Lipid metabolism and therapy: Edited by Philip C. Calder and Richard J. Deckelbaum
Last year in our Editorial  we highlighted the then recent American Heart Association (AHA) advice to consume at least 5–10% of energy as n-6 polyunsaturated fatty acids (PUFAs) in order to reduce coronary heart disease risk  and an article published in last years issue supported this advice . By far the major n-6 PUFA in the Western diet is linoleic acid, and the AHA advisory was based upon evidence obtained from intervention studies in which linoleic acid intake had been increased. The advisory caused alarm amongst some researchers, since it dismissed concerns about the sensitivity of low-density lipoprotein to oxidation being increased with an increased linoleic acid content , the evidence from animal models that a high linoleic acid diet can promote certain cancers , and the increased likelihood of inflammation and thrombosis that might result from enhanced arachidonic acid generation from its precursor linoleic acid . A recent review of the effects of linoleic acid in particular, and of n-6 PUFAs in general, reported that ‘n-6 PUFAs’ (used in some cases as a generalization for linoleic acid) lower total and LDL concentrations, and do not adversely affect blood pressure, platelet aggregation, or inflammation and concluded that an n-6 PUFA intake above 5% of energy and ideally about 10% of energy should be consumed . Furthermore, the review did not support recommending n-6 PUFA consumption below the current lowest levels . The issue was further discussed in a recent article which supported an intake of PUFAs (the sum of n-6 and n-3 PUFAs) of more than 10% of energy . However, Ramsden et al., in an elegant re-evaluation of randomized controlled dietary interventions that increased linoleic acid intake (these were the same trials considered by the AHA amongst the evidence that led to the advisory), suggested that the AHA had got it wrong. Ramsden et al. point out that quite a number of the trials of n-6 PUFAs actually also increased the intake of the plant n-3 PUFA α-linolenic acid or of marine n-3 PUFAs and restricted the intake of trans-fatty acids. They identified three trials of enhanced linoleic acid intake yielding four datasets. When these were combined there was a 13% increase in relative risk of nonfatal myocardial infarction (MI) and coronary heart disease mortality and a 17% increase in relative risk of coronary heart disease mortality . The conclusion of the study by Ramsden et al. is that the advice to maintain or increase intake of n-6 PUFAs should be reconsidered. There is a clear need to consider the evidence more deeply and to discuss it more widely, in order that the most appropriate advice be given .
One feature that becomes apparent when reading the papers cited above is that fatty acid terminology is used too loosely too often and that the boundaries are too frequently blurred: PUFAs, n-6 PUFAs and linoleic acid have been used interchangeably as if these mean the same thing. They do not, and the blurring of the distinctions amongst these terms and these entities can lead to inaccurate statements being made and, perhaps, inappropriate advice being given. Fatty acids have their own individual properties and functionalities: linoleic, γ-linolenic and arachidonic acids each have differing properties, biological functions and effects on human health related outcomes, and so they need to be considered as separate entities. In other words, there is a need for fatty acid-specific advice based upon the fatty acid-specific evidence base. If such an evidence base is weak and the question is important then there is a need to conduct the appropriate studies to fill the gap.
