthy effects of omega-3 fatty acids themselves, in addition to
the positive effects promoted by replacing unhealthy nutrients
like hard fat with marine fat.
Based on these facts, it is no surprise that omega-3 fatty acids also
have beneficial effects on many biological systems, including immune reactions, blood platelets, smooth muscle cells, endothelial
cells, liver cells, heart cells, adipocytes, osteoblasts and neurons.
They may also promote regulation of growth and apoptosis in
several different cell types (8, 9). It is not known which biological effects of omega-3 fatty acids are essential, but it is possible
that the omega-3 fatty acid-derived eicosanoids are crucial, as
well as the unique structural properties of omega-3 fatty acids
for cell membranes. In addition, it is possible that the function of
omega-3 fatty acids as ligands for transcription factors is essential.
The essentiality of a nutrient may be evaluated by the clinical signs
and symptoms of deficiency, omega-3 fatty acid deficiency being
exemplified by skin folliculitis, reduced growth and reduced visual
acuity among children, and reduced neuronal function (8, 10).
Table I. Food sources of omega-3 and omega-6 fatty acids.
Fatty AcidC-Atoms Double bonds Sources
Linoleic acid
α-linolenic acid
EPA
DPA
DHA
4
18:2 18:3 20:5 22:5
22:6
n-6
Vegetable oils, margarines, grain
n-3Green leaves, linseed, soybean and canola oil
n-3
Marine animals, cod liver oil and fish oil
n-3
Marine animals, cod liver oil and fish oil
n-3
Marine animals, cod liver oil and fish oil Omega-3 fatty acids – Möller´s
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2. Dietary sources of omega-3 fatty
acids
In most modern societies the quantitatively most important
source of omega-3 fatty acids is derived from α-linolenic acid
(ALA, C18:3 omega-3, also designated 18:3n-3) found mostly in
vegetable oils. Linseed oil, canola oil and soybean oil contain approximately 57%, 8% and 7% α-linolenic acid, respectively, but
these oils are without any eicosapentaenoic acid (EPA, C20:5n-3) or
docosahexaenoic acid (DHA, 22:6n-3) (Table I). Significant amounts
of very long-chain omega-3 fatty acids are obtained from fatty fish
(herring, mackerel, salmon, trout, eel, anchovies, sardines, etc), in
addition to fish oil, cod liver oil, tuna fish oil and krill oil (Table II). The
fattier the fish is, the more EPA and DHA it will contain. The ratio
of these two fatty acids will, however, differ between the species
of fish (15) (Table II). The omega-3 fatty acids in fatty fish or cod
liver are not synthesized in the fish itself but in very small organisms called phytoplankton before the marine fatty acids are transferred through the food chain to the respective fishes, seals and
whales. A traditionally important and widely used source of very
long-chain omega-3 fatty acids in some (Nordic) countries is cod
liver oil, whereas fish oil is used widely in many countries. Krill has
recently come into focus as a large source of marine oil in which
the substantial proportion of the fatty acids are bound in phospholipids, representing approximately 45% of the total fatty acids
present. In most other marine oils the majority of omega-3 fatty
acids are found in triglycerides.
The biological effects of very long-chain omega-3 fatty acids are
much stronger than those of α-linolenic acid on parameters that
are important for prevention of diseases (18). However, there are
some indications that α-linolenic acid may also be an important
cardioprotective nutrient (19), although these findings are controversial (20). In the Nordic countries the average intake of the
very long-chain omega-3 fatty acids (EPA, docosapentanoic acid
(DPA) and DHA) ranges from 0.2 to 0.7 g/day. Most of the human
intervention studies with very long-chain omega-3 fatty acid
supplementation have used 2-10 g/day (18,21), whereas the total
fat intake in most industrialized societies is approximately 80-100
g/day.
The dietary intake of α-linolenic acid ranges between 1 and 2 g/
day in most populations where vegetable oils are in common
use, whereas the intake of very long-chain omega-3 fatty acids
varies between 0 and 14 g/day (8,16). True vegetarians and vegans
consume just tiny amounts of the very long-chain omega-3 fatty
acids, whereas traditional Greenland Inuits have been reported to
eat more than 14 g/day (16) (Table III).
Table II. Fatty acid composition of vegetable oils, marine oils (% of fatty acids)
and grain (g/100 g) (15, 17).
Source of oilSaturatesMonoenes
Polyenes
n-3
n-6
Soy
Corn
Sunflower
Rape seed
Cod liver
Krill Tuna fish
Palm oil
Coconut oil Oatmeal
Wheat flour
Rye flour
Rice, natural 61
60
64
29
29
49
45
10
3
2
1
1
1
8
1.3
1
9
27
31
38
0.5
0
2
1
1
1
53
58
63
20
2
4
7
10
3
0.1
0.1
0.1
0
16
13
12
6
16
26
31
51
91
1
0.2
0.3
0.6
23
27
24
64
51
24
23
39
7
2
0.3
0.2
0.6
Table III. Dietary fats in Greenland Inuit and Danish food
(per 3000 kcal) (16)
Dietary FatInuitsDanes Fat (% of total energy)
39
42
Saturates (% of total fat)
23
53
Monoenes
58
34
Polyenes
18:2, n-6
5
10
18:3; 20:5; 22:5; 22:6, n-3 14
3
P/S ratio
0.84
0.24
n-3 PUFA (g/d)
14
3
n-6 PUFA (g/d)
5
10
n-3/n-6
3
0.3
Omega-3 fatty acids – Möller´s
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3. Essential fatty acids
4. Development and growth
3 i. Chemistry, origin and metabolism
Fatty acids are hydrocarbon-chains with a methyl group in one
end of the molecule (termed omega = ω or n) and an acid group
(often called carboxylic acid) in the other end (Figure 1). There are
two major nomneclatures of fatty acids. In the most commonly
used nomenclature the carbon atom next to the carboxyl group
is called the alfa-carbon (α-carbon) with the consecutive carbons
named β-carbon etc. The letter n is often used instead of the Greek
ω to describe the methyl end. Furthermore, it is quite common to
use the systematic nomenclature for fatty acids where the locations of double bonds are indicated with reference to the carboxyl
group.
4 i. Essentiality
Observations of patients on very limited diets for long periods of
time demonstrated that omega-3 fatty acids are essential (5). It
should be noted that in addition to being on an omega-3 fatty
acid-deficient diet for several months, the patients had very little
adipose tissue before they became essential fatty acid deficient
(5). This combination of several months of omega-3 fatty acid
deficiency and small stores of essential omega-3 fatty acids in the
adiopse tissue, prepares the ground for clinical signs of omega-3
fatty acid deficiency such as scaly and haemorrhagic dermatitis,
haemorrhagic folliculitis of the scalp, impaired wound healing,
reduced growth in children, reduced visual acuity and neuropathy
(5, 25-31). A biochemical hallmark of omega-3 fatty acid deficiency
is the low concentration of omega-3 fatty acids, in particular EPA,
in the different plasma lipid fractions (27).
Figure 1. Nomenclature of fatty acids
Figure 2 outlines the structures of different types of fatty acids.
Saturated fatty acids are “filled” (saturated) with hydrogen.
Monounsaturated fatty acids have one double bond in different
positions from the ω-end. In PUFAs the first double bond may be
between the 3rd and the 4th carbon atom from the ω carbon,
and these are called omega-3 fatty acids. If the first double bond
is between the 6th and 7th carbon atom counted from the methyl end, they are called omga-6 fatty acids. The body is unable
to introduce double bonds between position 7 and the ω end of
the molecule. PUFAs are produced only by plants and phytoplanktons, and are therefore essential to all higher organisms, including fish and mammals. Omega-3 and omega-6 fatty acids cannot
be interconverted, therefore both these classes of fatty acids are
required in the diet (8). Omega-3 and omega-6 fatty acids are
chain-elongated and desaturated in the body as illustrated in Figure 3.
Retroconversion of DHA to EPA often takes place and can thereby
provide an important precursor for eicosanoids like prostaglandins, thromboxanes, leukotrienes and hydroxy-fatty acids, although
the retroconversion is relatively limited in man (22). Retroconversion is a peroxisomal reaction, involving one cycle of β-oxidation
with some auxilliary enzymes (23).
ALA can be chain-elongated, desaturated and converted to EPA,
and thereafter to DHA in higher organisms like mammals (Figure 3).
In adults this conversion is efficient enough to provide sufficient
EPA and DHA to avoid any symptoms of omega-3 fatty acid deficiency, but in the foetus and in premature and newborn infants,
DHA as well as arachidonic acid (AA, 20:4n 6) are both essential
(24).
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4 ii. Foetal development
If the dietary intake of omega-3 fatty acids is well above minimum,
these fatty acids are found in all parts of the body, especially in
membrane phospholipids. It seems as if DHA is the most important
omega-3 essential fatty acid because it is found in large amounts
in certain tissues even in cases where dietary intake of omega-3
fatty acids is scarce. The highest concentration of omega-3 fatty
acids is observed in the non-myelin part of the central nervous
system, as exemplified by the grey matter of the brain and the rods
and cones of the retina (31-33). There is also a high concentration
of DHA in germ cells like sperm (34). A large part of the accumulation of PUFA in the brain occurs in the last trimester of pregnancy
(31,35-37), making preterm babies vulnerable, for omega-3 as well
as omega-6 fatty acid deficiency. In addition, there is a marked
increase in brain size during the first two years of life making the
initial years of life critical for the development of functions related
to the central nervous system (38).
During foetal development the essential fatty acids are transferred
from the mother via placenta to the developing foetus (39). There
are special proteins in placenta preferentially transporting DHA
and AA (40-43). Smuts et al. found an increase in fetal levels of DHA
after supplementation to mothers, but no effect on the mothers’
levels (44). When the stores of DHA before pregnancy are low,
DHA supplementation may primarily affect the fetal DHA status,
because DHA is preferentially transported to the fetus.
Blood pressure has been reported to respond to fish oil supplementation dose-dependently. A meta-regression analysis of 90
randomized controlled trials showed that the systolic blood pressure decreased by 2.1 mmHg and the diastolic blood pressure by
1.5 mmHg in a mixed population with a dose of ~ 3.7 g/d fish
oil mainly containing EPA and DHA (45). Some data also suggest
that omega-3 fatty acids may retard development of preeclampsia as this condition seems to be rare among women on a diet
containing a high amounts of omega-3 fatty acids (46, 47). Two
meta-analyses on the effect of controlled intervention with
marine oil supplementations both showed insignificant effects on
the development of preeclampsia (48, 49). However, it should be
noticed that omega-3 LC-PUFA supplementation during pregnancy may enhance pregnancy duration and head circumference,
although the effects are quite small.
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CH3 – (CH2)n – CH2 – CH2 – COOH
Figure 2. Structure of fatty acids
Stearic acid is a trivial name for a saturated fatty acid with 18 carbon atoms “filled” with hydrogen (18:0). Oleic acid has 18 carbon atoms and one
double bond in the ω-9 position (18:1n-9), whereas EPA is chemically written 20:5n-3. This is the most common systematic nomenclature used. It is
also possible to describe the fatty acids related to the acidic end called delta = ∆ = D from greek (presented in red in the figure).
Figure 3. Synthesis of very long-chain omega-3 and omega-6 fatty acids
The essential fatty acids (omega-3 and omega-6 fatty acids) can be produced only by plant cells or by phytoplankton. Phytoplankton also has
desaturases and elongases that are required for making very long-chain omega-3 fatty acids. The omega-3 and omega-6 fatty acids are not interconvertable. When animals eat PUFAs, the fatty acids will be transferred through the nutrition chain and end up in humans after eating seal, whale,
fatty fish or products thereof. In the body, the different essential fatty acids will be metabolized as shown in the figure above. Retroconversion of DHA
to EPA may also take place in humans.
