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Editorial |
Department of Nutrition Harvard School of Public Health Boston, Massachusetts 02115
Address all correspondence and requests for reprints to: Dr. Frank M. Sacks or Dr. Hannia Campos, 665 Huntington Avenue, Boston, Massachusetts 02115. E-mail: fsacks{at}hsph.harvard.edu or hcampos{at}hsph.harvard.edu.
For at least 50 yr, polyunsaturated fatty acids (PUFAs) have been studied intensively as nutrients that protect against cardiovascular disease (CVD). As new mechanisms have been identified, research and clinical emphasis have shifted from one type of PUFA to another. As a class, PUFAs vary in several characteristics, namely length of the carbon chain from 18 to 22 carbons, number of double bonds between carbon atoms, and the position of the first double bond in the chain denoted as omega-6 or omega-3 (alternatively, n-6 or n-3). The double bonds, as few as two or as many as six, are located in a series beginning at either the third or the sixth carbon atom from the methyl end of the molecule and extending toward the carboxyl group. The biological properties of PUFAs are related to these three characteristics, although not necessarily in a uniform way, as we will discuss.
In 1956–1957, four research groups published convincing experiments showing that linoleic acid (18 carbons, 2 double bonds, omega-6) substantially reduced serum cholesterol, and it remains the most potent cholesterol-lowering nutrient (reviewed in Ref.1). Lacking medications to treat hypercholesterolemia, high-linoleic acid vegetable oils were a mainstay of serum cholesterol treatment in the 1950s and 1960s, with patients daily swilling corn, sunflower, safflower, or soybean oils. The potential of linoleic acid to reduce CVD was put to a rigorous test in randomized clinical trials, and reduction in definite clinical cardiovascular endpoints was established in the range of 20–35%, in line with the serum cholesterol reduction that was achieved (1). Prospective epidemiological studies in very large populations confirmed that dietary linoleic acid is predictive of reduced CVD (2). Thus, one paradigm became established, that linoleic acid, an omega-6 PUFA, is cardioprotective.
Because two double carbon bonds in an 18-carbon fatty acid were so effective, then what about fatty acids with five or six double bonds in 20- or 22-carbon atoms? What about shifting the series of double bonds from omega-6 to omega-3? Unfortunately, neither more carbons, more double bonds, nor the omega-3 isomer improve blood cholesterol reduction. In fact, eicosapentaenoic acid (EPA) (20 carbons, 5 double bonds, omega-3) or docosahexaenoic acid (DHA)(22 carbons, 6 double bonds, omega-3), found in fish oils, given in doses less than 6 g/d (equivalent to 12–20 1-g fish oil capsules per day) increase low-density lipoprotein (LDL) cholesterol levels (3, 4). When large amounts of fish oil (containing 24 g of omega-3 fatty acid per day) replace saturated fat, lower LDL cholesterol levels are observed, similar to the effects of vegetable oil (5). In contrast, EPA and DHA are much more potent than linoleic acid for lowering plasma triglycerides (6). The molecular mechanisms mediating these effects of PUFAs on serum cholesterol and CVD are still not fully understood. Thus, linoleic acid remains the most effective PUFA for lowering serum cholesterol and the fatty acid most well established to prevent CVD.
Readers may find themselves surprised at this last statement in view of the dominance of the omega-3 PUFA theory in basic and clinical research. In the early 1980s, two lines of evidence coalesced to engender widespread excitement on the potentially cardioprotective effects of omega-3 fatty acids, particularly those from fish oil (EPA and DHA). Populations eating large amounts of fatty fish had low rates of CVD, and in many epidemiological studies, n-3 PUFA intake or blood levels are inversely related to CVD (7). Omega-3 fatty acids are metabolized to prostaglandins and leukotrienes that are antithrombotic, antiinflammatory, and vasodilating.
The omega-3-cyclooxygenase-lipoxygenase paradigm came to include a negative view of omega-6 PUFA (8). The theory considered the fact that dietary linoleic acid can be metabolized to arachidonic acid that can be metabolized further to prostaglandins and leukotrienes that are relatively prothrombotic, proinflammatory, and vasoconstricting. Also, n-6 PUFAs may reduce by competition for cyclooxygenase the formation of antiinflammatory mediators from n-3 PUFAs. Carried to its extreme, the theory called for the ideal fatty acid balance to be high in omega-3 and low in omega-6, producing a high omega-3 to omega-6 ratio. This vision was restricted because it did not recognize the known benefits of linoleic acid on LDL cholesterol and CVD.
The established benefits of omega-6 PUFAs raise the question that if omega-6 PUFAs are capable of being metabolized to undesirable prostaglandins and leukotrienes, why should they protect against CVD? One explanation is that LDL cholesterol is such a dominant force in atherosclerosis, effects on prostanoids are not completely offsetting. Another explanation is that omega-6 dietary PUFAs ordinarily in vivo may be minimally involved in cyclooxygenase reactions and do not stimulate appreciably the production of vasoactive and prothrombotic molecules. A third explanation is that omega-6 PUFAs operate in antiinflammatory metabolic pathways that do not involve cyclooxygenase, and that these pathways have a protective influence on CVD.
