FROM:
Alternative Medicine Review 2000 (Aug); 5 (6): 576–580 ~ FULL TEXT
Introduction
Many well-recognized problems are associated with excessive intake of
dietary fat, including obesity, insulin resistance, coronary heart disease,
and some forms of cancer. While intakes of saturated, trans, and arachidonic
fatty acids have been linked to the development of chronic disease, research
shows omega-3 (n-3) fatty acids, specifically fish oils, are essential
in the prevention and treatment of disease.
Mechanism of Action
EPA and DHA compete with arachidonic acid (AA) for the enzyme cyclo-oxygenase.
EPA is converted by platelet cyclo-oxygenase to thromboxane A3 (TXA3),
which is only a very weak vasoconstrictor, unlike thromboxane A2 (TXA2),
which is formed by the action of cyclo-oxygenase on AA and is a strong
vasoconstrictor. However, prostacyclin I3 (PGI3), formed from EPA in the
endothelium, is as potent a vasodilator and inhibitor of platelet aggregation
as is protacyclin I2 (PGI2) formed from AA. The net effect, therefore,
of an increased dietary EPA:AA ratio is relative vasodilation and platelet
aggregation inhibition. [2] EPA yields the
5-series of leukotrienes, which are only weakly chemotactic. A relative
reduction in chemotaxis might be expected to be antiatherogenic. Fish oil
decreases both very low density lipoproteins (VLDLs) and triglycerides
due to inhibition of hepatic triglyceride synthesis. Because VLDL is a
precursor to LDL, a reduction in LDL cholesterol is seen in some patients
with hypertriglyceridemia; however, fish oil does not appear to lower plasma
cholesterol in subjects with hypercholesterolemia. [4,5]
Clinical Indications
Arrhythmias
A series of animal studies by McLennan et al found that diets supplemented
with tuna oil (n-3 PUFA) significantly reduced the incidence and severity
of arrhythmias, preventing ventricular fibrillation during both coronary
artery occlusion and reperfusion. These studies also found that severity
of arrhythmias was significantly worsened by a diet supplemented with saturated
fat. [6-8]
Coronary Heart Disease
The beneficial effects of fish oil on coronary heart disease (CHD) have
been researched for more than two decades, particularly since the landmark
study of Greenland Eskimos showed lower mortality rates from cardiovascular
disease. [9] Fish oil has important metabolic
effects, such as inhibiting platelet aggregation and lowering serum triglyceride
levels, which could play a role in the prevention of CHD. A prospective
study of European men found an inverse association between fatty fish consumption
(but not lean or total fish consumption) and 20-year CHD mortality. [10]
Fish oil has successfully been proven to reduce serum triglyceride levels
in humans, [11] although the majority of studies
have been conducted on men. More recently, a study has been conducted on
the effects of n-3 fatty acid supplementation, specifically fish oil, on
postmenopausal women either receiving or not receiving hormone replacement
therapy (HRT). The fish oil supplement significantly reduced serum triglyceride
concentrations by an average of 26 percent in both HRT-status groups, without
affecting other lipid variables. The effect was estimated to decrease CHD
risk by 27 percent in postmenopausal women. [12]
A study by Thomas et al suggested fitness status, in addition to fish oil
supplementation, may be an important factor in determining postprandial
triglyceride levels. Sixty minutes of exercise, in addition to fish oil
supplementation, decreased plasma triglyceride levels by 33 percent. It
has been suggested that fish oil may inhibit lipoprotein lipase activity
via its effect on insulin release. [13]
Cancer
Epidemiological, experimental, and mechanistic data implicate n-6 PUFAs
as stimulators and long chain n-3 PUFAs (specifically fish oil) as inhibitors
of development and progression of a range of human cancers. [14,15]
Studies have found the antitumor effect of EPA is mainly related to its
suppression of cell proliferation. On the other hand, the effect of DHA
appears to be related to its ability to induce apoptosis. [16,17]
The dietary n-3/n-6 fatty acid ratio, rather than the quantity administered,
appears to be the principle factor in the antitumor effect of n-3 PUFAs.
