After ingestion, EFA (C18:2n-6 and C18:3n-3) are distributed between adipose TG, other tissue stores, and tissue structural lipids. A proportion of C18:2n-6 and C18:3n-3 provides energy, and these PUFA are oxidized more rapidly than are SAFA or MUFA. In contrast, long-chain PUFA derived from EFA (i.e., C20:3n-6, C20:4n-6, C20:5n-3, and C22:6n-3) are less readily oxidized. These acids, when present preformed in the diet, are incorporated into structural lipids about 20 times more efficiently than after synthesis from dietary C18:2n-6 and C18:3n-3. The liver is the site of most of the PUFA metabolism that transforms dietary 18-carbon EFA into long-chain PUFA with 20 or 22 carbons. Long-chain PUFA are transported to extrahepatic tissues for incorporation into cell lipids, even though there is differential uptake and acylation of PUFA among different tissues. The final tissue composition of long-chain PUFA is the result of the above complex processes along with the influence of dietary factors. The major elements in the diet that determine the final distribution of long-chain PUFA in cell PL include the relative proportions of n-3, n-6, and n-9 FA families, and the preformed long-chain PUFA versus their shorter-chain precursors ( 90).
Membrane structural PL contain high concentrations of PUFA and the 20- and 22-carbon PUFA that predominate from the two families of EFA. C20:4n-6 is the most important and abundant long-chain PUFA found in membrane PL and is the primary precursor of eicosanoids. The concentration of free C20:4n-6 is strictly regulated via phospholipases and acyltransferases. Most nonacylated C20:4n-6 is bound to cytosolic protein. In terms of EFA from the n-3 PUFA series, C20:5n-3 and C22:6n-3 are most prevalent in membrane PL. The long-chain PUFA derived from EFA are incorporated primarily in the 2-acyl position in bilayer PL of mammalian plasma, mitochondrial, and nuclear membranes. The 20-carbon FA, when released from their PL, can be transformed into intracellular metabolites (inositol triphosphate [IP 3] and diacylglycerol [DAG]) and extracellular metabolites (platelet-activating factor [PAF] and eicosanoids), which participate in many important cell-signaling responses. The relative proportions in tissue PL of C20:4n-6 and other long-chain PuFa (C18:3n-6, C20:4n-6, and C20:5n-3) are important, as these PUFA can compete for or inhibit enzymes involved in generation of intracellular and extracellular biologically active products. Also, dietary C18:1n-9, C18:2n-6, C18:2n-6 trans, C18:3n-6, C18:3n-3, and long-chain n-3 PUFA C20:5n-3 and C22:6n-3 can compete with C20:4n-6 for the acyltransferases for esterification into PL pools and thereby inhibit C20:4n-6-mediated membrane functions.
As fragile membranes in erythrocytes and mitochondria are typical of EFAD, an early function attributed to EFA was their role as integral components of PL required for plasma and intracellular membrane integrity. EFAD results in a progressive decrease in C20:4n-6 in membrane PL, with a concomitant increase in C18:1n-9 and its product, C20:3n-9. The fluidity and other physical properties of membrane PL are largely determined by the chain length and degree of unsaturation of their component FA. These physical properties, in turn, affect the ability of PL to perform structural functions, such as the maintenance of normal activities of membrane-bound enzymes. Dietary SAFA, MUFA, and PUFA, major determinants of the composition of stored and structural lipids, alter the activity and affinity of receptors, membrane permeability, and transport properties (91).
The heterogeneity and selectivity of PUFA with respect to their tissue membrane distribution among different organs may be related to their structural and functional roles (91). For example, long-chain derivatives of n-3 PUFA are concentrated in biologic structures involved in fast movement, such as that required in transport mechanisms in the brain and its synaptic junction and in the retina (92). Approximately 50% of the PL in the disk membrane of the retinal rod outer segment in which rhodopsin resides contains C22:6n-3 (93). The C22:6n-3 is concentrated in the major PL classes, i.e., PC, PE, and phosphotidylserine (PS) in the disk membrane, whereas C20:4n-6 is found in the minor PL components, such as phosphatidylinositol (PI). This observation has led to speculation that C22:6n-3 plays a structural role in these membranes while C20:4n-6 may play a more functional role (94).
In addition to their structural role and their movement across membranes, structural lipids can also modulate cell function by acting as either intracellular mediators of signal transduction or modulators of cell-cell interac-tions. These actions are initiated by phospholipases. Phospholipase A 2 cleaves FA, usually PUFA, present at the 2 position of PL. PUFA released under action of phospholipase A2 produce metabolites released extracellularly to act on other cells. These metabolites include PAF (a choline-containing PL with an acetate residue in the 2-position) and eicosanoids. Phospholipase C acts on phosphoinositides to break the bond between glycerol and phosphoric acid, releasing intracellularly diacylglycerols (DAG) and inositol phosphates (IP), which are involved in signal transduction. After receptor stimulation, DAG and IP act intracellularly as second messengers to activate protein kinase C and release intracellular stores of calcium, respectively ( 5). Activated protein kinase C mediates transduction of a wide variety of extracellular stimuli, such as hormones and growth factors, leading to regulation of such cellular processes as cell proliferation and differentiation. PL can act as a cofactor for some isoforms of protein kinase C by enhancing binding to DAG ( 95). In addition, unesterified PUFA can activate protein kinase C with differing potencies ( 96). As dietary PUFA can greatly modulate PUFA composition of structural lipids, generation of intra- and extracellular products can be greatly affected by dietary lipids. For example, thrombin-stimulated platelets from rabbits fed fish oil form less IP than platelets from those fed either corn or olive oil (97).
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