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Deficiencies of essential fatty acids, vitamin A and E and changes in plasma lipoproteins in patients with reduced fat absorption or intestinal failure.

OBJECTIVE: Deficiencies of essential fatty acids (EFA), vitamin A (retinol) and vitamin E (alpha- and gamma-tocopherol) were studied in non-HPN patients with different degrees of fat malabsorption (managing without home parenteral nutrition (HPN)), and in HPN-patients receiving HPN with and without parenteral lipids. DESIGN AND SUBJECTS: Phospholipid fatty acids (including EFA), cholesterol, retinol, alpha- and gamma-tocopherol in plasma and the intestinal absorption of fatty acids and energy (balance-studies) were measured in 40 non-HPN patients, 44 HPN patients and 35 controls. Subgroups were non-HPN patients with fat:total energy absorption ratios >25% (A), between 15 and 25% (B), and <15% (C), and HPN patients receiving (D) and not receiving parenteral lipids (E). RESULTS: Intestinal absorption of the EFA linoleic acid was 8.2, 4.4, 3.8, 0.5 and 0.5 g/day and corresponding plasma concentrations were 17.3%, 15.5%, 13.1%, 12.1% and 8.9% in groups A-E, respectively (P<0.001). Deficiencies in EFA, defined as a Holman index >0.2 (20:3n-9/20:4n-6 ratio), were confined to 42% of the patients in group E. Plasma cholesterol was decreased in groups B-E. Plasma retinol was reduced (below the lower 2.5% confidence interval of controls) in 7% of non-HPN patients and in 20% of HPN patients. Plasma alpha-tocopherol was reduced in 64% of patients from groups B-E. Plasma gamma-tocopherol was decreased in 33% of the patients, except in HPN-patients receiving parenteral lipids. CONCLUSIONS: Plasma linoleic acid may decrease considerably (from 26% to 8-10%) as fat absorption decreases before secondary signs of essential fatty acid deficiencies occur (an increase in 20:3n-9 and the Holman index). In this study this was confined to patients on lipid-free HPN. Vitamin A deficiencies were mainly seen in HPN patients. Vitamin E deficiencies were common in both HPN and non-HPN patients, but administration of parenteral lipids normalized plasma gamma-tocopherol. European Journal of Clinical Nutrition (2000) 54, 632-642.

Adult↗

Essential fatty acid deficiency and evidence for arachidonate synthesis in the cat.

1. There is controversy regarding the capacity of the cat to convert 18: 2 omega 6 to 20: 4 omega 6 and the ability of the essential fatty acid (EFA)-deficient cat to produce 20: 3 omega 9. 2. This paper reports the isolation and identification of 20: 3 omega 9 from kidney phospholipids of EFA-deficient cats. 3. The results suggest that the cat is capable of limited synthesis of 20: 4 omega 6 using a delta 5- and delta 8-desaturase.

Animals↗

Essential fatty acid deficiency after hepatic portoenterostomy for biliary atresia.

Gas chromatography was used to determine the fatty acid composition of total lipids extracted from plasma and erythrocytes of five patients who had received an hepatic portoenterostomy for treatment of extrahepatic biliary atresia. Three patients, including one with successful surgery, demonstrated evidence of essential fatty acid deficiency, including decreased levels of linoleic and arachidonic acids with concomitant increases in palmitoleic and oleic acids. In two of these patients, the ratio of 5,8 11-eicosatrienoic acid to arachidonic acid ("triene/tetraene") exceeded 0.3, diagnostic of essential fatty acid deficiency. Even patients with successful hepatic portoenterostomy are at risk to develop essential fatty acid deficiency.

Bile Ducts↗

Immunophenotyping of insulitis in control and essential fatty acid deficient mice treated with multiple low-dose streptozotocin.

