Eicosanoids dietary PUFA

To advance understanding of the dynamic influence of dietary lipids, research efforts are focusing on the importance of the balance between n-6 and n-3 fatty acids in the human diet. What is emerging is recognition that these PUFAs modulate eicosanoid biosynthesis in numerous tissues and cell types, alter signal transduction, and influence gene expression (87, 118). The effect of n-6 and n-3 PUFA on CVD, cancer and bone/joint health is related to the newer discoveries of how dietary PUFA impact health. 

Additionally, an increase in long-chain n-3 PUFAs in hepatic TAG and PL may also reduce inflammation associated with hepatic steatosis by increasing the biosynthesis of anti-inflammatory eicosanoids. In general, dietary PUFAs have been suggested to suppress A5 and A6 desaturase activity (Sekiya et al., 2003) however, the effects of dietary ALA on the regulation of these enzymes are controversial. A study by Morise et al. (2004) found no increase in the A5 or A6 desaturase index in hamsters when they were fed ALA in various amounts (the LA/ALA ratio varied from... 

Dietary polyunsaturated fatty acids (PUFAs), especially the n-3 series that are found in marine fish oils, modulate a variety of normal and disease processes, and consequently affect human health. PUFAs are classified based on the position of double bonds in their lipid structure and include the n-3 and n-6 series. Dietary n-3 PUFAs include a-linolenic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) whereas the most common n-6 PUFAs are linoleic acid, y-linolenic acid, and arachidonic acid (AA). AA is the primary precursor of eicosanoids, which includes the prostaglandins, leukotrienes, and thromboxanes. Collectively, these AA-derived mediators can exert profound effects on immune and inflammatory processes. Mammals can neither synthesize n-3 and n-6 PUFAs nor convert one variety to the other as they do not possess the appropriate enzymes. PUFAs are required for membrane formation and function... 

A variety of biochemical and molecular mechanisms have been described to explain how PUFAs can modulate immune cell fate and function. The primary mechanism of action of dietary n-3 PUFAs involves the replacement of AA in the lipid membrane of the cells with either EPA or DHA. This, in effect, competitively inhibits the oxygenation of AA by the COX enzymes. For example, the EPA-induced suppression in the production of AA-derived eicosanoids is followed by a subsequent increase in the production of those from EPA. Generally, the EPA-derived eicosanoids are considered to be much less potent than those from AA, thus explaining, at least partially, the anti-inflammatory effects of PUFAs. A similar mechanism of action can be demonstrated for DHA, either directly or by retroconversion to EPA. 

Eicosanoids derived from the n-3 PUEAs are up to 100-fold less biologically potent for inducing pro-inflammatory cellular responses than those derived from AA (121, 122). It is proposed that dietary n-3 PUEAs act by two different mechanisms to control the amount of n-6 eicosanoids maintained in tissues first, by competing for incorporation into tissue lipid esters, thus reducing the rate of tissue formation of active n-6 eicosanoids and second, by forming weaker n-3 eicosanoids (123, 124) that compete at cellular receptor sites and diminish signaling by eicosanoids derived from n-6 PUEAs. As a result, diets with n-3 PUFAs create conditions that reduce the formation and constrain the function of active n-6 eicosanoids in stimulated cells (116). 

The modulatory effect of n-3 PUFAs on eicosanoid production could also be achieved at the enzyme level. The action of n-3 fatty acids that decreases the production of PGE2 could be an effect of down-regulation of COX-2 activity in local tissues (129, 130). In a study with rats, dietary n-6 PUFA up-regulated COX-2 and, to some extent, COX-1 expression leading to a concomitant increase in COX enzyme activity and prostaglandin synthesis, but fats containing added menhaden oil (high in n-3 PUFAs) had an opposite effect (131). 

