Some chemistry sources define 'arachidonic acid' to designate any of the
eicosatetraenoic acids. However, almost all writings in biology, medicine, and nutrition limit the term to all cis-5,8,11,14-eicosatetraenoic acid.
In addition to being involved in
cellular signaling as a lipid
second messenger involved in the regulation of signaling enzymes, such as
PLC-γ, PLC-δ, and
PKC-α, -β, and -γ isoforms, arachidonic acid is a key inflammatory intermediate and can also act as a
vasodilator.[6] (Note separate synthetic pathways, as described in section below.)
Arachidonic acid is not one of the
essential fatty acids. However, it does become essential if a deficiency in
linoleic acid exists or if an inability to convert linoleic acid to arachidonic acid occurs.
Some mammals lack the ability or have a very limited capacity to convert linoleic acid to arachidonic acid, making it an essential part of their diets. (As linoleic acid consumption does not seem to affect levels of arachidonic acid in plasma/serum or erythrocytes, it is uncertain if humans can in fact convert linoleic acid to arachidonic acid.[7]) As little or no arachidonic acid is found in common plants, these mammal species are "obligate
carnivores"; i.e. they must consume meat to survive. The domesticated
cat (Felis catus) is a commonly-cited example of an obligate carnivore, as it is unable to desaturate essential fatty acids.[8][9] A commercial source of arachidonic acid has been derived, however, from the fungus Mortierella alpina.[10]
Arachidonic acid for signaling purposes appears to be derived by the action of group IVA cytosolic phospholipase A2 (cPLA2, 85 kDa), whereas inflammatory arachidonic acid is generated by the action of a low-molecular-weight secretory PLA2 (sPLA2, 14-18 kDa).[6]
Arachidonic acid is a precursor to a wide range of
eicosanoids:
The enzymes 15-lipoxygenase-1 (
ALOX15) and 15-lipoxygenase-2 (
ALOX15B). ALOX15B catalyzes the oxidation of arachidonic acid to 15-hydroperoxyeicosatetraenoic acid (15-HPETE), which may then be further converted to
15-hydroxyeicosatetraenoic acid (15-HETE) and
lipoxins;[14][15][16] 15-Lipoxygenase-1 may also further metabolize 15-HPETE to
eoxins in a pathway analogous to (and presumably using the same enzymes as used in) the pathway which metabolizes 5-HPETE to leukotrienes.[17]
The enzyme 12-lipoxygenase (
ALOX12) catalyzes oxidation of arachidonic acid to 12-hydroperoxyeicosatetraenoic acid (12-HPETE), which may then be metabolized to
12-hydroxyeicosatetraenoic acid (12-HETE) and to
hepoxilins.[18]
The production of these derivatives and their actions in the body are collectively known as the "arachidonic acid cascade"; see
Essential fatty acid interactions and the enzyme and metabolite linkages given in the previous paragraph for more details.
Arachidonic acid is one of the most abundant fatty acids in the brain, and is present in similar quantities to
docosahexaenoic acid (DHA). The two account for about 20% of its fatty-acid content.[24] Like DHA, neurological health is reliant upon sufficient levels of arachidonic acid. Among other things, arachidonic acid helps to maintain
hippocampal cell membrane fluidity.[25] It also helps protect the brain from oxidative stress by activating
peroxisome proliferator-activated receptor gamma.[26] AA also activates
syntaxin-3 (STX-3), a protein involved in the growth and repair of neurons.[27]
Arachidonic acid is also involved in early neurological development. In one study, infants (18 months) given supplemental arachidonic acid for 17 weeks demonstrated significant improvements in intelligence, as measured by the Mental Development Index.[28] This effect is further enhanced by the simultaneous supplementation of AA with DHA.
In adults, the disturbed metabolism of AA may contribute to neuropsychiatric disorders such as
Alzheimer's disease and
bipolar disorder.[29] There is evidence of significant alterations in the conversion of arachidonic acid to other bioactive molecules (overexpression or disturbances in the AA enzyme cascade) in these conditions.