Multiple injections of low-dose streptozotocin induce lymphocytic insulitis and autoimmune diabetes in male CD-1 mice. Prior to the onset of insulitis, macrophages infiltrate the islets (single cell insulitis) and presumably help initiate the lymphocytic response directed at streptozotocin-induced neoantigens on islet beta cells. Essential fatty acid deficiency ameliorates the lymphocytic insulitis and prevents diabetes in this model. We hypothesize that essential fatty acid deficiency, which perturbs eicosanoid pathways and blocks the production of inflammatory mediators such as leukotriene B4, might prevent or diminish the single cell insulitis and, thus, abrogate the lymphocytic response. The purpose of the study was to determine whether essential fatty acid deficiency causes any differences in the immunophenotype or the time course of single cell insulitis or insulitis after low-dose streptozotocin. Three to five essential fatty acid deficient and 3-5 control mice were treated with low-dose streptozotocin and killed on days 0, 3, 5, 8, 10, 12 and 15. Frozen sections of the pancreata were stained using an immunoperoxidase method with antibodies against mouse macrophages, CD4T-lymphocytes and CD8 T-lymphocytes. Sections were assessed for the presence and severity of single cell insulitis and insulitis. Based on cell counts in the most severely involved islet from each pancreas, there was no difference in the single cell insulitis in control and essential fatty acid deficient mice. Islets from control pancreata had a higher mean grade of lymphocytic insulitis. These findings suggest that autoimmune diabetes following low-dose streptozotocin in control mice is the result of both lymphocytic and histiocytic infiltrates with subsequent beta-cell destruction. Our results do not support the hypothesis that the protective effect of essential fatty acid deficiency is due to diminished influx of macrophages into the islets. It is, however, possible that essential fatty acid deficiency deleteriously affects macrophage function and, thus, blunts the lymphocytic response.

Animals↗

Essential fatty acid status during early human development.

Preliminary studies indicated that the EFA status of normal neonates is marginal, if not insufficient. Since a better knowledge of the physiology of maternal-fetal essential fatty acid transfer is relevant for nutritional recommendations during pregnancy, we investigated the course of the fetal EFA status during fetal development by analysing the absolute (micrograms/g dry fetal tissue) and relative (% of total fatty acids) fatty acid composition of phospholipids in human fetal tissue, (n = 40, gestational age 5-15.2 weeks). The total content of fatty acids (mg/g dry fetal tissue) increased with gestational age. The absolute amount of virtually all fatty acids increased with maturation. Linoleic acid (18:2n-6, LA), however, was an exception. A highly significant, negative correlation between gestational age and the relative amount of LA in fetal tissue was observed during this first trimester of pregnancy. Our results show that the fetal-maternal difference in linoleic acid content observed at birth, initiates early in pregnancy. Since the fetus completely depends on the mother for its EFA supply, the maternal EFA status was measured simultaneously by analysing the fatty acid composition of phospholipids, isolated from plasma and red blood cells. Significant positive correlations between maternal rbc and fetal tissue were found for the relative amounts of LA. Similar relationships were observed between maternal plasma and fetal tissue for the relative amounts of cervonic acid (22:6n-3), the most abundant essential fatty acid in brain and retina. The relation between maternal and fetal EFA in phospholipids is significantly more pronounced after 10 weeks of gestation than before. This might be connected with the increased importance of the placenta with respect to maternal-fetal fatty acid transfer after 10 weeks of gestation.

Embryonic and Fetal Development↗

The effect of essential fatty acids on epidermal atrophy due to topical steroids.

The effect of topical n-6 essential fatty acids in the form of evening primrose oil on the epidermal atrophy caused by a potent topical steroid was studied in 24 normal volunteers by measuring epidermal thickness and cross-sectional area and by histological examination. Epidermal thickness and cross-sectional area were significantly lower in normal forearm skin treated with 0.1% betamethasone valerate twice daily without occlusion for 3 weeks when compared with placebo-treated skin. The addition of evening primrose oil to the topical steroid did not prevent steroid-induced epidermal atrophy suggesting that steroid-induced epidermal atrophy is not mediated by the inhibition of essential fatty acid release from cell membranes.

Adult↗

The regulation of prostaglandin biosynthesis by the manipulation of essential fatty acid metabolism.

