Arachidonic acid is arguably the most important PUFA associated with membrane phospholipids. Upon release, AA can be enzymatically metabolized to a myriad of bioactive derivatives, eicosanoids, known to contribute to a variety of chronic diseases, but are also known to be involved in tissue homeostasis and the resolution of inflammation [1–4, 22]. The relative abundance of AA in membrane phospholipids positively influences eicosanoid production . It is well known that dietary PUFA can affect tissue AA levels; however, what is uncertain and controversial is whether modifying current intakes of dietary LA will result in concomitant changes in tissue AA content, i.e., increasing LA intake results in an increase in tissue AA content and decreasing LA has the opposite effect . The goal of this paper was to ascertain the relationship between dietary LA and tissue AA content (phospholipid pools of plasma/serum and erythrocytes) in adults consuming a Western-style background diet. It was not designed to address other controversies surrounding the issues of dietary n-6 or n-3 PUFA or in other population groups.
Many papers interchange the more general term n-6 PUFA for dietary LA, but there are two major n-6 PUFA, LA and AA, that are distributed unevenly in the Western diet. While LA is the major PUFA in most commonly consumed foods, AA is exclusively found in animal products, such as, muscle, organ meats and eggs . They have distinct biological activities that are biochemically linked via desatuation and elongation, and as such, LA is the conditionally essential fatty acid. Linoleic acid is specifically required in the skin to maintain the integrity of the epidermal water barrier and AA is the immediate precursor to eicosanoids, as well as being the n-6 PUFA selectively incorporated into the membranes of certain tissues, i.e., brain . When consumed (LA vs. AA), they appear to have differential effects on tissue fatty acid composition, where AA appears to more robustly modify tissue AA levels and eicosanoids [14, 26].
The data presented in this paper suggests that a dose response between dietary LA and tissue AA does not exists within the backdrop of individuals consuming a Western-type diet. Increasing LA by as much as 551% from baseline and reducing LA by as much as 90% from baseline failed to yield compelling evidence supporting the concept that any conversion of dietary LA to downstream metabolites results in tissue enrichment of AA, a notion commonly assumed. For example, "However, the higher concentrations of LA typically found in the Western diet results in a greater conversion of LA to arachidonic acid" and"Excessive n-6 precursors promotes formation of AA", suggesting enrichment of AA in tissues with increases in LA intake. We chose to evaluate the data by looking at changes from baseline in tissue AA content to standardize the data from one study to the next. Each study began with a baseline value and we reported percent changes from that baseline. Supplemental intakes of LA were reported based on energy and when that value could not be determined, we reported absolute supplemented values, and these data were reported seperately.
As observed from the distribution of the responses, there was wide variability. Some papers showed small increases in tissue AA levels when dietary LA changed, while other papers showed small decreases, but most of these changes lacked significance. When there was significance, the changes were minimal and the distribution pattern of the data did not favor an increase or a decrease. We chose plasma/serum and erythrocytes as the tissues of choice because here is where the bulk of data exists in the human literature. Erythrocytes represent a more stable pool of dietary lipids, contain very little neutral lipids and thus represents a membrane fraction of AA. Fasting plasma/serum phospholipid levels primarily (but not exclusively) represents in part phospholipids of lipoproteins that are derived from hepatic endoplasmic reticulum , and this pool is more responsive to more recent dietary PUFA intakes.