Alzheimer's disease
The biological roles of arachidonic acid and its metabolites have been explored in the context of various
neurodegenerative disorders, including Alzheimer's disease.[30]Dietary supplementation of arachidonic acid during the early stages of Alzheimer's disease has been suggested, but the potential for benefit remains unclear.[31]
Increased consumption of arachidonic acid will not cause inflammation during normal metabolic conditions unless
lipid peroxidation products are mixed in. Arachidonic acid is metabolized to both proinflammatory and anti-inflammatory eicosanoids during and after the inflammatory response, respectively. Arachidonic acid is also metabolized to inflammatory and anti-inflammatory eicosanoids during and after physical activity to promote growth. Chronic inflammation from exogenous toxins and
excessive exercise should not be confused with acute inflammation from exercise and sufficient rest that is required by the inflammatory response to promote the repair and growth of the micro tears of tissues.[32] However, the evidence is mixed. Some studies giving between 840 mg and 2,000 mg per day to healthy individuals for up to 50 days have shown no increases in inflammation or related metabolic activities.[32][33][34][35] Others show that increased arachidonic acid levels are actually associated with reduced pro-inflammatory IL-6 and IL-1 levels and increased anti-inflammatory
tumor necrosis factor-beta.[36] This may result in a reduction in systemic inflammation.[medical citation needed]
Arachidonic acid does still play a central role in inflammation related to injury and many diseased states. How it is metabolized in the body dictates its inflammatory or anti-inflammatory activity. Individuals with joint pains or active inflammatory disease may find that increased arachidonic acid consumption exacerbates symptoms, presumably because it is being more readily converted to inflammatory compounds.[medical citation needed] Likewise, high arachidonic acid consumption is not advised for individuals with a history of inflammatory disease, or who are in compromised health. Of note, while AA supplementation does not appear to have proinflammatory effects in healthy individuals, it may counter the anti-inflammatory effects of
omega-3 fatty acid supplementation.[37]
Health effects of arachidonic acid supplementation
Arachidonic acid supplementation in daily doses of 1,000–1,500 mg for 50 days has been well tolerated during several clinical studies, with no significant side effects reported. All common markers of health, including kidney and liver function,[34] serum lipids,[38] immunity,[39] and platelet aggregation[33] appear to be unaffected with this level and duration of use. Furthermore, higher concentrations of AA in muscle tissue may be correlated with improved insulin sensitivity.[40] Arachidonic acid supplementation of the diets of healthy adults appears to offer no toxicity or significant safety risk.
While studies looking at arachidonic acid supplementation in sedentary subjects have failed to find changes in resting inflammatory markers in doses up to 1,500 mg daily, strength-trained subjects may respond differently. One study reported a significant reduction in resting inflammation (via marker IL-6) in young men supplementing 1,000 mg/day of arachidonic acid for 50 days in combination with resistance training. This suggests that rather than being pro-inflammatory, supplementation of AA while undergoing resistance training may actually improve the regulation of systemic inflammation.[41]
A meta-analysis looking for associations between heart disease risk and individual fatty acids reported a significantly reduced risk of heart disease with higher levels of EPA and DHA (omega-3 fats), as well as the omega-6 arachidonic acid.[42] A scientific advisory from the American Heart Association has also favorably evaluated the health impact of dietary omega-6 fats, including arachidonic acid.[32] The group does not recommend limiting this essential fatty acid. In fact, the paper recommends individuals follow a diet that consists of at least 5–10% of calories coming from omega-6 fats, including arachidonic acid. It suggests dietary AA is not a risk factor for heart disease, and may play a role in maintaining optimal metabolism and reduced heart disease risk. Maintaining sufficient intake levels of both omega-3 and omega-6 fatty acids, therefore, is recommended for optimal health.
Arachidonic acid is not
carcinogenic, and studies show dietary level is not associated (positively or negatively) with risk of cancers.[43][44][45][46] AA remains integral to the inflammatory and cell growth process, however, which is disturbed in many types of disease including cancer. Therefore, the safety of arachidonic acid supplementation in patients with cancer, inflammatory, or other diseased states is unknown, and supplementation is not recommended.
See also
Aspirin—inhibits
cyclooxygenase enzyme, preventing conversion of arachidonic acid to other signal molecules
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