Arachidonic acid is a polyunsaturated fatty acid (PUFA) (AA, 20: 4 (n-6)) that is enzymatically converted to a number of pro-inflammatory eicosanoids. In particular, AA is converted via COX (cyclooxygenase) enzymes to the series 2 prostanoids (prostaglandins and thromboxanes) and via the LOX (lipoxygenase) enzymes the series 4 leukotrienes. Cell membranes are a store of AA, and the pro-inflammatory eicosanoids are formed when the enzyme phospholipase A2 liberates AA bound in phospholipids. Research has suggested that high levels of pro-inflammatory eicosanoids formed from AA are detrimental to the health because they lead to degenerative disease. Evidence suggests that reductions in AA levels and modulation of the formation of pro-inflammatory eicosanoids can prevent disease, and further more that dietary strategies are effective at achieving this. In particular, the intake of PUFA in the diet influences AA membrane levels and eicosanoid formation.
Formation of AA begins endogenously with the essential fatty acid linoleic acid (LA, 18:2 (n-6)). Synthesised of LA is not possible in humans and so it must be consumed in the diet. Conversion of LA to AA occurs through a series of enzymatic step that involve elongase and desaturase enzymes and involve the formation of the intermediary substances γ-linolenic acid (GLA, 18:3 (n-6)) and dihomo- γ-linolenic acid (DGLA, 20:3 (n-6)). Therefore, LA is a source of AA in the diet, but the conversion is tightly regulated. Increasing dietary levels of LA above 2-3 % of calories does not further increase AA levels in cell membranes. Typical Western diets may by 7-8 % LA (which is probably too high) and it would be therefore necessary to make drastic reductions in the levels of LA in the diet in order to effect tissue levels of AA.
Increasing levels of n-3 fatty acids in the diet reduces the tissue concentration of AA, while increasing the tissue concentration of the n-3 fatty acids. Both alpha linolenic acid (ALA, 18:3 (n-3)) found in flax and eicosapentanoic acid (EPA, 20:5 (n-3)) and docosahexanoic acid (DHA, 22:6 (n-3)) found in fish, are all able to raise tissue levels of n-3 fatty acids when incorporated into the diet. However, the EPA and DHA from fish oils are 2.5 to 5 times as effective as ALA. The similar structural shape of EPA probably explains the reason that AA is displaced from incorporation into phospholipids. Dietary ALA also appears to compete with LA for the elongase and desaturase enzymes responsible for the formation of AA, and thus increasing dietary intakes of ALA decreases the conversion of dietary LA to AA.
The diet can also provide a source of AA which is found in high concentrations in a number of foods such as red meat, milk and cheese. It is known that dietary AA is much better at repleting tissue levels of AA than is dietary LA. Tissue uptake of dietary AA shows a dose response at low intakes, is effective at increasing levels of AA in all types of tissue. The rapid storage of AA in tissues is explained because AA does not require elongation and desaturation, because it is a poor substrate for β-oxidation and because long chain fatty acids are preferentially incorporated into cell membranes. Decreasing dietary levels of AA, in combination with dietary sources of LA (below 2-3 % of calories) therefore reduces tissue concentrations of AA, and this strategy is made more effective by increasing dietary levels of EPA, DHA and ALA.
The series 2 and series 4 eicosanoids are beneficial to the body because they play an important role in immunity and cell signally. However, chronic raised production of these eicosanoids leads to disease and death. Levels of the pro-inflammatory eicosanoids are reduced in the presence of high tissue concentrations of EPA. This is because EPA uses the same COX and LOX enzyme during conversion to a different set of prostanoids and leukotrienes that are neutral in their inflammatory effects. However, by inhibiting the conversion of AA to the pro-inflammatory eicosanoids, inflammation is decreased. Dietary and endogenously formed GLA is converted to a number of anti-inflammatory eicosanoids that belong to the series 1 prostanoids. Because the series 1 prostanoids are formed using the same COX enzymes as the series 2 prostanoids they further reduce inflammation.
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