Two of the most widely used groups of drugs in medical practice are the non-steroidal anti-inflammatory agents and the steroids. Both act by modulating the conversion of essential fatty acids to prostaglandins, leukotrienes and related substances. The actions of these drugs are therefore likely to be modified by variations in the levels of substrates, notably arachidonic acid and dihomogammalinolenic acid, available for metabolism by lipoxygenase and cyclo-oxygenase enzymes. Yet most doctors who use the drugs and many scientists who carry out research on them seem unaware of the factors which determine the concentrations of the substrate essential fatty acids. This paper reviews in detail the metabolism of essential fatty acids and the interactions between nutrient intake and subsequent metabolism which determine the concentrations of the individual fatty acids. It is concluded that the efficacy of drug therapy as far as the steroids and the non-steroidal anti-inflammatory drugs are concerned could be substantially enhanced by greater knowledge of the factors which determine the availability of substrates to the key enzymes.

Animals↗

The effect of a low essential fatty acid diet on hibernation in marmots.

We investigated the effect of an essential fatty acid (EFA)-deficient diet on hibernation patterns in yellow-bellied marmots (Marmota flaviventris). Fatty acid (FA) analysis of white adipose tissue (WAT) from animals maintained for 2 mo on the EFA-deficient diet suggested that little or no EFAs were present in the gonadal or omental fat depots. Hibernation about lengths of the EFA-deficient animals were significantly shorter (P < 0.01) than control animals. Stated another way, these animals aroused twice as frequently compared with control animals and used more energy to survive winter. Analysis of WAT composition and blood samples revealed that animals were highly lipolytic during winter. Furthermore, the release of FAs was not random: linoleate (cis-9,cis-12-octadecadienoic acid; 18:2, a diene EFA) was significantly (P < 0.05) under-represented in venous outflow from the gonadal WAT pad based on the percentage of this species in WAT. The concentration of saturated FAs was higher than that predicted from the WAT-FA composition. We conclude that linoleate is preferentially retained within WAT and that concentrations of this EFA may influence hibernation behavior. Thus EFAs may have a thermoregulatory role in hibernation in addition to their role as essential precursors for physiologically important lipids after hibernation is over.

Adipose Tissue↗

[Are omega-3-fatty acids essential for newborn infants?].

omega-3 fatty acids have recently been placed into the center of interest because of their different effects on fatty acid metabolism as well as on blood coagulation. We do not know if omega-3 fatty acids are essential during childhood, because it was seen that they may have positive effects on the development of the brains of rats and are also present in breast milk. The following report presents the recent state of the scientific knowledge. In fish and grain oil one can find not only omega-6 fatty acids as e.g. arachidonic acid (AA: C 20: 4 omega-6), but also omega-3 fatty acids (e.g.: linolenic acid: C 18:3 omega-3). They are always in a specific ratio to the other: If there are higher concentrations of omega-3 fatty acids, one can find less amounts of omega-6 fatty acids, and vice versa. The most important representatives of the omega-3 fatty acids are metabolites of linolenic acid, such as docosahexaenoic acid: C 22: 6 omega-3 (DHA) and eicosapentaenoic acid: C 20: 5 omega-3 (EPA). The beneficial influence, especially of DHA, on the postnatal development of the retina and brain has been demonstrated in rats and rhesus monkeys. It could be shown that the fatty acid composition of phospholipids of red blood cells conforms to that of the CNS. Nearly the same values could be achieved in infants with both, a diet enriched with fish oil and a feeding with breast milk; this seems to be essential especially for preterm infants, who always have a DHA-deficiency.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

The effect of essential fatty acid deficiency on the adrenergic activation of glycogenolysis in rat hepatocytes.