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A normal pregnancy is characterised by increased inflammation,
insulin resistance and hyperlipidemia. In preeclamsia, these effects
of pregnancy are exaggerated and in many ways preeclampsia resembles the metabolic syndrome (50). Due to the effects of very
long chain omega-3 fatty acids in the metabolic syndrome it has
been hypothesized that the characteristics and risks of preeclampsia might be reduced by supplementation. However, the results
from a meta-analysis performed by Makrides et al. (48) stated that
the findings were too inconclusive to recommend routine supplementation of marine oils to reduce risk of preeclampsia. Still, some
studies suggest that supplementation with long-chain PUFA
during pregnancy promotes a small increase in pregnancy duration, birth weight and a reduced risk of early preterm delivery in
high risk pregnancies (44,48,49).
It should also be noted that maternal supplementation with 2.5
grams of very long-chain omega-3 fatty acids during pregnancy
and lactation provides more DHA to the infant and reduces
maternal plasma triacylglycerol levels compared to supplementation with n-6 fatty acids. (51).
After birth the infants obtain essential nutrients through breastmilk (52,53). There is a dose-dependent transfer of very long-chain
omega-3 fatty acids (EPA and DHA) from the maternal blood to
the mother’s milk (52,54,55). It is easy to supply fertile or pregnant
women with very long-chain omega-3 fatty acids via dietary intake of fatty fish or marine oils. Maternal intake of PUFA during
pregnancy is an efficient way to provide the foetus or neonate
with these essential fatty acids (56). A specific transport protein
for DHA has been purified from human placental tissue (57). Even
mothers with no dietary intake of DHA or EPA have up to 0.3% of
the milk fatty acids as very long-chain omega-3 fatty acids, suggesting that the supply of these fatty acids is of high priority. In
addition to providing omega-3 fatty acids via the mother’s milk, it
is also possible to give the infants very long-chain omega-3 fatty
acids directly in formulas or via supplementation with cod liver oil
or fish oil (58), although this does not seem to be as efficient as
maternal supplementation during pregnancy (59,60). An attempt
to increase the content of DHA in breast milk by providing flaxseed oil (rich in ALA) was inefficient (61), indicating that DHA must
be considered essential for neonates.
It has been shown that mothers on the Faeroe Islands give birth to
bigger babies than babies born in Denmark, partly due to longer
gestational period (62). This observation might be explained by
the higher intake of omega-3 fatty acids among the mothers
on the Faeroe Islands than the Danish mothers. Moreover, this
is supported by data from an intervention study where supplementation of 2.7 g/day very long-chain omega-3 fatty acid from
week 30 of pregnancy was associated with increased duration of
gestation (4 days) and higher birth weight (107 grams heavier) as
compared to the control group receiving olive oil as a supplement
(63). However, Helland et al (56) did not find any increased size
of infants born of Norwegian mothers supplemented with 10
mL of cod liver oil (~ 2.5 grams of long-chain omega-3 fatty acids
daily) from week 17 of pregnancy until 12 weeks after delivery, as
compared to supplementation with corn oil. The reason for this
difference among the Danish and Norwegian observation is not
clear, but Szajewska et al (49) did not find any enhanced growth
among infants delivered by mothers supplied with marine
PUFAs during pregnancy, except for a marginal increase in head
circumference.
Helland et al (59) also observed that maternal daily intake of 10
mL cod liver oil from week 17 of pregnancy and during the initial
12 weeks lactation, promoted a significant improvement of 4.1 IQ
points for cognitive function of children at 4 years of age (Figure 4).
This marked increase in IQ at 4 years of age might actually be large
enough to be of practical importance.
Figure 4. Scores for children whose mothers took cod liver oil (n=48) or corn oil (n=36) during pregnancy and lactation. Kaufman Assessment Battery for Children (K-ABC) : MPCOMP: Mental Processing Composite, SEQPROC: Sequential Processing, SIMPROC: Simultaneous Processing, NONVERB: Nonverbal Abilities.
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The beneficial effect reported on global IQ was not observed in
the Norwegian cohort of full term infants at the age of 6 and 9
months, or at 7 years of age. However, there was a significant correlation between maternal plasma concentration of alfa-linolenic
acid (18:3n-3) and DHA in phospholipids during pregnancy and
the child’s sequential processing at 7 years (64). Examples of abilities included in sequential processing are memory of numbers
and word order. The lack of lasting effect on IQ at the age of 7
years may be due to a dilution of the effects of very long-chain n-3
fatty acids supplied during pregnancy and via breast milk during
the three first months after delivery.
Bakker et al (65) found no correlation between cognitive performance at 7 years of age and long chain PUFA (LC-PUFA) levels in
umbilical venous plasma phospholipids, representing the prenatal fatty acid availability, and plasma phospholipids sampled at
7 years of age. However, they observed a significant association
between umbilical plasma DHA concentrations and Maastricht
Motor Test total score and quality score (66), suggesting that there
might be an association between the bioavailable DHA and motor
function.
Another study showed that supply of formula enriched with
0.45% arachidonic acid (AA) and 0.30% DHA for two months
promoted a significant reduction in general movement (sign of
immature central nervous system) in healthy term infants (67).
4 iii. Premature infants
The disruption of pregnancy poses pre-term infants at increased
risk of essential fatty acid deficiency. Several studies have examined the effect of LC-PUFA supplementation to preterm born
infants on cognitive functions in later life.
A recent randomized controlled trial among 143 preterm infants
on LC-PUFA supplementation revealed significantly higher visual
evoked potentials, indicating improved visual acuity, at 4 months
corrected age among the treatment group who had received
about triple the amount of DHA during the first months of life,
as compared to the control infants (71). The infants were fed milk
containing approximately 1 E% DHA versus ca 0.3 E% in the intervention and control group, respectively. It should be noted that
two Cochrane reviews from 2008 concluded that there was no
clear long-term effect of DHA supplemented formula on visual
function or general development in term (72) or preterm infants
(73). These reviews should be judged by some scepticism because
they select studies to be evaluated on peculiar criteria, often eliminating highly relevant studies.
Carlson et al (74) reported that visual acuity was increased among
preterm infants supplemented with very long-chain omega-3
fatty acids, while growth was slightly decreased (75). They
suggested that the relative growth retardation could be due to
EPA competing with AA, because a combination of DHA and AA
improved growth.
An interesting study from the Inuits in Arctic Quebec indicate
that cord blood DHA levels are significantly associated with a
better Fagan score at 6 months and Bayley Mental Development
Index and Bayley Psychomotor Performance at 11 months of age
(68). In contrast, DHA from breast-feeding was not related to any
indicator of cognitive or motor development in this group of full
term infants.
Visual functions are incompletely developed at birth, but there
is a rapid development during the first year of life. DHA is a
major structural lipid of retinal photoreceptor outer segment
membranes. Biophysical and biochemical properties of DHA may
affect photoreceptor membrane function by altering permeability, fluidity, thickness, and lipid phase properties. Tissue DHA
status affects retinal cell signalling mechanisms involved in photo
transduction and DHA insufficiency is associated with alterations
in retinal function (69).
Malcolm et al (70) reported an association between the DHA
status of term infants and retinal sensitivity, suggesting an essential role of this very long-chain omega-3 fatty acid in the development and function of retina. However, maternal DHA status was
not significantly associated with infant retinal sensitivity, and no
direct effect of maternal supplementation was observed.
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In an extensive study of severely preterm infants (birth weight
< 1500 g), Henriksen et al (76) found a significant effect of supplementation with approximately 30 mg of DHA and AA each per
100 mL to human milk fed on cognitive functions at 6 months of
corrected age. The infants given DHA and AA scored significantly
better on problem solving skills (measured by Ages and Stages
Questionnaire) and had lower Event Related Potentials after being
presented to a standard image, indicating better recognition. This
latter study by Henriksen et al (76) took advantage of electro encephalography in combination with visual stimulation with familiar and new objects. The stimuli included a pseudo-randomized
series of colorful images, in which a standard image (a cartoon
ball) was shown in 70% of the presentations and novel images
(different cartoon toys and animals) were shown in 30% of the
presentations. The novel images were never repeated, and 1 novel
image did not follow another novel image. This paradigm elicits
a negative, long-lasting, ERP deflection that is larger for novel
stimuli (figure 5). This negativity decreases with repetitions,
presumably because of recognition. Normal infants quickly
recognize the standard cartoon, whereas the novel images
continue to elicit large negative amplitudes. Thus, it is possible to infer memory function from the difference between ERPs
recorded in response to a unique image and those from standard
images (76).
It should be noted that α-linolenic acid is probably not as efficient
as very long-chain omega-3 fatty acids in providing the crucial
DHA to preterm infants (78). This is most likely due to low capacity for chain elongation and desaturation in premature infants.
Although most studies have been performed on preterm infants,
there is evidence that very long-chain omega-3 fatty acids may
be important also for term neonates (30,31,59). It is clearly recommended that very long-chain omega-3 fatty acids be included
in the formula for new-born, preterm, as well as term infants
(31,76,78,79). In preterm infants it is also recommended that AA be
given because the central nervous system as well as other tissues
need this essential fatty acid for optimal growth (76,80).
Uauy et al (81) have reviewed controlled trials in term infants given
formula with or without DHA. They conclude that there is a significant positive correlation between the total DHA equivalents provided (DHA plus a fraction of ALA) and visual acuity at 4 months
of age.
A randomized controlled trial on supplementation with DHA
and AA to 60 preterm born infants (< 33 weeks and 750-1800
g) showed increased lean mass and reduced fat mass at 1 year
corrected age among the supplemented group (77). However,
Henriksen et al (76) found no effect of DHA and AA supplementation in growth parameters at 6 months corrected age among
human milk-fed, very low birth weight infants.
Figure 5. Mean electroencephalogram (EEG) measurements (n 81) at the frontal position after standard (A) and novel (B) images. After the standard image (A), infants in the intervention group had significantly lower (negative) amplitude, compared with the control group. After the novel images (B), no significant differences between the groups could be detected.
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5. Mechanisms of action of
omega- 3 fatty acids
The different mechanisms by which omega-3 fatty acids can
influence biological systems and thereby health, are outlined in
Figures 6-8.
5 i. Eicosanoids
Eikosa means 20 in Greek and refers to the number of carbon
atoms in the PUFA from which the eicosanoids are formed.
Eicosanoids are important signal molecules (Figure 6) (8,82) including leukotrienes, prostaglandins, thromboxanes, prostacyclins,
lipoxins and hydroxy-fatty acids. In addition, two new families of
lipid mediators have been discovered, resolvins (resolution phase
interaction products) and protectins, both derived from omega-3
PUFA (83). These have potent anti-inflammatory, neuroprotective
and pro-resolving properties. EPA-derived mediators are named
resolvins of the E series (RvEs), and those synthesized from DHA
are resolvins of the D series (RvDs) and protectins. Eicosanoids are
important for several cellular functions like platelet aggregability, chemotaxis (movement of blood cells) and cell growth (Figure
7). Thus, eicosanoids influence hemostasis, inflammation and cell
differentiation including cancer.
5 ii. Substrate specificity
Omega-3 fatty acids may execute their action by having a different ability to interact with enzymes compared to other fatty
acids. For example EPA is a poorer substrate than all other fatty
acids for esterification to cholesterol (84) and diacylglycerol (85).
