Essential fatty acids and their metabolites in signal transduction.

The above examples argue that the diversity of eicosanoid structures is reflected in distinct actions, that the membrane-permeable nature of these molecules provides a system for interactive cellular signalling that may be particularly important in the nervous system, and that convincing evidence exists for direct actions of eicosanoids on both ion channels and kinases, as well as G-protein-coupled receptors.     

Essential fatty acids in adipose tissue

Among the numerous causes of lipomobilization of fatty acids from the adipose tissue it is also carbon tetrachloride (CCl4). The research shows that the saturated fatty acids decreased in this tissue of the rats injected with CCl4, even if the linolenic and alpha-linolenic acids are present in the diet.     

Essential fatty acids and immune response

The implication that essential fatty acids (EFA) can affect immune response was based on the observation that EFA deficiency can accentuate or improve symptoms of certain autoimmune diseases in animals, and that supplementation of linoleic acid to animals reversed such effects. Furthermore, treatment of animals with cyclooxygenase inhibitors abrogated the effect of linoleic acid. Administration of cyclooxygenase inhibitors to animals enhanced both cell-mediated and humoral immune responses. In vitro studies have shown that prostaglandin E (PGE) group inhibits both T and B lymphocyte functions; it is suggested that effects of EFA on immune response are, in part, mediated through eicosanoids. Growing evidence now suggests that the PGE group of prostaglandins can serve as a negative feedback modulator of immune response. However, in vitro effects of other cyclooxygenase-derived products, such as PGI2 and thromboxane A2 (TXA2) have not been well established, perhaps because of their instability in aqueous media. Unlike the PGE group, some of lipoxygenase-derived products of arachidonic acid have shown immunostimulatory effects, as assessed by lymphokine production in vitro. Whether such effects can be seen in vivo remains to be determined. Some lipoxygenase-derived products with strong chemotactic action may indirectly influence immune response by modulating the population of antigen-presenting macrophages in tissues. Thus, the net effect of eicosanoids synthesized in macrophages on modulating immune response may depend on relative amounts of cyclooxygenase-derived products as compared with lipoxygenase-derived products. Macrophages are the major source of eicosanoids among immunocompetent cells. The profile of eicosanoids, produced in vitro by macrophages, varies with type of stimuli and anatomical sites. It can also be affected by the fatty acid composition of tissue lipids, which in turn can be modified by the composition of dietary EFA. Whether manipulating dietary EFA can modulate immune response in normal humans and animals needs to be determined.     

Essential fatty acids in the fetal and newborn lamb

The concentrations of linoleic and linolenic acids and their metabolites in the liver, kidney, brain, erythrocytes and plasma of fetal lambs at various stages of gestation, and of newborn and 2-week-old suckled lambs was determined. Throughout gestation the fetal tissues, erythrocytes and plasma all contained low levels of linoleic and linolenic acids together with consistently high levels of their long-chain polyunsaturated metabolites. The triene: tetraene (eicosa-5,8,11-trienoic acid/arachidonic acid) ratio was always 0.4 or less except at birth when it reached 0.6 in liver and 0.9 in plasma. Milk intake significantly increased the linoleic and linolenic acid levels in the lamb by 2 weeks after birth. These results show that the developing fetal lamb should not be regarded as being deficient in essential fatty acids, as suggested by previous investigators. It is proposed that the total metabolites of linoleic and linolenic acids are the most appropriate measure of the essential fatty acid status of the fetal lamb.     

Essential fatty acids are not required for wound healing.

Rats with essential fatty acid deficiency (EFAD) exhibit mild body growth retardation, diminished leukocyte influx in certain models of inflammation, and skin lesions characterized by ulceration, thinning and decreased pigmentation. In the present study we examined the role of EFAD in cutaneous wound healing, a process in which the inflammatory response and the macrophage play a central role. We reproduced the EFAD condition in Lewis rats (n = 35), and examined its effects in wound healing using the paired rat surgical incision model. Rats were compared with weight-matched controls, receiving standard chow diet. Skin samples harvested at days 5, 7, 14 and 21 post-wounding were evaluated for tensiometry and histology. EFAD rats exhibited all the characteristics of this condition, and the typical alteration of liver lipids. Skin samples harvested at different days post-wounding did not show difference in maximal breaking strength when compared to weight-matched controls. Histological evaluation of skin samples showed no difference in the cellular inflammatory infiltration in either EFAD rats or in weight-matched controls. Immunohistochemical studies revealed no difference in the influx of macrophages in the different groups of rats. Fatty acid supplementation of EFAD rats (n = 7), successfully reversed the EFAD state as assessed by the macroscopic skin and liver changes and liver fatty acid content, without modifying either tensile strength or cellular inflammatory infiltration. Our results suggest that EFAD does not alter the normal course of the cutaneous wound repair in rats, despite all the cutaneous alterations produced by this condition. We conclude that essential fatty acids (EFAs) are not essential for cutaneous wound repair.     

