Review
The opposing effects of n−3 and n−6 fatty acids

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Abstract

Polyunsaturated fatty acids (PUFAs) can be classified in n−3 fatty acids and n−6 fatty acids, and in westernized diet the predominant dietary PUFAs are n−6 fatty acids. Both types of fatty acids are precursors of signaling molecules with opposing effects, that modulate membrane microdomain composition, receptor signaling and gene expression. The predominant n−6 fatty acid is arachidonic acid, which is converted to prostaglandins, leukotrienes and other lipoxygenase or cyclooxygenase products. These products are important regulators of cellular functions with inflammatory, atherogenic and prothrombotic effects. Typical n−3 fatty acids are docosahexaenoic acid and eicosapentaenoic acid, which are competitive substrates for the enzymes and products of arachidonic acid metabolism. Docosahexaenoic acid- and eicosapentaenoic acid-derived eicosanoids antagonize the pro-inflammatory effects of n−6 fatty acids. n−3 and n−6 fatty acids are ligands/modulators for the nuclear receptors NFκB, PPAR and SREBP-1c, which control various genes of inflammatory signaling and lipid metabolism. n−3 Fatty acids down-regulate inflammatory genes and lipid synthesis, and stimulate fatty acid degradation. In addition, the n−3/n−6 PUFA content of cell and organelle membranes, as well as membrane microdomains strongly influences membrane function and numerous cellular processes such as cell death and survival.

Introduction

Polyunsaturated fatty acids (PUFAs) are fatty acids containing two or more double bonds. PUFAs are classified as n−3 and n−6 on the basis of the location of the last double bond relative to the terminal methyl end of the molecule. Both types of fatty acids are obtained through diet. In westernized diets linoleic acid (LA), (n−6) is the primary PUFA followed by α-linolenic acid (n−3). Because these two fatty acids cannot be synthesized in mammals, they are defined as essential fatty acids. Major sources of n−6 fatty acids are vegetable oils such as corn, safflower and soybean oil, whereas n−3 fatty acid sources are fish, such as salmon, trout and tuna [1].

Once consumed, these fatty acids are further metabolized within mammalian cells (Fig. 1). LA (18:2 n−6) is converted to γ-linolenic acid (18:3 n−6), and dihomo-γ-linolenic acid (20:3 n−6) to form the key intermediate arachidonic acid (AA) (20:4 n−6) by various desaturase- and elongase-enzymes. AA is further metabolized to docosapentaenoic acid (22:5 n−6) or eicosanoids.

The n−3 fatty acid α-linolenic acid (18:3 n−3) is converted to stearidonic acid (18:4 n−3) and eicosatetraenoic acid (20:4 n−3) to form eicosapentaenoic acid (EPA) (20:5 n−3) using the same series of enzymes as those used to synthesize AA. EPA is further metabolized to docosahexaenoic acid (22:6 n−3) or eicosanoids.

Since conversion of n−3 and n−6 fatty acids share the same series of enzymes (Fig. 1), a competition exists between the n−3 and n−6 fatty acid families for metabolism with an excess of one causing a significant decrease in the conversion of the other.

Section snippets

Biosynthesis of eicosanoids and other autacoids

Eicosanoids are key products synthesized from the 20-carbon polyunsaturated fatty acids, AA (n−6) and EPA (n−3). Because membranes contain mainly AA compared to EPA, AA is the predominant precursor for eicosanoid biosynthesis. The carboxylgroups of n−6/n−3 PUFAs are esterified with the hydroxyl groups of the glycerol backbone of phospholipids or glycerides. Thus, n−6/n−3 PUFAs are stored in esterified form in phospholipids of the cytosolic leaflet of cell and organelle membranes or in lipid

Opposing effects of n−3- and n−6 fatty acid-derived eicosanoids

The difference between n−3 and n−6 fatty acid-derived eicosanoids is that most of the mediators formed from EPA and DHA are anti-inflammatory, whereas those formed from AA are pro-inflammatory or show other disease-propagating effects (Table 1) [9], [10].

Prostaglandins PGI2 and PGE2, generated from AA, have pro-arrhythmic effects, whereas the EPA-derived prostaglandins PGI3 and PGE3 are anti-arrhythmic [11]. Concerning inflammatory modulation PGE2 has both pro- and anti-inflammatory effects. PGE

Effects of n−3 and n−6 fatty acids on G protein-coupled receptors

Although evidence for direct PUFA–protein interaction is rare, there are a few important studies showing direct interactions between PUFAs and G protein-coupled receptors (GPCRs). Rhodopsin is a GPCR responsible for sensing light in the retina. Functional studies of rod outer segment membranes of the retina isolated from rats fed n−3 fatty acid deficient diets showed a dramatic decrease in G protein-coupled receptor signalling of the rhodopsin photocycle [34], [35]. Nuclear magnetic resonance

n−3 and n−6 fatty acid effects on membrane fluidity

Fatty acids as components of biological membranes strongly influence their fluidity. With an increase in unsaturated fatty acids membrane fluidity increases. The reason for this is that PUFA acyl chains are extremely flexible and can rapidly change conformational states [41]. The acyl chain flexibility differs substantially between n−3 and n−6 fatty acids and the number of double bonds significantly alters membrane fluidity [42], [43]. Thus, the n−3 and n−6 fatty composition of biological

Effects of n−3 and n−6 fatty acids on gene expression

Many of the effects of n−3 and n−6 fatty acids are exerted through altered gene expression (Fig. 3). Nuclear receptors (NR) are a family of ligand-activated transcription factors that directly and indirectly control several genes of lipid metabolism and inflammatory signalling. The structural organization of nuclear receptor family members is similar despite wide variation in ligand specificity. With few exceptions, these proteins contain an NH2-terminal region that harbours a

Conclusion

n−6 and n−3 fatty acids are stored in phospholipids of cell and organelle membranes and in glycerides and phospholipids of lipid bodies. These fatty acids are released from phospholipids by PLA2 and are further metabolised to eicosanoids and other autacoids. AA (n−6)-derived eicosanoids are mostly pro-active, whereas EPA (n−3)-derived eicosanoids are inhibitory. The n−6/n−3 content of cell and organelle membranes and lipid membrane microdomains strongly influence membrane function and numerous

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