For other enzymes, omega-3 fatty acids are the preferred substrate
(86), leading to preferential incorporation of omega-3 fatty acids
into some phospholipids. Altered substrate specificity of omega-3
fatty acids for acyl-CoA:cholesterol acyltransferase (ACAT) and
acyl-CoA:diacylglycerol acyltransferase (ADGAT) illustrates why
relatively little triacylglycerol (TAG) may be incorporated into very
low density lipoproteins (VLDL), and why EPA and DHA are preferentially found in certain phospholipids (84,85).
5 iii. Membrane fluidity
When large amounts of very long-chain omega-3 fatty acids are ingested, there is high incorporation of EPA and DHA into membrane
phospholipids, which may alter the physical characteristics of cell
membranes (87). Altered fluidity may lead to changes of membrane protein functions. The very large amount of DHA in phosphatidyl ethanolamine (PE) and phosphatidyl serine (PS) found in
certain areas of the retinal rod outer segments, is probably crucial
for the function of membrane phospholipids in light transduction, as these lipids are located close to the rhodopsin molecules
(88). It has been shown that the flexibility of membranes of blood
cells from animals fed fish oil is markedly increased (89,90), and
this might be important for the microcirculation, particularly in
cold environments. It seems as if phosphatidyl choline (PC) membranes containing DHA support faster flip-flop and permeability
rates than other less unsaturated PCs (91). Whole blood viscosity
is reduced during fish oil feeding (92,93), and increased incorporation of very long-chain omega-3 fatty acids into plasma lipoproteins changes the physical properties of low density lipoprotein
(LDL), promoting reduced melting point of core cholesteryl esters
(94).
Figure 6. Synthesis of eicosanoids from arachidonic acid (AA) or eicosapentaenoic acid (EPA).
The abbreviations in parenthesis demonstrate the eicosanoids formed from EPA. AA and EPA can be metabolized by different enzymes to form signal
molecules called eicosanoids. Eicosa, Greek = 20 (carbon atoms). The eicosanoids are local signals with short half-lives and with several effects on
smooth muscle cells, blood platelets, white blood cells and secretory cells.
Omega 3-fatty acids – Möller´s
11
29-12-09 14:14:26
5 iv. Lipid peroxidation
Lipid peroxidation products may act as biological signals in certain
cells (12). One of the major concerns with intake of omega-3 fatty
acids has been the high degree of unsaturation and thereby the
possibility of promoting peroxidation. Modified LDL might be endocytosed by macrophages and initiate development of atherosclerosis. Oxidatively modified LDL has been observed in atherosclerotic lesions (95), and LDL rich in oleic acid has been found
to be more resistant to oxidative modification than LDL enriched
with omega-6 fatty acids in rabbits (96).
There are several ways to quantify the degree of lipid peroxidation. Diene conjugation of PUFA, degradation of PUFA, appearance
of lipid peroxides (LPO), appearance of thiobabituric acid reactive
substances (TBARS), and antibodies against oxidized LDL have
all been used to evaluate lipid peroxidation in vivo (97). There is
also some evidence that expired ethane is a measure of peroxidized omega-3 fatty acids, although this is not yet well established
(98). Many experiments have been performed to examine if dietary intake of omega-3 fatty acids is associated with increased
lipid peroxidation in humans (97). The results of these studies are
somewhat controversial. In many of the studies demonstrating
enhanced LDL oxidation after omega-3 fatty acid supplementation, conclusions are based on measurement of the amount of
thiobarbituric acid reactive substances (TBARS) formed during
oxidation (99-102). Because TBARS are oxidation products of fatty
acids containing three or more double bonds, variations in TBARS
production reflect the lipid composition rather than the susceptibility to lipid peroxidation (103).
Some studies have focused on the susceptibility of LDL isolated
from subjects on different diets, to be oxidized in vitro in the presence of copper or azo-derivatives (97). In these cases the diene
conjugation, fatty acid pattern, LPO-formation, electrophoretic
mobility of LDL and uptake in macrophages have been measured
before and after incubation with the oxidizing agents (97,99102). Although the hypothesis of oxidative modification of LDL is
supported by many observations, it is still unclear which of the
abovementioned parameters that reflects the development of
atherosclerosis. It is possible that omega-3 fatty acids may influence another player in the modification of LDL in vivo, the mononuclear cells. These cells may release enzymes or H2O2 that may
modify LDL and thereby promote LDL uptake by macrophages
in the vessel wall. This was examined by supplementing male
smokers with combined hyperlipidemia with very long-chain
omega-3 fatty acids and with moderate amounts of antioxidants
in a randomized, double-blind placebo controlled trial (104).
With advanced methods to measure oxidation of circulating LDL
from high-risk subjects, there was no significant increase in lipid
peroxidation after intake of 5 g/day of very long-chain omega-3
fatty acids for 6 weeks.
Some data suggest that intracellular hepatic lipid peroxidation
might explain some of the hypolipidemic effects of dietary PUFA
via increased post-ER pre-secretory proteolysis of apoB100 degradation (105).
Unesterified DHA is chemically highly susceptible to peroxidation,
potentially forming several bioactive lipid peroxides. One class
of compounds is cyclopentenone neuroprostanes, which is very
reactive and structurally similar to anti-inflammatory cyclopentenone prostaglandins. Some of these neuroprostanes are potent
inhibitors of nuclear factor kB (NF-kB) signaling and may contribute to the anti-inflammatory actions of DHA (106). This is an
example of interactions between lipid peroxidation products and
the inflammatory processes.
The susceptibility of fatty acids to oxidation is often assumed to
be directly related to the degree of unsaturation. However, some
in vitro and in vivo studies suggest that the relation between
Figure 7. Biological effects of eicosanoids
derived from arachidonic acid (AA) and
eicosapentaenoic acid (EPA).
Different cell types preferentially produce
certain eicosanoids; eg. thromboxanes (TX)
in blood platelets, prostaglandins (PG) in endothelial cells and leukotrienes (LT) in white
blood cells. Eicosanoids derived from EPA are
usually less potent than eicosanoids derived
from AA.
12
29-12-09 14:14:27
chemical structure and peroxidation susceptibility is less
straightforward than deduced from a chemical point of view.
Based on in vivo data demonstrating unaltered or reduced formation of lipid peroxidation products after omega-3 fatty acid intake
(104,107), and more recent data on reactive oxygen species (ROS)
production and direct superoxide scavenging by the omega-3
fatty acids, it is possible that these fatty acids might act as indirect anti- rather than pro-oxidants (108). Although some of the
published data are conflicting (109), several of the well-performed
and widely accepted studies indicate few or no harmful effects
of omega-3 fatty acids. In some cases it seems as if EPA and DHA
promote less peroxidation as compared to shorter PUFA with
fewer double bonds (110). Based on epidemiological studies it
should be noticed that the dietary amount of saturated fatty acids,
trans-fatty acids and cholesterol are the lipids that are positively
correlated with the development of coronary heart diseases,
whereas the amount of PUFA is negatively correlated with the
incidence of coronary heart diseases (8,11). It is suggested that
proper amounts of antioxidants are required with increased intake
of PUFA to minimize the risk of lipid peroxidation (97).
5 v. Acylation of proteins
Acylation of proteins is important for anchoring certain proteins in
membranes or folding of the proteins, and it seems to be crucial
for the function of these proteins (111,112). Although saturated
fatty acids are most commonly linked to proteins, omega-3 fatty
acids may also acylate proteins (113). It has been demonstrated
that PUFAs (AA and EPA) may inhibit palmitoylation and alter
membrane localization of a protein kinase (Fyn) (114), whereas
C14:2 may be acylated to a protein kinase (Fyn), thereby altering
its raft localization and promote reduced T cell signal transduction
and inflammation (115).
5 vi. Gene interactions
Fatty acids or their derivatives (acyl-CoA or eicosanoids) may
interact with nuclear receptor proteins that bind to certain regions
of DNA and thereby alter transcription of these genes (Figure 8). The
receptor protein, often interacting with another nuclear receptor, may, in combination with a fatty acid, function as a transcription factor. The first described example of this is the peroxisome
proliferator-activated receptor (PPAR) (116). Fatty acids that are
blocked from being β-oxidised, may be better ligands for PPAR
than natural fatty acids (117). PUFA may also influence expression
of several glycolytic and lipogenic genes independent of PPAR
(118,119). Prostaglandin J2 (PGJ2), an eicosanoid derived from AA,
may bind to PPAR, although this is controversial (120). Fatty acids
(EPA and DHA) as well as eicosandoids can bind directly to PPARα
and PPARγ (121,122).
PUFAs have marked effects on gene expression by regulating
the activity or abundance of three other families of transcription
factors, including liver X receptors (LXRs) (α and β), hepatic nuclear
factor-4 alfa (HNF-4α) and sterol regulatory element binding proteins (SREBPs) 1 and 2 (123). These transcription factors play major
roles in hepatic carbohydrate, fatty acid, triglyceride, cholesterol
and bile acid metabolism. Non-esterified fatty acids or fatty acid
metabolites bind to and regulate the activity of PPARs, LXRs and
HNF-4. In contrast, PUFAs regulate the nuclear abundance of SREBPs by controlling the proteolytic processing of SREBP precursors,
or by regulating transcription of the SREBP-1c gene or turnover
of mRNA (SREBP-1c). The omega-3 and omega-6 PUFAs are feedforward activators of PPARs, whereas these same fatty acids are
feed-back inhibitors of LXRs and SREBPs. Saturated fatty acyl coenzyme A thioesters activate HNF-4α, whereas coenzyme A thioesters
of PUFAs antagonize HNF-4α action. It has also been shown that
PUFAs including DHA are ligands for another transcription factor,
retinoid X receptor (RXR), which is important for expression of
several genes regulated by different nutrients (124,125) (Figure 8).
Figure 8. Mechanisms of action for polyunsaturated fatty acids.
Eicosanoids (derivatives of PUFAs with 20
carbon atoms) are important signal molecules, often with different biological effect
if the eicosanoids are derived from AA or EPA.
Different types of fatty acids exhibit different substrate specificity for several types of
enzymes of importance for fatty acid metabolism, eg. causing formation of phospholipids
with different species of fatty acids. PUFAs
are chemically more prone to lipid peroxidation, although several in vivo data indicate
that peroxidation of marine omega-3 fatty
acids is required to produce important antiinflammatory and even antioxidatively active
fatty acid derivatives. There is some evidence
that membrane structure as well as acylation
of proteins (covalent binding of fatty acids
to proteins) may be functionally influenced
by VLC omega-3 fatty acids as compared to
other fatty acids. Fatty acids as well as fatty
acid derivatives can bind to certain transcription factors and thereby alter transcription of
genes.
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6. Omega-3 fatty acids and lipoproteins
The initial finding among Greenland Inuits living on a traditional
diet was that in spite of having a high intake of fat similar to that of
Danes living in Denmark, they had lower plasma concentrations of
triacylglycerols, cholesterol as well as VLDL and LDL (16). This was
probably due to a low intake of saturated fatty acids concomitant
with a substantially higher intake of monoenes and of very longchain omega-3 fatty acids than the Danish intake (Table III). An
overview of the most important effects of omega-3 fatty acids on
plasma lipoprotein metabolism is presented in Figure 9.