Essential fatty acids, lipid peroxidation and apoptosis

Essential fatty acids (EFAs) and their metabolites, especially gamma-linolenic acid, arachidonic acid, eicosapentaenoic acid and decosahexaenoic acid are known to induce apoptotic death of tumour cells. But the exact mechanism by which these fatty acids are able to induce apoptosis is not clear. Recent studies suggest that these fatty acids are able to induce apoptosis in cells over expressing cytochrome P450 following depletion of cellular glutathione and inhibition of carnitine palmitoyl transferase I (CPTI) activity. On the other hand, BCL-2 prevented apoptosis induced by these long-chain fatty acids, where as n-3 fatty acids suppressed ras expression leading to suppression of development of overt neoplasia. Phosphorylation of BCL-2 inhibits its ability to interfere with apoptosis and enhances lipid peroxidation leading to the occurrence of apoptosis. Tumour cells treated with long-chain fatty acids show increase in lipid peroxidation process, depletion of antioxidants and phosphorylation of proteins. Based on these results, it is suggested that long-chain fatty acids induce apoptosis by enhancing lipid peroxidation, suppressing BCL-2 expression possibly by phosphorylation and augmentation of P450 activity. Thus, these long-chain fatty acids may, infact act at the level of gene/oncogene expression in producing their cytotoxic action on tumour cells.     

Essential fatty acids: biochemistry, physiology and pathology

Essential fatty acids (EFAs), linoleic acid (LA), and alpha-linolenic acid (ALA) are essential for humans, and are freely available in the diet. Hence, EFA deficiency is extremely rare in humans. To derive the full benefits of EFAs, they need to be metabolized to their respective long-chain metabolites, i.e., dihomo-gamma-linolenic acid (DGLA), and arachidonic acid (AA) from LA; and eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) from ALA. Some of these long-chain metabolites not only form precursors to respective prostaglandins (PGs), thromboxanes (TXs), and leukotrienes (LTs), but also give rise to lipoxins (LXs) and resolvins that have potent anti-inflammatory actions. Furthermore, EFAs and their metabolites may function as endogenous angiotensin-converting enzyme and 3-hdroxy-3-methylglutaryl coenzyme A reductase inhibitors, nitric oxide (NO) enhancers, anti-hypertensives, and anti-atherosclerotic molecules. Recent studies revealed that EFAs react with NO to yield respective nitroalkene derivatives that exert cell-signaling actions via ligation and activation of peroxisome proliferator-activated receptors. The metabolism of EFAs is altered in several diseases such as obesity, hypertension, diabetes mellitus, coronary heart disease, schizophrenia, Alzheimer's disease, atherosclerosis, and cancer. Thus, EFAs and their derivatives have varied biological actions and seem to be involved in several physiological and pathological processes.     

Essential fatty acids and phospholipase A2 in autistic spectrum disorders

A health questionnaire based on parental observations of clinical signs of fatty acid deficiency (FAD) showed that patients with autism and Asperger's syndrome (ASP) had significantly higher FAD scores (6.34+/-4.37 and 7.64+/-6.20, respectively) compared to controls (1.78+/-1.68). Patients with regressive autism had significantly higher percentages of 18:0,18:2n-6 and total saturates in their RBC membranes compared to controls, while 24:0, 22:5n-6, 24:1 and the 20:4n-6/20:5n-3 ratio were significantly higher in both regressive autism and ASP groups compared to controls. By comparison, the 18:1n-9 and 20:4n-6 values were significantly lower in patients with regressive autism compared to controls while 22:5n-3, total n-3 and total dimethyl acetals were significantly lower in both regressive autism and ASP groups compared to controls. Storage of RBC at -20 degrees C for 6 weeks resulted in significant reductions in highly unsaturated fatty acid levels in polar lipids of patients with regressive autism, compared to patients with classical autism or ASP, or controls. Patients diagnosed with both autism and ASP showed significantly increased levels of EPA ( approximately 200%) and DHA ( approximately 40%), and significantly reduced levels of ARA ( approximately 20%), 20:3n-6 and ARA/EPA ratio in their RBC polar lipids, when supplemented with EPA-rich fish oils, compared to controls and non-supplemented patients with autism. Patients with both regressive autism and classical autism/Asperger's syndrome had significantly higher concentrations of RBC type IV phospholipase A2 compared to controls. However, patients with autism/ASP, who had taken EPA supplements, had significantly reduced PLA2 concentrations compared to unsupplemented patients with classical autism or ASP.     

