Effect of fish and fish oil-derived omega-3 fatty acids on lipid

Review
Effect of fish and fish oil-derived omega-3 fatty acids
on lipid oxidation
Trevor A. Mori
Published by Maney Publishing (c) W. S. Maney & Son Limited
School of Medicine and Pharmacology, The University of Western Australia; Cardiovascular Research Centre;
and The Western Australian Institute for Medical Research, Perth, Western Australia, Australia
There is evidence that omega-3 (ω3) fatty acids derived from fish and fish oils reduce the risk of
cardiovascular disease via mechanisms underlying atherosclerosis, thrombosis and inflammation.
Despite these benefits, there has been concern that these fatty acids may increase lipid peroxidation.
However, the in vivo data to date are inconclusive, due in part to limitations in the methodologies. In
this regard, our findings using the measurement of F2-isoprostanes, a reliable measure of in vivo
lipid peroxidation and oxidant stress, do not support adverse effects of ω3 fatty acids on lipid
peroxidation.
Keywords: Fish oil, omega-3 fatty acids, lipid oxidation, F2-isoprostanes
There is now considerable evidence that a diet rich in ω3
fatty acids derived from fish and fish oils, specifically
eicosapentaenoic acid (EPA, 20:5 ω3) and docosahexaenoic acid (DHA, 22:6 ω3), protects against atherosclerotic heart disease, myocardial infarction and sudden
death.1 ω3-Fatty acids have a wide range of biological
effects, including benefits on lipoprotein metabolism,
platelet and endothelial function, blood pressure, vascular reactivity, cytokine production, coagulation and fibrinolysis.1–3 Recent evidence also has demonstrated that,
in humans, EPA and DHA have differential effects on
lipids and lipoproteins,4 blood pressure5 and heart rate,5
and vascular reactivity.6
Despite the benefits associated with increased ω3 fatty
acid consumption, there remains a theoretical concern that
these fatty acids may increase the unsaturation index, consequent to the incorporation of EPA and DHA into membranes and lipoproteins, leading to increased lipid
peroxidation.7 The significance of this relates to the fact
that there is much evidence supporting a role for lipid oxiReceived 11 March 2004
Accepted 30 April 2004
Correspondence to: Dr Trevor A. Mori, School of Medicine and
Pharmacology, Medical Research Foundation Building, Box X 2213
GPO, Perth, Western Australia 6847, Australia
Tel: +61 8 9224 0273; Fax: +61 8 9224 0246;
E-mail: [email protected]
Redox Report, Vol. 9, No. 4, 2004
DOI 10.1179/135100004225005200
dation and oxidative stress in the pathogenesis of cardiovascular disease.8 It is thought that oxidative stress and
oxidized lipids play a critical part in the genesis and progression of the atherosclerotic lesion.8 The hypothesis that
increased intake of ω3 fatty acids may lead to increased
lipid peroxidation is based on the premise that fatty acid
oxidizability increases with an increase in the number of
double bonds in the fatty acid chain.9 Whilst this may be
true of in vitro studies of lipid peroxidation in homogeneous solutions, in vivo systems are more complicated and
influenced by additional factors. In support of this, Visioli
et al.10 showed that, under equal conditions of oxidative
stress, fatty acids oxidized at different rates and generated
different oxidation products, in a manner that was unrelated to their degree of unsaturation. Lipid peroxide levels
were in fact highest following oxidation of linoleic acid
(18:2 ω6).10 Arachidonic acid (20:4 ω6) and DHA generated lower levels of lipid peroxides, with lowest levels
arising from oxidation of EPA. Formation of conjugated
dienes was also maximal for 18:2 ω6. In particular, the
production of conjugated dienes from 20:4 ω6 and EPA
was approximately 25% of that of 18:2 ω6. DHA oxidation yielded only 10% of the conjugated dienes relative to
that of 18:2 ω6.10
The data relating to the effects of ω3 fatty acids on lipid
peroxidation and oxidative stress in vivo are contradictory.7
These inconsistencies may be related to differences in the
populations studied, the quantity and presentation of the
© W. S. Maney & Son Ltd
Published by Maney Publishing (c) W. S. Maney & Son Limited
194
Mori
Fig. 1. Change in urinary F2-isoprostane excretion from baseline to postintervention by intervention group. Mean ± SEM. P < 0.013 for the main
effect of fish after adjustment for baseline values, using general linear
models (GLM). Reproduced from Mori et al.41 with permission.
ω3 fatty acids (fish versus encapsulated fish oils), the
duration of the study, the study design, the antioxidant
content of the supplement, or the composition of the
background diet. It also has also been suggested that the
total concentration of polyunsaturates, rather than the
unsaturation index, may be more important in determining lipid peroxidation.11 However, the most plausible
explanation for the inconsistency between studies is differences in the methodologies employed to assess lipid
peroxidation.