6 i. VLDL and chylomicrons
Omega-3 fatty acids promote a striking reduction of triacylglycerols (TAGs) in VLDL and chylomicron particles (18,19,126). With
daily intake of 2-4 g/day of very long-chain omega-3 fatty acids,
the plasma concentration of TAGs is reduced by 20-30% (127),
and the hepatic synthesis of triaglycerols is decreased, probably
because omega-3 fatty acids inhibit esterification of other fatty
acids in addition to being poor substrates for TAG-synthesising
enzymes (85). Very long-chain omega-3 fatty acids may also reduce
TAG production by increasing fatty acid oxidation via peroxisomal
β-oxidation (128). Postprandial plasma concentration of free fatty
acids is also substantially decreased by feeding fish oil, probably
causing reduced availability of fatty acids for TAG synthesis (128130). It is shown that EPA and oleic acid are absorbed and secreted
in association with chylomicrons to similar extents (131,132). EPA
as well as DHA cause enhanced clearance of postprandial plasma
TAG via lipoprotein lipase (133,134).
6 ii. Cholesterol and LDL
Intake of PUFA may reduce the concentration of plasma LDL
levels, but many studies demonstrate unaltered or sometimes
even increased plasma LDL levels with intake of marine omega-3
fatty acids (126). The amount of cholesteryl esters in nascent VLDL
is markedly reduced in the presence of EPA (84).
This might cause a decrease in plasma LDL-cholesterol concentration observed in some reports (126). However, the reported fall
in plasma LDL-cholesterol concentration may be due to the concomitant reduction in dietary intake of saturated fat (21). Moreover, there is substantial evidence that in normal subjects, as well
as in patients with type IV and V hyperlipoproteinemia, intake of
more than 3 g/day of very long-chain omega-3 fatty acids causes
a fall in plasma concentration of VLDL and a concomitant increase
in LDL (21,126,135). The reason for this response is not known,
but a similar effect is observed in subjects whose plasma TAG is
significantly reduced by drugs or diets.
6 iii. High density lipoprotein (HDL)
In most studies of human lipoprotein metabolism, gram quantities of very long-chain omega-3 fatty acids cause a small increase
(1-3%) in the plasma concentration of HDL cholesterol (18,21,126).
Very often this increase in HDL occurs simultaneously with a fall in
plasma VLDL concentration. The increased concentration of HDL
cholesterol may be explained by the reduced concentration of
free fatty acids in plasma (128-130) causing reduced net flux of
cholesteryl esters from HDL to LDL and VLDL via reduced activity
of the cholesteryl ester transfer protein (136,137).
Figure 9. Model showing how omega-3 fatty acids interact with lipid metabolism as indicated with yellow arrows. The plasma level of triacylglycerol in chylomicrons (CM) (1) and very
low density lipoproteins (VLDL) (2) is decreased in non-fasting and fasting conditions, respectively. CM triacylglycerol are probably reduced because of higher activity of lipoprotein lipase (3), whereas
VLDL triacylglycerol is reduced because of reduced synthesis and secretion from hepatocytes (4), and possibly because hepatic peroxisomal fatty acid oxidation is increased (5), in addition to whole
body glucose oxidation being increased (6). Plasma concentration of free fatty acids and glycerol is reduced for unknown reasons (7), whereas some adipose tissues decrease in size in rats during
feeding with omega-3 fatty acids (8), (ref 165).
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29-12-09 14:14:30
7. Omega-3 fatty acids and vascular
changes
It has been suggested that blood platelets, viscosity, coagulation
and fibrinolysis might be influenced in advantageous ways by
dietary intake of omega-3 fatty acids. However, the data in the
rheological area are somewhat conflicting (138). Most of the
reported findings show that primary bleeding time is increased
when fish, fish oil or fish oil concentrates are consumed, but a
significant number of studies do not show any alteration of
bleeding time (139). There is also evidence that platelet survival
time is extended in subjects receiving fish oil. β-thromboglobulin,
a measure of in vivo platelet activation, was reduced in some
studies with supplementation of very long-chain omega-3 fatty acids, but there are conflicting data (82,92,140). The type of
eicosanoids produced by platelets and endothelial cells might
explain the increased bleeding time observed in many studies
(Figure 7). Provision of very long-chain omega-3 fatty acids to healthy
volunteers as well as to subjects with increased risk of cardiovascular disease, reduced the generation of platelet activating factor
(PAF; important for platelet aggregation) (141,142), which may be
of importance for suppression of rolling and adherence of monocytes on activated endothelial cells (143).
Dietary intake of fish oil may increase erythrocyte deformability
and fluidity, increase plasma fluidity and decrease red cell aggregation (92,144). Fish oil intake may also reduce plasma concentration of fibrinogen, but this issue is controversial. Although some
studies have shown that fibrinolysis is increased with intake of
omega-3 fatty acids, a series of other studies have failed to confirm
these findings (145-147).
A cross-sectional study from Tanzania reported that fish eaters
had markedly lower blood pressure than a vegetarian population
living close by (157). A meta-analysis of 36 randomised trials found
a reduction in systolic blood pressure of 2.1 mmHg and in diastolic blood pressure of 1.6 mmHg (158). Most trials have used relatively high doses of fish oils (~ 3.6 g/day), and the effect of lower
intakes of omega-3 fatty acids remains to be established. Several
mechanisms could account for this effect. Incorporation of EPA
and DHA in membrane phospholipids may increase systemic arterial compliance (159). It is also possible that EPA and DHA might
improve endothelial function (160) via eicosanoids or working
as ligands for transcription factors. Moreover, a meta-analysis of
30 randomized trials found that fishoil intake (~ 3.5 g/day EPA
plus DHA) reduced heart rate by 1.6 heartbeats per minute as
compared to the controls (161). It has been suggested that a
reduced number of heartbeats per minute may reduce the risk
of dying from cardiovascular disease (CVD) (162), although the
results are controversial (163).
It has been observed that supplementation with omega-3 fatty
acids (3.4 g/day) may reduce the long-term continuous rise in
blood pressure after heart transplantation and this supplementation may offer a direct or indirect protective effect on the kidneys
(164). From the intervention trials it can be concluded that supplementation of very long-chain omega-3 fatty acids decreases
blood pressure markedly, but relatively high doses are required to
obtain significant effect. The high doses of omega-3 fatty used in
these studies were not associated with serious adverse effects.
It has been shown that fish oil given to pigs (148), or EPA and
DHA incubated with aortic rings (149), increases the release of
endothelium derived relaxing factor (EDRF; NO radical released
from l-arginine, promoting dilatation of blood vessels). Also it
has been shown that long-term supplementation with EPA in
patients with CHD augments both NO-dependent and non-NOdependent endothelium-dependent forearm vasodilatation in
patients with coronary artery disease (150).
Release of platelet derived growth factor (PDGF; promotes
increased aggregation of platelets) is markedly reduced in cultured
aortic endothelial cells exposed to EPA (151), and mRNA for PDGF
is reduced in mononuclear cells from humans supplemented with
EPA and DHA (152,153).
Supplementation with omega-3 fatty acids may reduce blood
pressure, in particular among hypertensives (154-156). Although
relatively high doses are required to give significant reduction in
blood pressures, the effect is comparable to some of the drugs
used for treatment of high blood pressure. From a meta-analysis
of clinically controlled trials it has been estimated that systolic and
diastolic blood pressures are decreased by 0.66 and 0.35 mmHg,
respectively, per gram of very long-chain omega-3 fatty acids
supplied through the diet (155).
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8. Omega-3 fatty acids and diseases
8 i. Cardiovascular diseases
Cardiovascular diseases can be due to several different genetic and
environmental factors (166) as outlined in Figure 10. Cardiovascular
diseases are mainly caused by atherosclerosis, and give rise to development of myocardial infarction, cerebral infarction, cognitive
decline, and gangrene and loss of function in the extremities. In
addition to being the most common cause of death in developed
countries, cardiovascular diseases cause fear, sorrow, pain, serious
handicaps and loss of productivity. Moreover, cardiovascular diseases are very expensive to treat.
It has been shown that dietary factors such as saturated and trans
fatty acids, cholesterol, some coffee lipids and sodium, in addition to lack of omega-3 fatty acids may promote development of
atherosclerosis (11,167-170). Smoking, high blood pressure, high
plasma concentration of homocysteine, diabetes mellitus, obesity and low physical activity are additional factors that promote
development of atherosclerotic lesions. All these factors are influenced by genes, as well as environmental factors, resulting in the
outlined conditions or so called risk factors (Table IV).
8 i. a. Atherosclerosis
Development of atherosclerosis is a very complex process in
response to insults to the endothelium and smooth muscle cells in
the vessel wall (168). Atheros is a Greek word for porridge, pointing
to the central necrotic area of the atherosclerotic plaque, whereas
sclerosis indicates the hardening of the surrounding area typical of
several chronic inflammations (Figure 11).
The first cell biological precursor of atherosclerosis may be the adhesion of monocytes to the endothelial cells in the middle-sized
arteries, whereas the first macroscopic sign of atherosclerosis is
the appearance of fatty streaks. These are small yellow/white
elevations aligned in the longitudinal direction of the arteries just
beneath the endothelial cell layer, containing lipid-rich macrophages and T-lymphocytes (Figure 11). These fatty streaks can develop
into intermediate lesions loaded with lipid-rich macrophages and
some smooth muscle cells. These lesions may develop further
into fibrous plaques that contain a fibrous cap, more lipids, more
inflammatory cells and some necrotic tissue with a significant
amount of cholesterol mainly derived from digested LDL-particles.
Blood platelets are attracted to the dysfunctional endothelium
covering the lesion. Activation of several types of hydrolytic enzymes may lead to weakening of the fibrous cap and plaque rupture, promoting release of dead material (debris) into the blood
stream. This is followed by immediate coagulation and thereby
reduction of blood flow to an extent where the tissue may die (171).
Thus, development of atherosclerosis is related to disturbance
of the vessel wall functions including diffusion of lipoproteins;
expression of adhesion molecules on the surface of endothelial
cells and white blood cells; adhesion of white blood cells to the
endothelium; and migration of these inflammatory cells between
the endothelial cells into the intima of the arteries (Figure 11). LDL
diffuses into the vessel wall and interacts with proteoglycans in
the subendothelial space before it may be modified by oxidation
and taken up via specialized scavenger receptors in macrophages,
causing accumulation of cholesteryl esters and lipid loaded “foam”
cells (Figure 11).
Effects of dietary factors on intermediary risk factors and cardiovascular outcomes
Nutrients
Fatty acids
Saturates
Monounsaturated
Trans fatty acids
Polyunsaturated
n-3
n-6
Coffee lipids
Carbohydrates, type & quality
Nuts
Legumes
Fruits
Vegetables
Salt
Micronutrients
Food processing
Cooking
Intermediate risk factors
Cholesterol levels
Blood pressure
Hemodynamics
Endothelial function
Inflammation
Immune response
Oxidative stress
Satiety & weight
Insulin sensitivity
Thrombosis
Cardiovascular diseases
Atherogenesis
Atrial fibrillation
Congestive heart failure
Acute plaque rupture
Myocardinal infarction
Stroke
Sudden death
Cognitive decline
Peripheral arterial disease
Modifying dietary factors
Figure 10. Cardiovascular risk and diet. Many dietary factors influence cardiovascular disease risk, eg saturated, monounsaturated, trans, polyunsaturated fatty acids of the omega–3 and -6
family; carbohydrate quantity and type; legumes, nuts, fruits, and vegetables; alcohol; micronutrients; food processing; and food preparation methods. Dietary habits also affect several intermediary
risk factors, including all classes of lipoproteins, vascular hemodynamics, inflammation, endothelial function, insulin sensitivity, satiety and weight gain, coagulation and thrombosis, and risk of
having arrhythmias (166).