Essential fatty acid deficiency and platelet fatty acids of normotensive and genetically hypertensive rats

Termination of pregnancy in missed abortion and intra-uterine fetal death was accomplished using vaginal suppositories of 20 mg PGE₂ in 31 cases and the results were compared with oxytocin induction (with or without estrogen pre-treatment) in 17 cases at the doses routinely used in our hospital. The PG suppositories proved much more superior (96.7%) than oxytocin (47.7%), but induced a higher rate of side effects. The latter were not serious and were generally tolerated by the patients. There was a positive correlation between duration of fetal retention in utero and the induction expulsion time. The over all patient acceptance of the method was quite favourable and the approach appears to be a definite advance towards management of these cases.     

Essential fatty acids and serine as plasmalogen precursors in relation to competing metabolic pathways.

Interest in altered ether-lipid metabolism, associated with peroxisomal disorders including adrenoleukodystrophy and Zellweger's syndrome, has highlighted present limitations in our understanding of the biosynthesis and turnover of plasmalogens. These 1-alkenyl ethanolamine phosphoglycerides are major phospholipids in brain, vascular tissue, neutrophils, and most tumors, and they constitute 15-20% of total phospholipids in cultured glioma cell. In glioma, turnover of polyunsaturated acyl chains in the sn-2 position of plasmalogens was examined in relation to selectivity for the (n - 3) and (n - 6) families. Remodeling of acyl chains was more dependent on chain length than on selectivity between families, consistent with plasmalogens enriched in polyunsaturated, but not specifically (n - 3), fatty acids. Extracellular serine was a precursor of serine and ethanolamine phosphoglycerides and was associated with plasmalogens due to decarboxylation and headgroup exchange. Incorporation of extracellular serine ceased within 8 h, even though more than 50% of the label remain in the medium. Analyses of medium and cellular water-soluble components indicated rapid conversion of serine to glycine and other metabolites not used in phospholipid biosynthesis. Thus, nutrient molecules as precursors of plasmalogens are involved in complex competitive interactions. As functions of plasmalogens are clarified, regulation of plasmalogen turnover becomes an increasingly important issue and elucidation of these processes is essential.     

Essential fatty acids and their role in the treatment of impulsivity disorders

Essential fatty acids (EFAs) have been shown to benefit patients with depression, schizophrenia and dementia. More recently, their role in disorders characterised by impulsivity has attracted some attention. The psychiatric conditions of attention-deficit hyperactivity disorder and borderline personality disorder as well as the phenomena of deliberate self-harm and violence have been ameliorated by the supplementation of EFAs in a number of recent clinical trials. This paper summarises the burgeoning clinical and basic research indicating the existence of significant deficits of EFAs in impulsivity disorders and the supplementation studies of EFAs in these diverse conditions, all of which remain a major therapeutic challenge.     

Essential fatty acids in tissue phospholipids and triglycerides of the zinc-deficient rat

This study addressed the possibility that zinc deficiency has different effects on the fatty acid composition of triglyceride compared to total phospholipid. Male weanling Sprague-Dawley rats were maintained for 6 weeks on a semisynthetic diet deficient in zinc (3 mg/kg zinc). Control rats (40 mg/kg zinc) were pair-fed. Lipid fractionation and fatty acid analysis were by thin-layer and gas chromatography, respectively. In zinc-deficient rats, the percentage of linoleic acid was increased or that of arachidonic acid was decreased in total phospholipids of plasma, liver, and testis, and in skin total lipids. Saturated and monounsaturated fatty acids were increased in the triglyceride of liver but decreased in the triglyceride of epididymal fat of zinc deficient rats. Essential fatty acids, as a proportion of total fatty acids, were decreased in triglyceride of liver but increased in triglyceride of epididymal fat of zinc-deficient rats. Our fatty acid data from tissue total phospholipids therefore support the concept that linoleic acid desaturation is impaired in zinc deficiency.