Regulation of Prostaglandin and Leukotriene Synthesis by Dietary Fatty Acids

The diverse physiologic and pathologic functions mediated by eicosanoids highlight the importance of their fatty acid precursors in the diet. Unlike cellular proteins that are genetically predetermined, the PUFA composition of cell membranes is dynamic and is pivotally dependent on dietary intake. The typical Western diet is high in the n-6 family of PUFA (up to 25-fold more n-6 fats than n-3 fats are consumed). This predominance of n-6 fat is due to the abundance in the diet of the 'parent' 18-carbon PUFA linoleic acid (LA; 18:2 n-6), which is present in high concentrations in corn, soy, safflower, and sunflower oils. Once ingested, LA can be converted to AA by a series of elongation and desaturation enzymes (Figure 6). Hence AA is the predominant PUFA of membrane n-9

18-Carbon fatty acids

Oleic acid Linoleic acid a-Linolenic acid

y i i elongase and desaturase enzymes if \ >|r

20-Carbon Eicosatrienoic acid Arachidonic Eicosapentaenoic fatty acids (ETrA; 20:3) acid* (AA; 20:4) acid* (EPA; 20:5)

* Competitive substrates for eicosanoid synthesis • Major synthesis Minor synthesis phospholipids and substrate for eicosanoid biosynthesis in the Western context.

The enzymes involved in the metabolism of the 20-carbon PUFAs to PGs and LTs can use either n-9 (eicosatrienoic acid; EtrA 20:3), n-6 (arachidonic acid; AA 20:4), or n-3 (eicosapentaenoic acid; EPA 20:5) PUFAs as the substrate (Figure 7). When n-3 PUFAs are included in the diet, EPA, the n-3 homolog of AA competes with AA for incorporation into the cellular phospholipids. An increase in the concentration of EPA in cell membranes displaces AA, which will result in reduced substrate for the synthesis of the n-6 eicosanoids. EPA can also compete with AA as the substrate for either COX or 5-LO enzymes. This results in inhibition of the synthesis of n-6-derived PGs and LTs and the formation of the n-3 PGs and LTs. The n-3-derived PGs and LTs are similar in structure but can be considerably different in their biological activity. On balance, the n-3 PGs and LTs are less thrombotic and less inflammatory than the homologous n-6-derived mediators (Figure 6).

Although the n-9 fatty acid oleic acid (OA; 18:1 n-9) is consumed in substantial amounts in the diet, the elongase and desaturase enzymes that catalyze the conversion of OA to ETrA (20:3 n-9)

n-6 PUFA

n-3 PUFA

n-6 PUFA

n-3 PUFA

COOH

COOH

COX 5-LO

COX 5-LO

pge2

ltb4

PGE3

LTB5

pain

potent

pain

weak

swelling

neutrophil

swelling

neutrophil

activator

activator

Figure 7 A comparison of the physiological activities between the n-6- and n-3-derived PGs and LTs.

Figure 6 Dietary fatty acids and their metabolism after ingestion via the desaturase/elongase pathways.

Figure 7 A comparison of the physiological activities between the n-6- and n-3-derived PGs and LTs.

COOH

COOH

preferentially metabolize the n-3 and n-6 20-carbon PUFAs, a-LA and LA, respectively. Metabolism of OA to ETrA is only quantitatively significant in essential fatty acid deficiency, which is very rare due to the abundance of essential fatty acids available in the diet and the small amounts required to avoid deficiency. Furthermore, ETrA can be metabolized by 5-LO but not COX because it lacks the n-6 bond necessary for PG and TX formation.

While Western diets are rich in n-6 and relatively poor in n-3 fats, there are populations in which n-6 fats are less dominant and more n-3 fats are consumed in total and relative terms (e.g., Greenland Eskimo, Japanese, and Mediterranean diets). In the extreme case of the Eskimos eating their aboriginal diet, which is based almost entirely on marine foods, there is a striking reduction in thrombotic vascular events and inflammatory diseases. The cardiovascular benefit has also been associated with traditional Japanese and Mediterranean diets. These benefits may be, in part, ascribed to a more favorable balance of n-6 and n-3 derived eicosanoids, although a myocardial membrane stabilizing effect of n-3 fats, independent of PG and LT synthesis, is also important.

See also: Bone. Cancer: Epidemiology and Associations Between Diet and Cancer. Cytokines. Fatty Acids: Omega-3 Polyunsaturated; Omega-6 Polyunsaturated; Saturated. Immunity: Physiological Aspects. Pregnancy: Nutrient Requirements. Stomach: Structure and Function.

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