16
29-12-09 14:14:30
Blood platelets also stick to the endothelium of the affected arterial wall and release their content of growth factors (like platelet
derived growth factor = PDGF). These growth factors stimulate
smooth muscle cells to migrate from the outer part of the vessel
wall (muscular layer) and divide to make up a “tumor” the intima.
Several of these events promote the accumulation of proteoglycans (important components in connective issue) followed by
calcification. All these events are influenced by growth factors and
cytokines produced by the different cell types in the blood and
the vessel wall.
The effects of very long-chain omega-3 fatty acids on some
parameters of importance for the development of atherosclerosis
are outlined in Figure 10 and Table V. Some of these effects of omega-3 fatty acids have been demonstrated in controlled clinical
trials, whereas other findings refer to studies in animals or in vitro
(8,12,82,172,173). Among the positive effects of omega-3 fatty
acids are reduced activity of blood platelets via thromboxanes
(TXA2), reduced platelet activating factor (PAF), reduced PDGF,
reduced chemotactic effect via leukotrienes (LTB4) and relaxation of smooth muscle cells via EDRF which promotes increased
blood flow and reduced blood pressure. Furthermore, omega-3
fatty acids may reduce blood viscosity via membrane alterations
(although this is controversial), reduced expression of adhe-
sion molecules on cell surface membranes, and lower plasma
concentration of TAG in chylomicrons as well as VLDL. The reduced
level of serum TAG is partly due reduced hepatic synthesis of TAG
(85,174) and partly to due to enhanced clearance of chylomicrons
in the fed state (133,175). It should be noted that the TAGs exhibit
enhanced clearance, whereas apoB is not cleared more rapidly
when marine fatty acids are added to the diet (174).
Genetic factors
Conditions
Sex
Plasma cholesterol
Age
LDL
Gene mutations
HDL
Plasma homocystein
Platelet reactivity
Blood pressure
Plasma glucose
Environmental factors
Smoking
Physical activity
Pollution
Diet
Fatty acids
saturates
monounsaturates
n-3 fatty acids
n-6 fatty acids
Coffee lipids
Sodium
Antioxidants
Table IV. Factors related to development of cardiovascular diseases.
Genetic and some environmental factors in combination will result in conditions like
high plasma concentration of cholesterol and glucose, and high blood pressure.
Figure 11. Longitudinal section of the vessel wall during development of atherosclerosis
High plasma concentration of low density lipoproteins (LDL), glucose and homocysteine, high blood pressure, smoking, low physical activity and several genetic factors, are risk factors for development
of atherosclerosis. We do not know how all the single risk factors promote atherosclerosis, but one of the first events is exposure of adhesion molecules for white blood cells on the surface of endothelial
cells. Then the monocytes will bind to these receptors, roll along the surface of the endothelial cells, migrate into the subendothelial space and settle to take up among several other altered proteins,
modified LDL (LDL’). Some LDL will diffuse into the vessel wall, interact with proteoglycans and be oxidized to LDL’ in intima. LDL’ will be taken up via a special type of receptor (scavenger receptor)
which is unregulated by cholesterol influx. Cholesterol ester will accumulate in large amounts inside the macrophages (foam cells), whereas T-cells and smooth muscle cells will migrate into the vessel
wall and contribute to formation of a tumor. This tumor contains large amount of dead macrophages and smooth muscle cells filled with LDL’-derived cholesterol, some lymphocytes and proteoglycans
that the macrophages can attach the centre of the tumor is most often surrounded by a fibrous cap. This fibrous cap can be digested and suddenly release the debris from the atherosclerotic lesion into
lumen of the artery. This sudden liberation of dead material and lipids into the circulation promotes an instant formation of a blood clot that can reduce the blood flow and thereby irreversibly damage
the tissue. Often the atherosclerotic lesion will be complicated by platelet aggregation. The numbers in this figure refer to the numbers given in Table V, outlining some of the known effects of omega-3
fatty acids on reactions that are important for development of atherosclerosis. 1-5, rheological (blood) effects; 6-8, immune effects including; 9, 14, 15, blood pressure; 10, platelet aggregation; 11,
lipoproteins; 18 rupture of the fibrous cap with release of debris from atherosclerotic plaque promoting acute thrombus formation and ischemia.
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FactorFunctionEffects of omega-3 fatty acids
=>
1. Thromboxane (TXA2) Platelet aggregation
Vasoconstriction
(TXA3)
2. Prostacyclin (PGI2)
Platelet aggregation
Vasodilatation
=>(PGI3)
3. Tissue plasminogen activator (tPA)
Thrombolysis Thrombolysis (LTB5)
4. Fibrinogen
Blood clotting ?
5. Platelet activating factor (PAF)
Platelet activation
6. Leucotriens (LTB4)
Chemotactic factor
Neutrophil aggregation (LTB5)
7. Growth factor (PDGF)
Chemotactic factor
Mitogen Inflammation & cell growth
8. Cytokines (IL-1, TNF)
Monocyte adhesion
Stimulates PAF
Inhibits plasminogen activation Tissue reactions
Smooth muscle cell proliferation
O2 radicals in neutrophils
9. Endothelial derived relaxation factor (EDRF)
Reduced vasoconstriction in arteries Vasodilatation
10. Endothelial leakage
Capillary integrety
11. Cell adhesion
Cell adhesion Inflammation
12. Oxygen free radicals
Cell damage
Modification av LDL
=> / ?
13. Serum lipids
cholesterol
Lipoprotein synthesis and clearance
=> /
triacylglycerols
14. Blood pressure Hypotensive
15. Arterial compliance
EDRF?
16. Cardiac excitability
Reduced fast voltage-dependent
sodium channels and maintenance Antiarrhytmic
of L-type calcium channels
17. Fibrous plaque stability
Reduced proteolytic activity
=> => =>
=>
=>
=>
=>
=>
=>
=> =>
=>
=> =>
=>
=>
Table V. Effects of very long-chain omega-3 fatty acids on factors related to the development of atherosclerosis.
8 i. b Arrhythmias
In cells and animal studies it has been shown that incorporation of marine omega-3 fatty acids reduces the risk of arrhythmias, probably due to inhibition of the fast voltage-dependent
sodium-channel (176-178). Arrhythmias causing sudden cardiac
death often arise from ischemia-induced electrical instability in
the heart muscle. Ischemia may promote depolarization of cardiac
membranes by reducing the activity of sodium/potassium ATPase,
which enhances interstitial potassium concentration, making the
resting membrane potential more positive. This may make myocytes more likely to depolarize due to small stimuli and thereby
initiate an arrhythmia (179).
Several randomized clinical studies in patients have been performed to examine the effect of marine fatty acids on cardiac
arrhythmias (180). See later section on page 30.
Beneficial effects of supplementation with very long-chain
omega-3 fatty acids have been shown on development of atherosclerosis in pigs (181-185) as well as monkeys (186-188) (Figure 11 and
Table V). These animal studies might provide important clues as to
what mechanisms operate in vivo in different animal models for
development of atherosclerotic diseases.
18
8 i. c Human studies
In spite of indications based on animal studies we have to rely on
data from humans based on epidemiological, clinical and laboratory studies. These human studies suggest that very long-chain
omega-3 fatty acids may be important in preventing development of atherosclerosis as well as thromboembolic events (189197). There are, however, some reports of no beneficial effects
of omega-3 fatty acids (198-200), and a number of studies have
not shown an inverse correlation between fish consumption and
coronary heart disease (201-202).
8 i. c. I Epidemiological studies
Dyerberg et al (189-191) published observations on Greenland Inuits that initiated a widespread interest in omega-3 fatty
acids. Inuits following a traditional life-style had significantly
lower incidence of coronary heart diseases compared to Danes
on an industrialized diet (191), in spite of both groups consuming
approximately the same amount of total fat. The Inuits had a high
intake of fat from seals, whales and fish, whereas Danes ate fat
predominantly from milk and meat products (16), leading to a
striking difference between the type of dietary fatty acids eaten
(Table III). The Danes had a high intake of saturated fat and low
intake of very long-chain omega-3 fatty acids, whereas the Inuits
had on average 14 g/day of very long-chain omega-3 fatty acids
in their diet (16). Later, Kromhout et al. (192) published a prospective observational study demonstrating that a moderate intake of
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fish (1-2 meals of fish/week) was associated with a 50% decrease
in risk of developing coronary heart disease (CHD). Studies from
coastal and inland villages in Japan suggested that a high intake
of omega-3 fatty acids from fish was associated with low mortality
of cardiovascular diseases (193,194).
The Chinese traditional diet is low in dietary fat with considerable regional variability in the amount and type of fat consumed
and the pattern of chronic diseases. An epidemiological survey
of 65 rural counties in China (6500 subjects) (203) conducted in
the 1980s reported that fish consumption correlated significantly
with the levels of DHA in red blood cells (RBC), selenium and glutathione peroxidase in plasma, and that the proportion of DHA in
RBC was inversely associated with total plasma triglyceride concentrations. A strong inverse correlation was found between DHA
in RBC and cardiovascular disease (CVD). DHA in RBC also correlated negatively with most chronic diseases and appeared to be
more protective than EPA and DPA. These results suggest that the
protective effect of fish consumption and DHA also extends to a
diet with low intake of dietary fat (203).
Among 3910 adults aged ≥65 years followed prospectively for an
average of 9.3 years, modest consumption of tuna or other broiled
or baked fish, but not fried fish or fish sandwiches, is associated
with lower risk of ischemic heart diseases (IHD) death, especially
due to arrhythmia. Cardiac benefits of fish consumption may vary
depending on the type of fish meal consumed (204).
Erkkillä et al. showed that high proportions of long-chain omega-3
fatty acids in the diet as well as serum lipids were associated with a
substantially reduced risk of death in patients with previous coronary artery disease (205). Other studies from Finland also reported
beneficial effects of fish/omega-3 fatty acid intake on the progression of atherosclerosis among women with previous coronary
artery disease (206,207).
He et al. (208) performed a meta-analysis of 11 eligible studies including 222 364 individuals with an average 11.8 years of follow-up
in prospective cohort studies that indicated an inverse association
between fish consumption and CHD mortality rates. Eating fish
once per week significantly reduced CHD mortality rates by 23%.
Yamagishi et al (209) monitored approximately 58 000 Japanese
men and women for on average 12.7 years. They observed inverse
associations of fish and dietary omega-3 PUFA intakes with risks
of mortality from IHD, myocardial infarction, heart failure, and total cardiovascular disease, although these were attenuated with
adjustment for other risk factors. These inverse associations were
more evident between dietary omega-3 PUFA intake and heart
failure. Compared with the lowest quintile, dietary intakes of fish
and omega-3 PUFA in the highest quintile were associated with
18 - 19% lower mortality rates of total cardiovascular disease with
no effect on stroke.
Sun et al (210) investigated the effect of long-chain omega-3 fatty
acids in blood on the risk of nonfatal myocardial infarction among
32 826 participants of the Nurses’ Health Study. Higher plasma
concentrations of EPA and DPA were associated with a lower risk
of nonfatal Myocardial infarction among women.
Among 79 839 female nurses followed for 14 years, those who ate
fish more than twice per week had a lower risk of total stroke and
a significantly reduced risk of thrombotic infarction compared to
those who ate fish less than once a month (211).