An effective ratio appears to be in the range of 1.8-1.9.16 EPA and DHA
supplementation, in the form of fish oil, have also been found to suppress
both breast and colon cancer tumor growth and metastasis. [18,19]
Cognitive Function
AA and DHA accrue rapidly in the prenatal human brain during the third
trimester and the early postnatal period when the rate of brain growth
is maximal and most vulnerable to nutritional deficiencies. Postnatal deficiencies
of DHA have specifically been found to relate negatively to visual acuity,
neurodevelopment, and behavior. In general, breast milk contains sufficient
amounts of long chain PUFAs, including DHA, to meet these needs, assuming
the maternal diet is adequate. A study examining breast milk and DHA content
in Pakistani mothers versus Dutch mothers found significantly lower amounts
of DHA which were directly correlated to the decreased amount of fish eaten
in North Pakistan. [20] There is also controversy
at present over whether or not the infant formulas that contain only linoleic
acid and alpha-linolenic acid are sufficient for brain development. [21]
Depression
In several observational studies, low concentrations of n-3 PUFAs were
predictive of impulsive behaviors and greater severity of depression. [22,23]
Dopaminergic and serotonergic functions in the frontal cortex seem to be
affected by the fatty acid composition of the diet. An n-3 deficiency may
be related to catecholaminergic disturbances in depression. [24]
Recently it was demonstrated that EPA, DHA, and total n-3 fatty acid levels
are significantly lower in red blood cell membranes of depressed subjects
compared to the control group. [25]
Diabetes
Rats fed diets high in fish oil and with a low n-6/n-3 PUFA ratio maintained
normal insulin action. Diets high in saturated and mono-unsaturated fats
led to profound insulin resistance in numerous tissues, as did diets high
in omega-6 PUFAs. [1] Similar studies by Storlien
et al found providing 5-10 percent of dietary energy from fish oil accelerated
glucose uptake and maintenance of normal glucose metabolism, even at high
levels of fat intake. [26] More importantly,
the ability of fish oil to enhance the rate of glycogen storage allows
skeletal muscle to increase its uptake of glucose, even under conditions
where fatty acid oxidation is accelerated. [27]
Fish oil enhances insulin secretion by incorporation of n-3 fatty acids
into the plasma membrane to compete with AA production. This reduces the
concentration of AA in the plasma membrane, decreasing the production of
PGE2, which, in turn suppresses the production of cAMP, a well-known enhancer
of glucose-induced insulin secretion. Consequently, fish oil enhances insulin
secretion from b-cells, regulating blood sugar. [28]
The effect of fish oil on blood lipids should be evaluated in diabetics.
A randomized trial conducted on 41 type 1 diabetics found 15 g fish oil
per day resulted in statistically significant elevations in LDL cholesterol. [29]
It should be pointed out, however, that this study used a very high daily
dose of fish oil 15 g daily versus an average therapeutic dose of
5 g daily.
Rheumatoid Arthritis
Clinical and biochemical studies have shown that fish oil, and to a
lesser extent fish, can be used as a source of n-3 fatty acids in the treatment
of rheumatoid arthritis. Studies found EPA and DHA reduced eicosanoid and
proinflammatory cytokines. The synthesis of interleukin 1b decreased by
20 percent after a diet high in omega-3 fatty acids was consumed for two
weeks and was decreased further at the end of four weeks. The synthesis
of tumor necrosis factor-alpha decreased 40 percent after two weeks on
the diet; at four weeks there was no significant change. [3]
Other Therapeutic Considerations
Studies also show fish oil to be effective in the treatment of acute
respiratory distress syndrome, psoriasis, multiple sclerosis, and dysmenorrhea. [30-33]