Arachidonic Acid (AA) and Eicosapentaenoic Acid (EPA)
Arachidonic Acid (AA)
Arachidonic acid (AA) is a
20-carbon n-6 polyunsaturated fatty acid with 4 double bonds (20:4n6). Its
double bonds contribute to the fluidity of the cell membrane and predispose it
to oxygenation. This can lead to several important metabolites that ensure a
properly functioning immune system, as well as regulate inflammation, brain
activity and other signaling cascades.
The metabolites of AA are
called eicosanoids, which are signaling molecules. They can be produced through
cyclooxygenases, lipoxygenases, cytochrome P450 and reactions triggered by
oxygen species. These pathways produce molecules such as prostaglandins, isoprostanes,
thromboxane, leukotrienes, lipoxins and epoxyeicosatrienoic acids.
AA can be obtained in the diet
from eggs, fish, and animal meats and fats—or produced directly from DGLA using
the enzyme delta-5-desaturase. Although often maligned, adequate AA intake is
necessary to achieve a balance between its inflammatory and resolution effects
to support a healthy immune system. It is also fortified in infant formulas due
to its importance in growth and development.
AA plays a crucial role in
regulating innate immunity and resolution of inflammation. When tissues become
inflamed or infected, AA metabolites (eicosanoids) amplify these inflammatory
signals to recruit leukocytes, cytokines, and immune cells to aid in resistance
and elimination of pathogens.
After initial inflammatory
signaling, these metabolites balance these signals by producing resolution
metabolites for host protection.
Elevated levels
Dietary intake of animal
meats, fats, and eggs contributes to elevated levels. AA can also be produced
from DGLA using the delta-5-desaturase enzyme, therefore, high intake of
omega-6 fatty acids or DGLA supplementation should be considered as a cause of
elevations.
AA is then metabolized to
docosatetraenoic acid using the enzyme elongase. Lack of vitamin and mineral
cofactors, or an SNP in elongase, may slow the enzyme and contribute to
elevations. It should also be noted that omega-3 and omega-6 fatty acids compete
for use by the elongase and desaturase enzymes.
Due to its role in the inflammatory cascade and ability to induce oxidative stress, AA is a relevant factor in the pathogenesis of cardiovascular and metabolic diseases, such as diabetes mellitus, nonalcoholic fatty liver disease, atherosclerosis, peripheral vascular disease, and hypertension. Neuroinflammation and brain excitotoxicity are also regulated by an AA cascade.
Elevations are associated with
Alzheimer’s disease and mood disorders. There is also a substantial correlation
between COX-catalyzed AA peroxidation and the development of cancer (prostate,
colon, and breast).
Low levels
Reduced intake of meats and
animal fats, or low dietary intake of omega-6 fatty acids in general, may
result in lower AA levels. Lack of vitamin and mineral cofactors for the
upstream desaturase and elongase enzymes in omega-6 metabolism may contribute to
lower levels.
Because of the important
immune and inflammatory signaling that AA requires, and its role in cell
membrane phospholipid metabolism, lower AA levels are of clinical significance.
Psychiatric disorders such as schizophrenia and neurological disorders such as
tardive dyskinesia show depletion of AA in red blood cell membranes.
Improving AA levels has been
shown to decrease symptoms in some patients.
Monitoring levels and ensuring
adequate dietary intake of AA is important in pregnant women, infants,
children, and the elderly because of its importance for the development and
optimization of the nervous system, skeletal muscle, and immune system.
Eicosapentaenoic acid
Eicosapentaenoic acid (EPA) is
a 20-carbon omega-3 fatty acid with 5 double bonds (20:5n3). EPA can be made
from downstream metabolism of ALA or can be obtained from the diet. Dietary
sources include oily fish such as salmon, mackerel, cod, and sardines.
In addition to dietary and
desaturation of ALA, EPA is also available as a fish oil supplement.
Desaturation of ALA to EPA is not a very efficient process, so dietary intake
or supplementation is important.
As a precursor of the
eicosanoids prostaglandin-3 (which inhibits platelet aggregation),
thromboxane-3, and leukotriene-5, EPA is of particular importance in the
inflammatory cascade. EPA may also reduce plasma triglyceride levels without
increasing low-density lipoprotein cholesterol levels. Some studies suggest
that in cardiovascular disease, EPA may decrease plaque vulnerability, prevent
progression, and decrease macrophage accumulation. It is also a vasodilator,
which may reduce blood pressure.
Elevated levels
Elevations in EPA may be due
to high dietary intake of foods containing EPA, and fish oil supplementation.
It should also be noted that
there is competition for the elongase and desaturase enzymes between omega-3
and omega-6 fatty acids, which may affect the levels of fatty acid metabolites.
High levels of EPA and its
downstream metabolite DHA have been used to treat many clinical conditions.
Studies have shown benefits in
cardiovascular disease, depression, cognitive decline, autoimmune diseases,
skin diseases, inflammation, cancer, and metabolic syndrome.
Because of EPA’s antiplatelet
effects, excessive supplementation was thought to increase the risk of
bleeding, especially when taken with other blood thinners.
However, new literature finds
no increased risk of bleeding in patients taking fish oil supplements while
undergoing surgeries and invasive procedures. In fact, some literature
demonstrates a reduced need for blood transfusion in these patients.
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