It has been demonstrated that dietary intake of long-chain
omega-3 fatty acids reduces the risk of cardiac arrest (194). Feeding experiments in animals (176,177) support this observation,
whereas one report showed increased risk of coronary heart
diseases with high intake of omega-3 fatty acids (199). Some other
studies show neither beneficial nor harmful effects of omega-3 fatty acids/fish intake in relation to cardiovascular diseases (200,201).
Overall, fish consumption seems to be beneficial, and a systematic
review of 11 prospective cohort studies concluded that fish intake
notably reduced mortality due to coronary heart disease in populations at increased risk (202). Moreover, another review of several
epidemiological and intervention studies concludes that omega-3
fatty acids protect against cardiovascular disease (212).
8 i. c II Clinical trials
Several secondary prevention trials have assessed the effects of
omega-3 fatty acids. Studies on patients undergoing percutanous
transluminal coronary angioplasty (PTCA; blocking of narrow arteries), have revealed conflicting data regarding the effect of very
long-chain omega-3 fatty acids on the frequency of restenosis.
Although several reports show reduced restenosis after PTCA following supplementation of very long-chain omega-3 fatty acids
(213-216), several larger studies show no effects (217-219). However, supplementation with very long-chain omega-3 fatty acids
has been reported to improve graft patency after coronary bypass
operations (196). This finding is in line with a prospective study
among more than 2000 myocardial infarction survivors, which
reported a significant decrease in all cause mortality (29%) after
consuming at least two fatty fish meals weekly for two years (197).
About 20% of the subjects in the fish group used supplementation with fish oil capsules instead of increased fish intake. The results for these individuals were similar to the rest of the fish-eating
group (197). The open label GISSI Prevenzione trial randomised 11
324 patients after myocardial infarction to either a daily capsule
of about 850mg omega-3 fatty acid, 300 mg vitamin E, both, or
neither. After 3.5 years, participants randomised to fish oil capsules
had a reduction in relative risk of 15% in the composite primary
end point of total mortality, non-fatal myocardial infarction, and
stroke (P = 0.023) (219). The relative risk of cardiovascular death
was reduced significantly by 30%, and of sudden death by 45%.
These benefits were apparent within just four months of randomisation (220).
In an Asian population, patients with suspected myocardial infarction randomised to fish oil capsules experienced a significant
reduction in mortality from coronary heart disease after one year
compared with placebo (221). This study has been heavily critisized due to lack of scientific credibility (222).
A Norwegian study reported no benefit of fish oil supplementation after 1.5 years in patients who had suffered a myocardial infarction, compared with placebo (223). This may be caused by the
habitually high fish consumption among the general population
in that area, with omega-3 supplementation conferring no additional benefit.
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Benefit for secondary prevention was observed in a high-fishconsuming population in The Japan EPA Lipid Intervention Study
(JELIS) (224). The study included 18,645 patients (14,981 subjects
with no history of coronary artery disease and 3664 patients with
a history), all of whom were on statin treatment. They were randomized to 1.8 g/day EPA (no DHA) and followed for 4.6 years. Compared with statin-only, the EPA/statin group showed a significant
19% reduction in major coronary events. The effect was similar in
both the primary and secondary subgroups. The beneficial effects
of EPA on CHD risk was not associated with changes in the levels of
total cholesterol, TG, HDL cholesterol, or LDL cholesterol, indicating that non-lipid factors played a major role in the cardioprotective effect of EPA.
In a subanalysis of the JELIS study it was shown that administration of highly purified EPA appeared to reduce the risk of recurrent
stroke in a Japanese population of hypercholesterolemic patients
receiving low-dose statin therapy (225).
A diet and reinfarction trial (DART2) among 3114 men with angina,
unexpectedly found that individuals advised to eat oily fish, and
particularly those given fish oil capsules, had a higher risk of cardiac death than people not given advice to eat fish (11.5% v 9%,
P = 0.02) (226). The investigators speculated that this may have
arisen from risk compensation or other changes in patients’ behaviour. When these unexpected results from a large number of
subjects were included in a recent Cochrane Review (227), it was
concluded that there was no reduction in risk of total mortality or
CVD with increasing intake of long-chain omega-3 fatty acids. In
spite of these findings the authors state: “there is no evidence we
should advice people to stop taking omega-3 fats”.
Thies et al. (228) has found that atherosclerotic plaques readily incorporated long chain omega-3 fatty acids, which induced
changes that can enhance stability of the plaques, whereas increased consumption of long-chain omega-6 fatty acids did not
affect carotid plaque fatty acid composition or stability. Stability of
plaques may explain reduction in non-fatal and fatal cardiovascular events associated with increased intake of long-chain omega-3
fatty acids.
Whereas results from observational studies on fish consumption and risk of stroke are inconsistent, He et al (229) assessed
the relationship between fish intake and incidence of stroke by
meta-analysis of 9 independent cohorts, and found a significant
negative trend between fish intake and risk of stroke. These results
suggest that intake of fish is inversely related to risk of stroke, particularly ischemic stroke.
One extensive meta-analysis of primary and secondary CHD prevention trials has shown that intake of fish or omega-3 fatty acids
can significantly reduce the risk of all-cause mortality, CHD death,
and sudden death (230).
20
Sudden death
The cardioprotective effects of fish oil have been attributed to
antiarrhythmic effects of EPA plus DHA (180). Some clinical trials
have examined whether omega-3 fatty-acid supplementation affects arrhythmias in patients with implantable cardioverter defibrillators (ICD).
Leaf et al. (231) randomized 402 patients with ICDs to 2.6 g/day EPA
+ DHA vs. placebo and found significant reduction in time to first
ICD discharge, with most benefit observed among patients with
preexisting CHD. In contrast, Raitt et al. (232) observed no benefit
of EPA + DHA (1.3 g/day), although they excluded patients with
recent myocardial infarction. The most recent clinical trial included
546 patients with ICDs, randomized to either 0.8 g/day of EPA +
DHA or control, to assess appropriate ICD discharges for ventricular tachycardia/ventricular fibrillation (233). Whereas no difference
in the primary endpoint was observed, there was a trend (P = 0.13)
towards longer event-free survival in the EPA + DHA group among
the prespecified subgroup with prior Myocardial infarction (n =
342). Although the authors of this study concluded that their results did not indicate a strong protective effect of intake of marine
omega-3 PUFAs against ventricular arrhythmia in patients with
ICDs, Harris et al. (226) concluded in their review that the data support the use of omega-3 fatty acids in post-Myocardial infarction
patients with or without ICD placement. However, in non-ischemic patients with ICDs, there is little support for the use of fish oils in
arrhythmia suppression.
8 ii. Cancer
In spite of the fact that animal fat is associated with many of the
carcinogenic effects of dietary fat (234), there is some scientific
evidence that omega-3 fatty acids may protect against development of certain types of cancers (235,236). In a study including 24
European countries, fish and fish oil consumption were shown to
protect against the later promotional stages of colorectal carcinogenesis (235). Augustsson et al (237) found that men who ate fish
more than 3 times a week, had lower risk of prostate cancer (the
strongest association was found for metastatic cancer) compared
with those who ate fish less than twice per month. Additional intake of long-chain omega-3 fatty acids (0.5 g/d from food) was
associated with 24% reduced risk of metastatic cancer.
Although the extensive report on “Food, nutrition, physical activity
and the prevention of cancer: a global perspective“ by World Cancer Research Fund and the American Institute for Cancer Resaerch,
2007 (238), concluded that there is limited evidence suggesting
that eating fish protects against colorectal cancer, there are several recent studies reporting beneficial effects on risk of developing colorectal cancer (239-241). The findings are, however, mixed
(242).
In patients with an abnormal rectal cell proliferation pattern, lowdose fish oil supplementation had both short-term and long-term
normalizing effects (243). Similar results were obtained in a study
on patients with colon or rectum adenocarcinoma (244). In a
prospective cohort study including more than 34 000 American
women, Oh et al. (245) suggested that higher intake of omega-3
fatty acids may reduce the progression of small adenomas to large
adenomas.
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Although some studies have shown no effects of omega-3 fatty
acids (246,247), several reports suggest that these fatty acids may
inhibit development of cancer. Narayanan et al (248) observed altered expression of genes important for apoptosis and regulators
of colon cancer cell proliferation, explaining how DHA might protect against colonic cancer development. Another explanation for
the inhibitory effect of omega-3 fatty acids on colorectal cancer
may be due to cytotoxic peroxidation products generated during
lipid peroxidation of EPA and cyclooxygenase (COX) activity (249).
Feeding experiments with rodents showed that omega-3 fatty acids decreased colon carcinogenesis at both the initiation and promotion stages (250-252). A large number of studies in animals and
in cultured cells demonstrate that omega-3 fatty acids may inhibit
initiation, growth and metastasis of malignant cells (12). When
omega-3 fatty acids are administered to cultured cancer cells or
animals with tumors, inhibitory effects on cell proliferation have
been observed in several types of cancers, in vitro as well as in vivo.
For example, in female nude mice implanted with human breast
cancer cells, primary tumour growth and the number of metastases were reduced in those receiving fish oil, compared to those
receiving corn oil (253). The proliferation of malignant prostate
and white blood cell lines may also be inhibited by omega-3 fatty
acids (254,255). A case-control study from Canada showed that a
diet including high intake of carotenoids and DHA may reduce the
risk of breast cancer (256).
Rhodes et al (257) performed a double-blind randomized study
of 42 healthy subjects who were given 4 g of purified EPA or oleic
acid daily for 3 months. The skin content of EPA at 3 months was
8-raised fold from baseline. Sunburn sensitivity was reduced on
EPA as measured by several markers for skin cancer development.
No significant changes were seen in any parameter with oleic acid
supplement. It has also been observed that ultraviolet-B induction of prostagladin E2 was abolished after intake of EPA but not
oleic acid (258). Thus, these data showed reduction in early cancer
markers indicating protection by dietary EPA against acute ultraviolet ray-induced genotoxicity. Longer-term supplementation
might reduce skin cancer in humans.
In conclusion, there are suggestive data for decreased risk of colorectal cancer (242), and some data point to a beneficial effect of
EPA on skin cancer (257, 258). Thus, the data on dietary omega-3
fatty acids and cancer are not convincing.
8 iii. Inflammatory diseases
A significant number of reports indicate that supplementation with
a few grams daily of very long-chain omega-3 fatty acids provide
health benefits in relation to some inflammatory diseases (12,173).
The mechanism behind these effects may be related to altered
eicosanoid formation or any of the other mechanisms described
in Figures 5-7. For the eicosanoids, it has been shown that LTB5 derived from EPA may replace some of the more potent inflammatory agent LTB4 derived from AA (Figure 6). Another possibility for
a reduced inflammatory response with intake of omega-3 fatty
acids may be reduced formation of interleukin-1 (IL-1) and tumor
necrosis factor (TNFα) by mononuclear blood cells (259). Søyland
et al (260) have demonstrated that proliferation of T-lymphocytes
may be inhibited by omega-3 and omega-6 fatty acids to a similar extent. The inhibitory effect of pure fatty acids was dependent
on fatty acid concentration, chain length and number of double
bonds, with adrenic acid (22:4n-6) and DHA being most potent.
Saturates and monoenes did not exhibit any effect on T-cell proliferation. These findings have later been confirmed by others (261).
Omega-3 fatty acids may inhibit the adhesion of monocytes and
endothelial cells possibly due to generation of platelet activating
factor (262).
In vitro studies have demonstrated that replacement of omega-6
fatty acids with omega-3 fatty acids may cause a decreased cellular response to mitogenic and inflammatory stimuli via reduced
proliferation of inflammatory cells, reduced expression of COX-2
and reduced release of IL-6 due to lower biological effects of PGE2
than PGE3 (263).