Much of the literature regarding the effect of ω3 fatty
acids on lipid peroxidation is based on indirect and/or
non-specific assays. Studies utilizing the oxidizability of
LDL have shown either enhanced,12–17 or reduced, or no
effect,11,18–22 of ω3 fatty acids. In this assay, LDL is isolated from plasma and then subjected to oxidative conditions. It is feasible that in patients on various
medications, LDL oxidizability could be affected by partition of drugs into the LDL. Indeed, a divergence has
been shown between the measurement of LDL oxidative
susceptibility and urinary F2-isoprostanes as a measure
of oxidative stress.23
One of the most common methods for assessment of
lipid peroxidation measures thiobarbituric acid reactive
substances (TBARS) by a colorimetric assay. This assay
has been widely criticized on the basis of its lack of
specificity and results need to be interpreted with care.24
Studies of ω3 fatty acids using this methodology have
shown either elevated levels16,17,25–28 or no change29,30 in
TBARS. The limitation of this assay was exemplified by
Higdon et al.25 who showed that, in post-menopausal
women given ω3 fatty acids, plasma TBARS were 10fold higher than malondialdehyde (MDA) measured by
gas chromatography mass spectrometry. In addition,
plasma TBARS were significantly elevated following
ω3 fatty acids, whereas MDA was reduced. When
plasma MDA levels were normalized to plasma polyunsaturated fatty acid concentrations, significant differences were eliminated.25
Other measures of oxidative stress include electron
spin resonance detecting free radical species,24 measurement of antibodies to oxidized LDL31 and breath excretion of ethane and pentane.24 The latter assay, however,
has yielded variable results in animals32 and humans27
supplemented with ω3 fatty acids. Other literature
reports have shown that ω3 fatty acids had no adverse
effects on plasma protein oxidation26 and rendered erythrocytes more resistant to haemolysis following oxidative challenge.33
On the basis of studies reporting adverse effects on
lipid peroxidation, some researchers have suggested that
ω3 fatty acids may affect the antioxidant status and,
therefore, should be taken in conjunction with vitamin
supplementation. The data from such studies, however,
are inconclusive.16,27,34–37
Although most of the above-mentioned methods represent different aspects of lipid oxidation and collectively provide some knowledge of oxidative damage,
none is considered a reliable measure of oxidative stress.
In this regard, the F2-isoprostanes are prostaglandin-like
metabolites of free radical peroxidation of arachidonic
acid38 and there is now good evidence that they provide a
reliable measure of in vivo oxidative stress.39,40 In support of this, elevated F2-isoprostanes have been reported
in animal models of free radical injury, in human conditions associated with increased oxidative stress, and in
vitro experimental models.38–40
Using F2-isoprostanes, measured by gas chromatography–mass spectrometry, we have demonstrated that
these metabolites are significantly reduced following
consumption of ω3 fatty acids taken as fish oils or in fish
meals. We showed that fish meals providing approximately 3.6 g/day of ω3 fatty acids for 8 weeks to Type 2
diabetic patients, significantly (P = 0.013) reduced urinary F2-isoprostanes by 20% (Fig. 1).41 Relative to a
control group, urinary F2-isoprostanes were reduced by
0.83 nmol/24-h. This effect was independent of age,
gender, body weight change and the increase in ω3 fatty
acids or the fall in ω6 fatty acids in plasma, platelets and
red blood cells.
We recently have shown that cord plasma and urinary
F2-isoprostanes were reduced in infants whose mother
received fish oil during pregnancy.42 Pregnant atopic
women received 4 g daily fish oil or olive oil from 20
weeks’ gestation. Cord plasma F2-isoprostanes were significantly lower (P < 0.001) in the offspring of women
who had taken fish oil during pregnancy compared with
those who took olive oil (Fig. 2). These differences were
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Effect of fish and fish oil-derived omega-3 fatty acids on lipid oxidation 195
Fig. 2. Cord plasma F2-isoprostane excretion in neonates whose mothers
were supplemented with fish oil or olive oil during pregnancy. Mean ±
SEM. Between group differences were assessed using GLM. *P < 0.001
after adjustment for red cell 20:4 ω6. Reproduced from Barden et al.42
with permission.
independent of red cell 20:4 ω6 levels. Urinary F2-isoprostanes corrected for creatinine excretion tended to be
lower in infants whose mother had taken fish oil (P = 0.06).