Similar arguments can be made about the use of the n-6 to n-3 fatty acid ratio [11,12]. This ratio is most often used by aggregating all n-6 fatty acids and all n-3 fatty acids, respectively, an approach which assumes all n-6 fatty acids are biologically equivalent to one another and that all n-3 fatty acids are biologically equivalent to one another. Clearly this is not correct – few would argue that linoleic acid is biologically equivalent to arachidonic acid, and it is evident that α-linolenic acid is not biologically equivalent to marine n-3 fatty acids [13–15]. Thus, in relation to diet and to biological status, the focus should be on specific fatty acids and absolute amounts/concentrations rather than on fatty acid classes and ratios. This becomes evident when examining data from a recent study comparing apo E-deficient mice with apo E-deficient fat-1 mice . Transgenic fat-1 mice express the desaturase enzyme that enables synthesis of n-3 fatty acids from n-6 fatty acids, which is normally absent in animals . Thus fat-1 mice have higher n-3 fatty acid status [α-linolenic acid, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)] than wild-type mice when fed on the same diet [17,18] and many of the phenotypes manifested by fat-1 mice resemble those achieved in wild-type mice fed marine n-3 fatty acids. In this recent study, the apoE−/−/fat-1 mice had higher plasma and tissue levels of α-linolenic acid, EPA, docosapentaenopic acid (DPA) and DHA than apoE−/− mice and this translated into lower ratios of n-6 to n-3 fatty acids. The apoE−/−/fat-1 mice had reduced aorta lesion areas and substantial reductions in inflammatory markers in the aorta and the plasma . In this article much fatty acid data are summarized as an n-6 to n-3 fatty acid ratio, but some detailed data on plasma, blood monocytes and the aorta are provided. Scrutiny of these data demonstrates that the differences in abundance of individual n-6 PUFAs (10–50%) are much smaller than the differences in the abundance of individual n-3 PUFAs (several hundred%), suggesting that both the n-6 to n-3 fatty acid ratio and the biological effects are driven by large increases in the various individual n-3 PUFAs . The use of the n-6 to n-3 fatty acid ratio disguises the contribution of each class of fatty acid (and also the individual fatty acids) to the changed fatty acid status and to the altered biology. In addition, the use of the ratio perpetuates the notion that all n-6 fatty acids are equivalent, that all n-3 fatty acids are equivalent, and that the actions of n-6 and n-3 fatty acids always oppose one another. Further, it allows an assumption to be made that the ratio is the major target for dietary change, and removes the focus from individual fatty acids and from absolute amounts or contributions. These arguments have been made in detail elsewhere [11,12].
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8 Calder PC, Dangour AD, Diekman C, et al
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10 Calder PC. The American Heart Association advisory on n-6 fatty acids: evidence based or biased evidence? Br J Nutr 2010; 104:1575–1576.
11 Harris WS. The omega-6/omega-3 ratio and cardiovascular disease risk: uses and abuses. Curr Atheroscler Rep 2006; 8:453–459.
12 Stanley JC, Elsom RL, Calder PC, et al
. UK Food Standards Agency Workshop Report: the effects of the dietary n-6:n-3 fatty acid ratio on cardiovascular health. Br J Nutr 2007; 98:1305–1310.
13 Burdge GC, Calder PC. Dietary α-linolenic acid and health-related outcomes: a metabolic perspective. Nutr Res Rev 2006; 19:26–52.
14 Arterburn LM, Hall EB, Oken H. Distribution, interconversion, and dose response of n-3 fatty acids in humans. Am J Clin Nutr 2006; 83:1467S–1476S.
15 Akabas SR, Deckelbaum RJ. Summary of a workshop on n-3 fatty acids: current status of recommendations and future directions. Am J Clin Nutr 2006; 83:1536S–1538S.
16 Wan JB, Huang LL, Rong R, et al
. Endogenously decreasing tissue n-6/n-3 fatty acid ratio reduces atherosclerotic lesions in apolipoprotein E-deficient mice by inhibiting systemic and vascular inflammation. Arterioscler Thromb Vasc Biol 2010; 30:2487–2494.
17 Kang JX, Wang J, Wu L, Kang ZB. Transgenic mice: fat-1 mice convert n-6 to n-3 fatty acids. Nature 2004; 427:504.
18 Kang JX. Fat-1 transgenic mice: a new model for omega-3 research. Prostaglandins Leukot Essent Fatty Acids 2007; 77:263–267.
19 Deckelbaum RJ. n-6 and n-3 Fatty acids and atherosclerosis: ratios or amounts? Arterioscler Thromb Vasc Biol 2010; 30:2325–2326.