Several lines of evidence support this last possibility. De Caterina et al. (9) discovered that both omega-6 and omega-3 fatty acids have antiinflammatory properties that suppress the atherogenic activation of vascular endothelial cells. Both PUFA classes inhibit the production by endothelial cells of adhesion molecules, chemokines, and ILs, key mediators that propagate the atherosclerotic process. PUFAs reduced the activation of nuclear factor-
B (NF-B), a transcription factor for these proinflammatory genes. These antiinflammatory effects of omega-6 and omega-3 PUFAs were also found in monocytic cells (10). The protective action of a specific PUFA was directly related to the number of double carbon bonds in the molecule. Even oleic acid, a monounsaturated fatty acid with only one double carbon bond, had a protective effect, albeit relatively weak. Reduction in inflammation was not affected by the isomeric omega-3 or omega-6 configuration and did not work through cyclooxygenase or lipoxygenase reactions. De Caterina et al. (9) hypothesized that double carbon bonds could scavenge reactive oxygen molecules and reduce generation of hydrogen peroxide that activates NF-B.
Omega-6 PUFAs inhibit activation of NF-B in endothelial cells by yet another mechanism that involves antiinflammatory epoxyecosatrienoic acids (EETs) (11). EETs are produced from omega-6 PUFAs by a cytochrome P450 epoxygenase (CYP2J2) (11). EETs also have important vasodilatator properties via hyperpolarization and relaxation of vascular smooth muscle cells (12). A polymorphic variant –50G>T in the promoter region of CYP2J2 is associated with increased prevalence of CHD (13). Interestingly, this variant is associated with reduced plasma concentrations of 14, 15 dihydroxyeicosatrienoic acid, a stable EET metabolite. Availability of omega-6 fatty acids is therefore essential for the production of these protective metabolites.
The CHIANTI study by Ferrucci et al. (14) reported in this issue of JCEM adds clinical relevance to these mechanistic studies on PUFAs. Higher plasma levels of omega-6 PUFAs, mainly arachidonic acid, and of omega-3 fatty acids, mainly DHA, were both associated with decreased levels of serum proinflammatory markers, particularly IL-6 and IL-1-ra, and increased levels of antiinflammatory markers, particularly TGF-ß. DHA was also associated with increased IL-10, a powerful antiinflammatory cytokine. 
-Linolenic acid was associated with lower C-reactive protein levels. Overall, a more powerful effect on inflammatory markers was observed for longer chain fatty acids (20-carbon or greater) than for 18-carbon fatty acids.
Taken together, the data suggest that higher plasma levels of n-6 fatty acids such as linoleic or arachidonic acids will lead to decreased CVD via their beneficial effects on inflammatory markers. This hypothesis is consistent with the observation that arachidonic acid in platelets or plasma is significantly lower among CVD cases than controls (15). However, a caveat is in order regarding studies of fatty acid biomarkers. As opposed to results in studies of arachidonic acid levels in blood, a high arachidonic acid content in adipose tissue was associated with higher risk of myocardial infarction (16, 17). Discrepant results have even been observed in the same study where an association with myocardial infarction was found with lower platelet but not adipose tissue arachidonic acid (18). Thus, the finding of a correlation between fatty acid and inflammatory markers in a specific tissue may only be indicative of effects in that location, particularly for fatty acids with so many known functions that can be both beneficial and detrimental.
In conclusion, traditional paradigms for cardioprotective effects of omega-6 and omega-3 PUFAs tell an incomplete story of their multivalent potential. Linoleic acid, the principal omega-6 PUFA in the diet, and the omega-3 PUFAs are clearly beneficial as a result of shared mechanisms as in reduced inflammation, and distinct mechanisms as in serum LDL cholesterol reduction by linoleic acid and triglycerides reduction by omega-3 PUFAs. A more complete understanding is needed of the role of arachidonic acid in atherosclerosis. Information is needed on the control of arachidonic acid levels in tissues by endogenous mechanisms as well as by dietary intake of its precursor, linoleic acid; on actions of arachidonate-rich lipoproteins in cells; on the effects of arachidonic acid on vascular function and inflammation; and on the metabolic routing of arachidonic acid through proinflammatory vs. antiinflammatory pathways. Finally, the future holds promise to exploit genetic variation that controls the metabolic fate of dietary PUFAs and their potential benefit for CVD.
Footnotes
Abbreviations: CVD, cardiovascular disease; DHA, docosahexaenoic acid; EET, epoxyecosatrienoic acid; EPA, eicosapentaenoic acid; LDL, low-density lipoprotein; NF-B, nuclear factor-B; PUFA, polyunsaturated fatty acid.
Received November 9, 2005.
Accepted December 13, 2005.
References
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