Our findings are in accordance with several other studies
in which ω3 fatty acids have been supplemented. Quaggiotto
et al.43 showed that, compared to beef tallow, high doses of
ω3 fatty acids reduced plasma F2-isoprostanes after coronary
occlusion in pigs. Similarly, Higdon et al.25 demonstrated a
fall in plasma F2-isoprostanes in post-menopausal women
given ω3 fatty acids compared with diets enriched in oleate
or linoleate. In the latter study, however, significant differences were eliminated when F2-isoprostanes were adjusted
for plasma arachidonic acid concentrations.25
We have demonstrated in two trials that both EPA and
DHA equally reduced F2-isoprostanes.44,45 In overweight,
mildly hyperlipidaemic men, supplementation with 4 g
daily of purified EPA or DHA for 6 weeks decreased postintervention urinary F2-isoprostane levels by 27% following EPA (1.24 nmol/24-h, P < 0.0001) and 26% following
DHA (1.20 pmol/24-h, P < 0.0001), relative to an olive oil
control group, after adjusting for baseline values (Fig.
3A).44 In a study of similar design in treated hypertensive
Type 2 diabetic patients, we showed that post-intervention
urinary F2-isoprostanes were reduced 19% by EPA (P =
0.017) and 20% by DHA (P = 0.014), relative to an olive
oil group (Fig. 3B).45
In each of these studies,41,42,44,45 the changes in F2-isoprostanes were unrelated to changes in EPA, DHA, 20:4
ω6, total ω3 or ω6 fatty acids. This lack of association
with changes in fatty acids is noteworthy, in view of the
fact that F2-isoprostanes are derived from free radical
oxidation of arachidonic acid, which is significantly
reduced following ω3 fatty acids. Therefore, the changes
in F2-isoprostanes most likely reflect a true reduction in
oxidative stress, rather than as result of a reduction in the
supply of substrate.
How F2-isoprostanes are reduced following ω3 fatty
acid supplementation remains unresolved. We suggested
this might be explained, at least in part, by the antiinflammatory effects of ω3 fatty acids and a reduction in
leukocyte free radical formation. Activated leukocytes
generate powerful oxidants during phagocytosis46 and
cytokines such as TNF-α and IL-6 stimulate leukocytes
and endothelial cells to generate free radicals, further
propagating the pro-oxidant condition. In support of this
hypothesis, we showed that the changes in urinary F2isoprostanes were significantly positively associated
with changes in TNF-α concentration.45 Numerous studies have demonstrated anti-inflammatory actions of ω3
fatty acids, with falls in cytokines most often observed
following leukocyte stimulation.47 ω3-Fatty acids also
Fig. 3. Change in urinary F2-isoprostanes in (A) overweight, hyperlipidaemic men and (B) hypertensive Type 2 diabetic patients. Mean ± SEM. *P < 0.01
for a treatment effect (GLM). Reproduced from Mori et al.44,45 with permission.
196
Mori
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have been shown to suppress production of reactive oxygen species (superoxide and hydrogen peroxide) in stimulated leukocytes.48–54 Superoxide production was
reduced in isolated human52 and rat54 polymorphonuclear leukocytes, as well as in human monocytes.48,53
Other potential mechanisms may relate to the assembly
of ω3 fatty acids in membrane lipids and lipoproteins
making the double bonds less susceptible to free radical
attack,55 inhibition of the pro-oxidant enzyme phospholipase A2,56 and stimulation of antioxidant enzymes.57,58 In
this regard, there is evidence that ω3 fatty acids up-regulate gene expression of antioxidant enzymes and downregulate genes associated with production of reactive
oxygen species.59
CONCLUSIONS
There is no evidence for a pro-oxidant effect of ω3 fatty
acids. Our findings and the recent literature demonstrate
that ω3 fatty acids do not adversely affect, and indeed
may attenuate, oxidative stress. The results clearly highlight the need for caution in choosing methodologies for
the assessment of oxidative stress. Further studies are
also required to explore potential mechanisms for the
observation of an association between oxidative stress,
markers of inflammation and atherosclerosis following
ω3 fatty acids. Nonetheless, there appears no reason why
ω3 fatty acids should not be taken either as fish meals or
fish oils capsules, in view of their overall favourable
effects on cardiovascular risk reduction.
ACKNOWLEDGEMENTS
The studies described were supported by grants from the
National Health and Medical Research Council of
Australia, the West Australian Health Promotion
Foundation (Healthway) and the Royal Perth Hospital
Medical Research Foundation. Purified eicosapentaenoic and docosahexaenoic acids and olive oil capsules were kindly provided by the Fish Oil Test
Materials Program and the US National Institutes of
Health. I would like to acknowledge my collaborators,
Assoc. Prof. Kevin Croft, Prof. Ian Puddey, Prof. Lawrie
Beilin, Dr Valerie Burke, Dr Anne Barden, Assoc. Prof.
Susan Prescott, Dr David Dunstan, Dr Richard
Woodman and Dr Jan Dunstan, and the technical assistance of Jennifer Rivera.
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