Lipid metabolism and therapy: Edited by Philip C. Calder and Richard J. Deckelbaum
High intakes of saturated, monounsaturated trans and polyunsaturated trans fatty acids have long been labeled ‘bad’ because of their adverse effects in cardiovascular disease and other health outcomes. In contrast, higher intakes of marine n-3 polyunsaturated fatty acids (PUFA), especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are being described as ‘good’ with increasing clinical benefits and improved mechanistic understandings relating to cardiovascular health, growth and development, inflammatory processes, mental and neurodegenerative diseases, and perhaps certain forms of cancer [1,2]. Preceding this recognition of the benefits of n-3 fatty acids there was a period of high enthusiasm for replacing dietary saturated fatty acids with n-6 PUFA with the primary goal being to reduce cardiovascular disease. Thus, the American Heart Association (AHA) and other governmental and nongovernmental organizations recommended n-6 PUFA intake up to 10% of dietary energy. However, concerns about n-6 PUFA intake and especially about high n-6/n-3 PUFA ratios have been raised [3–5]. These latter concerns have largely been based on in-vitro and animal experiments showing that the n-6 essential fatty acid, linoleic acid, leads to production of arachidonic acid, which is the substrate for proinflammatory and prothrombotic eicosanoids. In contrast, EPA and DHA are associated with production of less inflammatory and in some cases anti-inflammatory molecules [2,6].
The study by Harris (pp. 125–129) in this issue, along with a recent advisory from the AHA on n-6 fatty acids , review substantial evidence that, in fact, n-6 fatty acids remain ‘protective’ in terms of decreasing risk of coronary heart disease. n-6 PUFA also have other benefits in terms of their essential roles in brain growth and cognitive development, lowering blood pressure, and in factors relating to insulin resistance . The AHA advisory summarizes a wide body of evidence showing that n-6 PUFA actually reduce inflammatory states in a large number of human and animal studies . It is important to realize that arachidonic acid produces potent anti-inflammatory and proresolution lipoxins [6,8]. Furthermore, Pischon et al.  reported that dietary n-6 PUFA do not inhibit the beneficial anti-inflammatory effects of EPA and DHA and suggest that a combination of both may actually be associated with lowest levels of inflammatory markers.
Recent studies shed new light on the relative importance of n-6 and n-3 PUFA. Block et al.  found that red blood cell membrane contents of both n-3 and n-6 PUFA are lower in cases of acute coronary syndrome as compared with controls and suggested that it is n-3 PUFA intakes that drive the n-6: n-3 ratio of red cell membranes. In other human studies, the absolute amounts of α-linolenic acid and linoleic acid in the diet influence the conversion of α-linolenic acid to EPA and DHA, but the ratio of linoleic acid to α-linolenic acid has much less influence on such conversion [11,12]. Of note, dietary linoleic acid had little effect on the arachidonate content of platelets and red blood cell membranes . Still, higher dietary intakes of linoleic acid and of arachidonic acid were associated with increased intima–media carotid thickness, but this occurred only in a small number of individuals carrying a variant for the arachidonate 5-lipoxygenase promoter genotype with no effect in the majority of the population with the more common genotype .
In summary, considerations regarding an optimal n-6: n-3 fatty acid ratio are losing ground in relation to considerations about adequate intakes for both n-3 and n-6 fatty acids [11,12] and (pp. 125–129) in this issue. The meaning and usefulness of ratios has been questioned recently [11,12], with the obvious recognition that the use of a ratio can disguise extremely low or very high intakes of n-6 and/or n-3 fatty acids. What should be included when considering using a ratio has also been questioned: linoleic acid to α-linolenic acid, total n-3 to total n-6 fatty acids, arachidonic acid to EPA or something else . The bulk of current evidence suggests that it is the absolute intakes of specific n-6 and n-3 PUFA that are associated with many different endpoints. What is often overlooked is whether different intakes of fatty acids are required for different health and disease states. We do not yet know whether beneficial intakes of n-6 and n-3 PUFA with regard to coronary heart disease also elicit benefits in terms of mental health or immune/inflammatory disorders. However, at this point in time, even in the absence of recommendations for optimal intakes of n-6 and n-3 PUFA for each health and disease parameter, we can conclude that extremely low intakes of either might be harmful. We should encourage adequate intakes of both n-6 and n-3 fatty acids. Evidence related to intake amounts for n-6 and n-3 PUFA are best defined for coronary artery disease, but with increasing interest in the beneficial roles of both n-6 and n-3 PUFA in other health and disease areas, we might expect better definition of the required amounts for each biological sphere in the not too distant future.
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