It has been reported that short-time infusion (48 h) of fish oilbased lipid emulsions reduced monocyte proinflammatory cytokine generation and adhesive interaction with endothelium in
humans (264). There are some preliminary indications that these
intravenous (iv) infusions may be of benefit compared to omega-3
fatty acid-free lipid emulsions for surgical as well as septic patients
although the evidence is too scarce to formulate firm recommendations (265).
Experimental animal models indicate that iv infusions of omega-3
fatty acid-based emulsions improve survival or metabolic markers
of endotoxemia and improved heart and lung function and decreased lung edema in endotoxic rats and pigs (265).
Some data have suggested that the beneficial anti-inflammatory
effect of omega-3 fatty acids might be attenuated by omega-6
fatty acids. However, data from 859 healthy men and women suggest that a combination of both types of fatty acids is associated
with the lowest levels of inflammation (266), as also indicated by
previous findings of Søyland et al (267).
It has also been observed that exercise-induced “inflammation”
due to eccentric exercise in untrained males, as evaluated by
changes in IL-6 and C-reactive protein (CRP), was significantly reduced by dietary supplement with DHA (268).
21
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An oxidation product of DHA (10,17S-docosatriene) seems to
be an important brain messenger that may potently inhibit leukocyte infiltration and promote neuroprotection (269). It should
be pointed out that some studies do not demonstrate any effects
on inflammatory markers like plasma concentration of C-reactive
protein (CRP) in spite of supplementation with 2-6.6 g of very longchain omega-3 fatty acids for 12 weeks in healthy subjects (270).
In a meta-analysis of randomized and double-blinded studies in
patients with ulcerous colitis, there was no significant effect of
supplementation with omega-3 fatty acids on clinical outcomes
(292). Although it is still unclear which groups of patients with
inflammatory bowel diseases might benefit from supplementation with omega-3 fatty acids, it should be considered a realistic
therapeutic option (288).
8 iii. a Rhematoid arthritis / joints
Several studies have shown that dietary supplementation with
very long-chain omega-3 fatty acids (>3 g/day) reduces the clinical symptoms of rheumatoid arthritis as evaluated by morning
stiffness and number of swollen joints, in meta-analyses (271,272).
It also appears that the amount of nonsteroid anti-inflammatory
drugs (NSAIDs) commonly used by patients, may be reduced or
even discontinued if very long-chain omega-3 fatty acids are supplied (273,274). Although the clinical impact of very long-chain
omega-3 fatty acids is less than that provided by drugs normally
given for rheumatoid arthritis, the effect is significant and virtually
without side effects (275).
8 iii. e Asthma and allergy
Data from a prospective epidemiological study suggested that
regular dietary intake of fish was associated with better pulmonary
function (293). However, in a clinical trial with asthmatic patients,
no improvement with omega-3 fatty acid supplementation was
observed (294). In a randomized controlled study among asthmatic children, the results suggest that dietary supplementation with
long-chain omega-3 fatty acids was beneficial in a strictly controlled environment in terms of inhalant allergens and diet (295).
8 iii. b Psoriasis
Even though there may be some positive effects of very long-chain
omega-3 fatty acids for patients with psoriasis (276,277), there are
some very well controlled and large clinical studies demonstrating no significant effect of supplementing these fatty acids as
compared to omega-6 fatty acids (278,279). Still, it is possible that
some subgroups of psoriatic patients would benefit from using
omega-3 fatty acids in combination with other treatments (280) or
as intravenous injection (281).
8 iii. c Atopic dermatitis
The intake of vitamin D and very long-chain omega-3 fatty acids
was shown to be low among a group of 138 Norwegian patients
with atopic dermatitis, especially among female patients (282). In
a small controlled randomized clinical trial including patients with
atopic dermatitis, dietary supplementation with very long chain
omega-3 fatty acids lead to positive effects on subjective symptoms, compared to supplementation with olive oil (283). However,
in two large clinical intervention trials including 268 patients with
moderate to severe atopic dermatitis, no difference was found between supplementation with fish oil and oils with high amounts
of omega-6 fatty acids (284,285). It should be noted that both the
intervention group and the control group improved objectively
as well as subjectively during the 4 month treatment period in
the largest study (285). Thus, it is possible that both omega-3 and
omega-6 fatty acids might have a beneficial effect on this condition, as pointed out in more recent studies (266,286). Iv administration of omega-3 fatty acids acutely (up to 10 days) improved
the clinical status of atopic dermatitis, but the long-term effect is
unknown (287).
8 iii. d Inflammatory bowel diseases
There have been some large clinical trials on patients with Crohn’s
disease (288-291). In these studies patients in remission received
omega-3 fatty acids or control treatment for up to approximately
one year. In one of the studies (288) omega-3 fatty acids significantly reduced the rate of relapse, whereas there was no significant effect in the other studies (289,290).
22
Higher omega-3 fatty acid levels in the colostrum did not protect
against development of atopy in a prospective study among highrisk breastfed infants (296), whereas a potential reduction in infant
allergy after maternal intake of long-chain omega-3 fatty acids
among atopic mothers was shown in a randomized, controlled
trial (297). It has also been reported that dietary fish oil supplementation has a protective effect in suppressing exercise-induced
bronchoconstriction among elite athletes (298). Another study by
Olsen et al. (299) suggest that there might be a beneficial effect of
supplementing pregnant momen with 2.7 grams of marine omega-3 fatty acids during the last 10 weeks of pregnancy. Assuming
that intake of olive oil was inert, the results support that increasing
n-3 PUFAs in late pregnancy may have a prophylactic potential in
relation to offspring asthma.
Some experimental data on mice suggest that resolvins (derived
from EPA) promote resolution of inflammatory airway responses in
part by directly suppressing the production of IL-23 and IL-6 in the
lung (299). Also contributing to the pro-resolution effects of resolvin treatment were higher concentrations of interferon-gamma
in the lungs of RvE1-treated mice.
8 iii. f Diabetes
Some reports have indicated that supplementation with very
long-chain omega-3 fatty acids causes the blood glucose level to
increase among non-insulin-dependent diabetics (NIDDM) (300).
Although this observation is somewhat controversial (301), a
number of reports suggest no or few negative effects of omega-3
fatty acid supplementation on glucose metabolism in hypertensives (302) or hypertriacyl-glycerolemics (303) or patients with
coronary heart diseases (304). Because of the many positive effects of very long-chain omega-3 fatty acids, like reduced plasma
concentrations of TAG and of free fatty acids, reduced blood pressure, reduced platelet aggregability and even increased insulin
sensitivity in animals (305), it has been advised that patients with
noninsulin dependent diabetes mellitus (NIDDM) may benefit
from supplementation with small to moderate amounts of marine oils (306). In a meta-analysis it was concluded that intake of
omega-3 fatty acids had no significant effect on glycemic control
or fasting insulin (307).
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An interesting observation is that Alaskan natives with high intake of very long-chain omega-3 fatty acids exhibit reduced risk of
developing NIDDM (308). Hu et al (309) examined prospectively
the association between intake of fish and omega-3 fatty acids
and risk of CHD and total mortality among 5103 female nurses
with diagnosed type 2 diabetes, but free of cardiovascular disease
or cancer at baseline. They report that a higher consumption of
fish and long-chain omega-3 fatty acids was associated with a
lower CHD incidence and total mortality among diabetic women.
8 iii. g Obesity
Obesity is a global and rapidly increasing disease (310) that is
closely associated with development of inflammatory markers like
enhanced plasma concentration of TNFα, IL-6, CRP, sialic acid, orosomucoid and alpha1-antichymotrypsin (311). These markers are
adipokines (protein hormones secreted from the adipose tissue
like TNFα, IL-6 and CRP) or acute phase proteins (like CRP, sialic acid,
orosomucoid and a1-antichymotrypsin). Although there is data
suggesting a relation between inflammation and obesity (312),
the inflammatory markers are often hard to detect (313). Inflammation may represent a link between obesity and complications
of obesity (eg cardiovascular diseases and diabetes type II (314).
Supplementation of omega-3 fatty acids may have a significant
beneficial effect on insulin sensitivity among individuals with high
markers of inflammation, whereas there appears to be little effect
in subjects with small signs of inflammatory response (314). These
observations might explain the large difference in effects reported
using supplements with marine fatty acids in patients with type II
diabetes.
9. Omega-3 fatty acids and central
nervous system
Several reports have suggested that supplementation with marine omega-3 fatty acids are important for treatment of schizophrenia, depressions or borderline personality disorder (315-319).
Yet in other studies, no differences were found between groups
in positive or negative symptoms, mood, cognition, or global impression ratings (320,321). In a double-blind, placebo-controlled
trial including 302 subjects over the age of 65, supplementation of 1800 or 400 mg EPA plus DHA daily for 26 weeks caused
no effect on mental well-being (322). Although there are some
indications of improved central nervous function with enhanced
intake of long-chain omega-3 fatty acids, the studies are small,
short-term and often with low dosage. There is, therefore, a need
for larger placebo-controlled randomized trials to evaluate if
omega-3 fatty acid supplementation will benefit patients with
serious psychiatric disorders.
9 i. Depressions
Frangou et al (323) examined the efficacy of EPA in treating depression in bipolar disorder in a 12-week, double-blind study by giving
1 or 2 gram/day of EPA ethylester as compared to a control group.
Significant improvement was noted with ethyl-EPA supplementation irrespective of dose, as compared to placebo in the Hamilton
Rating Scale for Depression (P=0.04) and the Clinical Global Impression Scale (P=0.004) scores. However, a meta-analysis showed
that four other small studies demonstrated no significant beneficial effect of omega-3 fatty acid supplementation of patients with
bipolar disease (324).
Severus et al. (325) present data connecting cardiovascular disease, depression, omega-3 fatty acids and homocysteine, suggesting that omega-3 fatty acids, as well as homocysteine, might be
closely related to depression.
9 ii. Schizophrenia
Data indicate that the level of omega-3 fatty acids is low in red
blood cells as well as in some cortical areas of the brain in schizophrenic patients (326,327), although the data are based on very
small numbers of cases and are somewhat controversial (328). The
intervention studies on high risk subjects or chronic schizophrenics are also small and the results are not solid enough to recommend anything other than new, large and better designed studies
in the future.
9 iii. Alzheimer’s and Parkinson disease
The risk of developing Alzheimer’s disease (AD) has been inversely
related to the dietary intake of fish in several epidemiological studies (329-332). The omega-3 fatty acids in fish might explain part
of this beneficial effect. It is clearly possible to influence the content of DHA in the brain by dietary intake (333). In two prospective
studies it was observed that lower plasma DHA levels increased
the risk of developing AD later in life (334,335).
There are too few data on Parkinson disease in relation to dietary
intake of omega-3 fatty acids to conclude on the potential effects
of supplementation.
23
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9 iv. Attention deficit hyperactivity disorder (ADHD)
Dietary intake of omega-3 fatty acids has been linked to ADHD
and related disorders in some studies (336). The Oxford-Durham
randomized, controlled trial was conducted with 117 children
with developmental coordination disorder (DCD) aged between
5–12 years. The children were supplemented with 730 mg of EPA
plus DHA and 60 mg of gamma-linolenic acid (18:3,n-6), or a control. Intervention for 3 months in parallel groups, was followed by a
1-way crossover from placebo to active treatment for an additional 3 months (337). No effect of treatment was apparent on motor
skills but significant improvements for active intervention versus
placebo were observed in reading, spelling, and behaviour during
3 months in parallel groups. After the crossover, similar changes
were seen in the placebo-active group, whereas children continuing with active treatment maintained or improved their progress.