Complex interactions and displacements of the omega-3 and omega-6 fatty acids take place in plasma and cellular lipids after dietary manipulations. Early steps of cell activation, such as generation of inositol phosphates, are induced by dietary fatty acids (Galli et al., 1989). The effects of dietary fatty acids on the inositol phosphate pathway indicate that diet-induced modifications of PUFA at the cellular level affect the activity of the enzymes responsible for the generation of lipid mediators in addition to the formation of products (eicosanoids) directly derived from their fatty acid precursors. This shows that dietary fats affect key processes in cell function. 

Studies altering dietary fatty acids have provided support that eicosanoid synthesis regulates immune-mediated forms of renal injury. A diet enriched with fish oil containing co —3 polyunsaturated fatty acids (PUFA) protects murine strains with lupus nephritis from the formation of renal disease. These CO —3 fatty acids, such as eicosapentaenoic (EPA) and docosahexenoic acid... 

The n-3 LC-PUFA have a beneficial effect on plasma triglycerides, high blood pressure, whole-blood viscosity, and platelet function they inhibit the expression of cell-adhesion molecules, shift the eicosanoid profile to one of lesser thrombotic and inflammatory potential, improve vessel-wall compliance, and have antiarrhythmic potential (1,2). A number of intervention trials have associated the consumption of fish with decreased mortality from CVD (3-5). High doses of fish oil eliminate both vascular thrombus as well as vascular lesion formation (6). In men who had had a recent myocardial infarction, low-dose dietary supplementation with n-3 LC-PUFA, in addition to the recommended secondary prevention treatments, reduced by 45% the risk of sudden cardiac death, but not the risk of nonfatal myocardial infarction (7). It has been shown to mitigate the course of coronary atherosclerosis in humans (8). 

In conclusion, our results suggest that n-3 PUFA decrease TNF-a production partially through inhibiting the production of the proinflammatory eicosanoids, LTB and TXAj. It has been suggested that diets with an increased ratio of n-3 to n-6 PUFA may provide a condition favorable to effective drug treatment because the current Western diet, with its low n-3/n-6 ratio, may be suboptimal for the effectiveness of drug therapies that require inhibition of proinflammatory cytokines as well as proinflammatory eicosanoids derived from n-6 PUFA (41). By decreasing the proinflammatory eicosanoids and cytokines, EPA or fish oil may have its special value as a food component or supplement for dietary intervention of a series of inflammatory diseases. 

In this aspect, novel anti-inflammatory mediators, including resolvins and protectins derived from docosahexaenoic acid (DHA, 22 6 FA), are discovered in association with the beneficial effects of dietary DHA on prevention of cardiovascular diseases [37, 38], In contrast, lipidomics research further confirmed the association of a variety of eicosanoids, oxylipins, and endocannabinoids with initiation and progression of cardiovascular diseases [39], These studies strongly suggest that the levels of n-3 and n-6 PUFA should be well balanced. 

There is much controversy around the optimal dietary ratio of n-6 to n-3 PUFAs. Increased dietary consumption of n-6 PUFAs has been shown to decrease the production of n-3 eicosanoids, and vice versa (reviewed by Simoponlos, 2002). This is due to competition in vivo of ALA and LA for the elongation and desaturation enzymes that are involved in the synthesis of long-chain PUFAs (Thomas, 2002). Humans evolved on a diet in which the n-6 to n-3 ratio was about 1, however, over the past 50-100 years there has been rapid changes in the human diet (Simopoulos, 2002). Currently, the typical North American diet is rich in n-6 PUFAs, which has resulted in an n-6 to n-3 ratio of 16 1 (Simoponlos, 2006). Intakes of n-3 PUFAs are much lower and... 

Data in the literature clearly show that CLA seems to positively interfere with hpid metabolism, in particular with n-6 PUFAs for eicosanoid formation, mitochondrial and peroxisomal beta oxidation, energy expenditure and eicosanoid catabolism, and with cholesterol metabolism. Most of these data are confined to experimental models, but human studies, even if scarce (especially long-term trials), suggest that CLA enriched products may have a positive impact on human health, extending the dietary inclusion of dairy products to those patients affected by metabolic syndrome. 

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