In an effort to identify why dietary LA may not modify tissue AA levels, we reviewed the literature for dietary GLA using the same search strategy. Was the conversion of LA to AA rate-limiting, or were tissue levels of AA saturated? Delta-6 desaturase is the rate-limiting enzyme in the metabolism of LA to AA. GLA is a dietary n-6 PUFA that enters the metabolic pathway after the delta-6 desaturase step. If delta-6 desaturase is rate-limiting and tissue AA content is not saturated, then there should be evidence that including GLA in the diet increases tissue AA levels. When GLA was supplemented as the triacylglycerol form or as a component of a dietary oil containing GLA (i.e., blackcurrant, evening primrose or borage oil), tissue AA content increased in a dose responsive manner. These effects appeared to be less prominent in those studies [27–29] that used oils containing appreciable amounts of the more highly unsaturated n-3 PUFA stearidonic acid, i.e., blackcurrant . When AA was supplemented in the diet, there was further enrichment in tissue AA content above that observed with either LA or GLA. These results suggest that delta-5 desaturase potentially becomes rate limiting when GLA is supplemented. The reaction mediated by delta-5 desaturase is an intermediate step between GLA and AA and by-passing that step with dietary AA leads to further enrichment. These data seem to suggest that while dietary LA maybe a metabolic precursor for AA, its influence on tissue levels in populations consuming Western diets are limited by the enzymatic conversion through delta-6 desaturase and not due to tissue saturation of AA. These data are supported by the poor rates of conversion of plasma/serum LA to AA in adults. In tracer studies involving stable isotopes, the estimated fractional conversion of LA to AA was between 0.3% and 0.6% .
The levels of LA in the diet required to achieve essentiality could be as low as 0.5-2.0% of energy in infants [32, 33] and it has been reported that tissue levels of AA no longer respond to dietary LA intakes above 2% energy in adults . Our study was designed to chose studies that incorporated a Western-type diet where LA is not typically limiting, reflective of the general public. This means a full compliment of PUFAs were being consumed along with LA supplementation. The DRIs for LA and alpha-linolenic acid (ALA, 18:3 n-3) are 12 g-17 g/d and 1.1 g-1.6 g, respectively (women the lower figure, men the higher figure). This would be equivalent to intakes approximating 6% and 0.7% of calories per day for LA and ALA, respectively. It is not unreasonable to think that with a background diet containing LA, ALA, AA, and long-chain n-3 PUFAs, i.e. eicosapentaenoic acid (EPA, 20:5 n-3) and docosahexaenoic acid (DHA, 22:6 n-3) at typical intakes, that modifying dietary LA levels may not influence tissue AA levels. It is possible that as LA increases in the diet it maybe competing with AA for reacylation into phospholipids [13, 14, 16–18, 21, 34].
A small number of studies modified LA intakes by using oils that also contained some ALA, such as soybean and canola oil [17, 35, 36], but the results from these studies were not significant and were similar to the other results. There could be some concern that some of the supplemented oils contain ALA, such as soybean oil. It must be remembered that soybean oil has a LA:ALA ratio similar (8:1) to that found in the US diet (10:1) and if you included or excluded these papers the results were unaffected. We also included two studies that supplemented LA with recommended fish restrictions (because they met our inclusion/exclusion criteria) [19, 37]. One study (+176% LA) reported no changes in AA levels, while the other (+86% LA) reported a 10% increase in AA.
Some of the weaknesses of this review are reflected in the studies that qualified for our evaluation. Most were not designed to specifically address our research question; however, those that were specifically designed to evaluate the effect of dietary LA on tissue AA content yielded results that were similar to the overall results . Each study used a different population with potentially different background diets, but overall this would better reflect the consumption patterns of the general public. Not all studies were blinded (61% were blinded) and dietary LA was not exclusively modified. The methods for modifying LA intakes were varied and other dietary PUFA were not controlled for with the exceptions identified previously, and data for only two tissues were evaluated. When LA was modified, it was done so by typically changing the levels of an oil rich in LA (i.e., corn oil, safflower oil, sunflower oil) or foods containing LA (as opposed to adding pure LA), reflecting how LA would be consumed by the general public. There were no standard length to the studies. For example, studies involving plasma/serum ranged between 14 days-5 months, and those looking at erythrocyte data ranged between 14-180 days. Importantly, the subjects were used as their own controls, the studies addressed changes in LA in relationship to Western-type diets, and the results were not different between those studies that were double-blind randomized placebo controlled trials (1/3) and those that were not. Despite these weaknesses, positive results were still identified with intakes of GLA and AA, helping to support those results reported with LA.