Another study included a randomized, 3-months, omega-3 and -6
placebo-controlled, one-way crossover trial with 75 children and
adolescents (8–18 years), followed by 3 months with omega-3
and -6 for all (338). The majority of subjects did not respond to
omega-3 and -6 fatty acid supplementation. However, a subgroup
representing 26% of subjects responded with more than a 25%
reduction of ADHD symptoms and a drop of Clinical Global Impression scores to the near-normal range. After 6 months, 47% of
all treated subjects showed such improvement. These responders
tended to have ADHD inattentive subtype and co-morbid neurodevelopmental disorders (338).
In spite of these findings the data are too scarce to recommend
specific therapy for ADHD-like conditions before more studies
have demonstrated beneficial effects.
10. Safety of intake
Several hundred clinical studies have demonstrated that intake of very long-chain omega-3 fatty acids is very safe
(12,82,90,104,126,173,195,196,273-279,302,339). Although some
have suggested theoretical reasons why omega-3 fatty acids may
cause bleedings, lipid peroxidation with development of atherosclerosis or cancer, and increased risk of infections due to antiinflammatory effects, there is very little experimental support for
these concerns.
10 i. Bleedings
The large clinical problem today is not bleedings, but rather
thrombo-embolic disorders. Thus, it is probably advantageous
that blood platelets have somewhat reduced reactivity. There has
been a report of an interaction between omega-3 fatty acids and
anticoagulant therapy (340), but in combination with reasonable
doses of acetyl salicylic acid or Warfarin, there are no reported unfavourable side effects (304,341). Even intravenous injections of
0.2 g fish oil /kg body weight daily (related to major abdominal
surgery) promoted no alterations in blood coagulation or platelet
function (342).
10 ii. Lipid peroxidation
Lipid peroxidation in relation to cancer and atherosclerosis has
been extensively discussed above (90, 94,97,234-237,243-246). Al-
24
though lipid peroxidation related to intake of PUFAs may be harmful in certain situations, the net effects of omega-3 fatty acids are
beneficial in relation to cancer as well as atherosclerosis based on
available data. Some of the beneficial effects of PUFA may even
depend on peroxidation of these fatty acids in relation to VLDL
secretion (343) and/or induction of apoptosis in certain cancer
cells (344).
10 iii. Inflammations
It seems that in industrialized countries, a modern diet is associated with increased inflammatory reactions. Intake of very longchain omega-3 fatty acids may moderately reduce these pathological reactions, e.g. rheumatoid arthritis. It has been shown that
intake of very long-chain omega-3 fatty acids reduces the clinical
consequence of malaria infection (345). Lipid peroxidation is probably important for the beneficial effect of omega-3 fatty acids in
this connection, since supplementation with vitamin E abolishes
the positive effect. The effects of omega-3 fatty acids on the defence against infections have been tested in various animal models and there are many positive and some negative results for different types of infections (346). From clinically controlled studies
among patients with infectious diseases there is insufficient evidence to draw firm conclusions, but some results suggest that the
positive effects outweigh the potential negative effects (347-349).
Some studies indicate a significant modification of the inflammatory process caused by surgery or short bowel syndrome by infusion of long-chain omega-3 fatty acids (350-351). Larger studies
are needed to evaluate the effects on complication rates, hospital
stay and mortality.
10 iv. Diabetes
The effect of very long-chain omega-3 fatty acids on glucose metabolism may provide some concern, but used in reasonable doses
there are probably more positive than negative effects of omega-3
fatty acids in diabetic patients (352). In a prospective study among
female nurses with diagnosed type 2 diabetes, but free of cardiovascular disease or cancer at baseline (309), a higher consumption
of fish and long-chain omega-3 fatty acids was associated with
a lower CHD incidence and lower total mortality among diabetic
women.
From a case-control study among 545 cases of childhood-onset
type 1 diabetes and 1668 population control subjects, it was
shown that use of cod liver oil in the first year of life was associated
with significantly lower risk (26%) of type 1 diabetes (353).
Overall, glycemic control does not appear to be adversely affected
by omega-3 fatty acids at amounts of up to 3 g/d (354).
10 v. Body weight
All types of fat are energy-rich, and a high intake of fat may thus
represent an increased risk of weight gain. However, some fats are
required because they are essential and represent important factors to develop and maintain good health. Five mL of cod liver oil
represent 42 kcal (175 kJ), and this amount of energy can easily
replace a corresponding amount of saturated fat in most industrialized diets.
29-12-09 14:14:33
10 vi. Contaminants
Environmental pollutants like PCB and dioxins originate on shore
and accumulate in the fat of sea-living animals like fish and seal,
particularly in European and arctic areas (355). Omega-3 fatty acid
supplements made from marine oils produced by the major Norwegian producers are processed to remove these contaminants
through several purification steps. The amounts of contaminants
remaining in the final product are tightly controlled by bleaching, deodorizing and distillation of the marine oils, thus only minor amounts remain. Both European and Norwegian legislation
stipulate safe limits for the amounts of particular contaminants in
marine oil supplements. All marine oil products on the market in
Norway must comply with this legislation and are regularly controlled by The Norwegian Food Safety Authority.
In conclusion, intake of very long-chain omega-3 fatty acids represents a very small risk for harmful side effects. In addition, several
beneficial effects may be obtained as discussed above.
11. Diagnostics
During the last years, increasing amounts of data have been published on the use of the omega-3 index as a marker of marine fatty
acid status (356-357). The omega-3 index is measured as erythrocyte or whole blood concentration of EPA and DHA. It is considered a potential risk factor for coronary heart disease mortality,
especially sudden cardiac death. The omega-3 index fulfils many
of the requirements for a risk factor including consistent epidemiologic evidence, a plausible mechanism of action, a reproducible assay, independence from classic risk factors, modifiability,
and, most importantly, the demonstration that raising levels will
reduce risk for cardiac events. Measuring membrane concentrations of omega-3 fatty acids is a rational approach to biostatus
assessment because these fatty acids appear to exert their beneficial metabolic effects because of their actions in membranes.
They alter membrane physical characteristics and the activity of
membrane-bound proteins, and, once released by intracellular
phospholipases from membrane stores, they can interact with
ion channels, be converted into a wide variety of bioactive eicosanoids, and serve as ligands for several nuclear transcription factors,
thereby altering gene expression. The omega-3 index compares
very favorably with other risk factors for sudden cardiac death. Proposed omega-3 index risk zones are (in percentages of erythrocyte
fatty acids): high risk, < 4%; intermediate risk, 4-8%; and low risk,
> 8% (figure 12). Before assessment of omega-3 fatty acid biostatus
can be used in routine clinical evaluation of patients, standardized
laboratory methods and quality control materials must become
available (264).
12. Conclusions and recommended
intake
Although the available data on the required intake of essential
fatty acids are scarce, the present knowledge suggests that 0.20.3% of dietary energy should be derived from omega-3 fatty acids
to avoid signs or symptoms of deficiency (Table VI). This corresponds
to approximately 0.5 g of omega-3 fatty acids (5,25-27,358,359).
It should be stressed that this is the minimum intake in order to
avoid symptoms of omega-3 fatty acids deficiency.
Table VI. Suggested intake of essential fatty acids
Omega-3 Omega-6
Omega-3 Omega-6
(% of energy) (mg/day)
Minimum
0.2-0.3
1-3
400-600 2400-7200
Optimum
1-2
3-7.5*
2400-4800 7200-18000
The Norwegian National Council for Nutrition recommends daily
intake of cod liver oil to everyone from the age of 4 weeks, to secure intake of vitamin D as well as of long-chain omega-3 fatty
acids.
Many epidemiological and experimental studies provide relatively
strong evidence of significant beneficial effects of additional intake of very long-chain omega-3 fatty acids (EPA and DHA). It is
possible that the beneficial effects are obtained at intakes as low
as one fish meal weekly, but many of the measurable effects on
risk factors are observed at intakes of around 1-2 g/day of very
long-chain omega-3 fatty acids (Table V, Figure 9). This amount is much
less than that obtained via a traditional Greenland Innuit diet (16),
and this intake can be achieved by eating fatty fish 2-4 times a
week. If fish intake is not possible, a daily dose of cod liver oil or fish
oil will provide the necessary amount of very long-chain omega-3
fatty acids.
If 1-2 g/day of EPA and DHA is eaten in combination with proper
amounts of fruits and vegetables and limited amounts of saturated
and trans fatty acids, most people will probably benefit with better
health. For pregnant women there are some data demonstrating
beneficial effects of 2.5 grams marine omega-3 fatty acids daily for
the mother as well as for the child (51,59). For patients with hypertension or rheumatoid arthitis the dosage of omega-3 fatty acids
needed for clinically meaningful effects is from 2 to 4 grams daily.
Figure 12. Risk evaluation for the omega-3 fatty acid index (red blood cell EPA + DHA). Proposed
cut-points are obtained from review of the literature (357).
Proposed risk zones for the Omega-3 index
Undesirable
0%
Intermediate
4%
Desirable
8%
Percent of EPA+DHA in RBC
25
29-12-09 14:14:34
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33
29-12-09 14:14:37
14. Abbreviations
34
AA: Arachidonic acid (20:4n 6)
ACAT: Acyl-CoA:cholesterol acyltransferase
ADGAT: Acyl-CoA:diacylglycerol acyltransferase
ADHD: Attention deficit hyperactivity disorder
ALA: α-linolenic acid (18:3n 3)
apoB: Apolipoprotein B
ATP: Adenosin triphosphate
COX: Cyclooxygenase
CRP: C-reactive protein
CVD: Cardiovascular disease
CHD: Coronary heart disease
DCD: Developmental coordination disorder
DHA: Docosahexaenoic acid (22:6n 3)
DPA: Docosapentanoic acid (22:5n-3)
EDRF: Endothelium derived relaxing factor
(nitric oxide radical released from l-arginine)
EPA: Eicosapentaenoic acid (C20:5n 3)
ER: Endoplasmatic reticulum
ERP: Evoked response potential
HDL: High density lipoproteins
HNF-4α: Hepatic nuclear factor-4 alfa
ICD: Implantable cardioverter defibrillators
IHD: Ischemic heart disease
IL: Interleukin
IQ: Intelligence quotient
K-ABC: Kaufman Assessment Battery for Children
LC-PUFA:long-chain poyunsaturated fatty acids
LDL: Low density lipoproteins
LPO: Lipid peroxides
LTB: Leukotriene
LXR: Liver receptor X
MI: Myocardial infarction
MLDL: Modified LDL
Monoenes: monounsaturated fatty acids
MPCOMP: Mental Processing Composite
mRNA: Messenger ribonucleic acid
NF-kb: Nuclear factor kB
NIDDM: Noninsulin dependent diabetes mellitus
NONVERB: Nonverbal Abilities
NSAIDs: Nonsteroid anti-inflammatory drugs
PAF: Platelet activating factor
PC: Phosphatidyl choline
PDGF: Platelet derived growth factor
29-12-09 14:14:38
Omega-3 fatty acids – Pikasol
35
29-12-09 14:14:38
Written by Christian Drevon in cooperation with the development department at Axellus, Oslo, Norway
Axellus AS
P.O. Box 4293 Nydalen
NO-0401 Oslo
tel: +47 22 89 64 00
www.axellus.no
29-12-09 14:14:38

Omega-3 fatty acids

Transcription

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