The fatty acid composition of total lipids and the adrenoceptor-mediated activation of glycogenolysis were studied in isolated hepatocytes from rats maintained on a control diet or on an essential fatty acid (EFA)-free diet. In cells from rats on the EFA-free diet there was a marked reduction in linoleic and arachidonic acid (AA) contents and an increase in eicosatrienoic, oleic, and palmitoleic acid contents compared to controls. In freshly isolated cells from both groups, phosphorylase a activity was increased by phenylephrine or epinephrine but not by isoproterenol, and the effect of epinephrine was inhibited by phenoxybenzamine but not by propranolol. When control cells were preincubated in a serum-free buffer for 4 h before testing, the effect of phenylephrine on phosphorylase a activity was reduced, isoproterenol became a potent agonist and the effect of epinephrine was partially inhibited either by phenoxybenzamine or by propranolol. The emerging beta-adrenergic response in 4-h cells was associated with a marked potentiation of isoproterenol-induced cAMP accumulation. A similar 4-h preincubation of EFA-deficient cells resulted in a reduced response to phenylephrine while isoproterenol remained ineffective for increasing either phosphorylase a activity or cAMP production. The response of these 4-h cells to isoproterenol could be restored by in vivo replacement of the EFA-deficient diet with control diet for the last 4 weeks prior to the experiment, but not by the in vitro exposure of the EFA-deficient cells to 10 microM AA throughout the 4-h incubation period. Extending previous observations (Refs. (6-8)), the present results suggest that the time-dependent emergence of beta-adrenergic glycogenolysis, but not the parallel reduction of the alpha-adrenergic response, is mediated by AA or its metabolite(s), which probably act by facilitating the G-protein-dependent coupling of beta-receptors.

Animals↗

Essential fatty acid requirements of vegetarians in pregnancy, lactation, and infancy.

Long-chain polyunsaturated fatty acids (LCPUFAs) derived from linoleic (18:2n-6) and alpha-linolenic (18:3n-3) acids are required for the normal development of the retina and central nervous system, but the extent to which they can be synthesized from the parent fatty acids is debated. Consuming LCPUFAs markedly increases their proportions in tissue lipids compared with their parent fatty acids. Thus, it has been argued that LCPUFAs must be supplied in the diet. LCPUFAs are generally absent from plant foods, thus it is important find out how essential fatty acid requirements are met by vegetarians. A developing fetus obtains LCPUFAs via selective uptake from its mother's plasma and LCPUFAs are present in the breast milk of vegetarians. There is no evidence that the capacity to synthesize LCPUFAs is limited in vegetarians. However, there are greater proportions of n-6 LCPUFAs and lower proportions of n-3 LCPUFAs in vegetarians compared with omnivores. This difference is probably a consequence of the selection of foods by vegetarians with high amounts of linoleic acid. Although lower concentrations of docosahexaenoic acid (22:6n-3; DHA) have been observed in blood and artery phospholipids of infants of vegetarians, it is uncertain whether their brain lipids contain lower proportions of DHA than do those of infants of omnivores. On the basis of experiments in primates that showed altered visual function with a high ratio of linoleic acid to alpha-linolenic acid, it would be prudent to recommend diets with a ratio between 4:1 and 10:1 in vegetarians and that excessive intakes of linoleic acid be avoided.

Central Nervous System↗

[Effect of pregnancy and lactation on the nutritional status of essential fatty acids in rat].

BACKGROUND: Pregnancy and lactation could be high risk situations for the development of essential fatty acid deficiencies. AIM: To study the effect of pregnancy and lactation on red blood cell phospholipids percentual fatty acid composition of virgin, pregnant and lactating rats. MATERIALS AND METHODS: Twenty four pregnant rats of 50 +/- 1 days of age were supplement with soy and 24 with fish oil during 21 days. Twelve rats of each group were sacrificed after 18 days of lactation, twenty four non pregnant rats received soy oil and acted as controls of pregnant and lactating rats. Red blood cell phospholipid fatty acid composition was analyzed by gas chromatography. RESULTS: The percentage of total omega-6 fatty acids of red blood cell phospholipid was 37.8 +/- 5.9, 32.6 +/- 0.6 and 38.3 +/- 3.5% in non pregnant, pregnant and lactating rats respectively (p < 0.001). The figures for total omega-3 fatty acids were 6.33 +/- 1.52, 4.31 +/- 0.39 and 2.7 +/- 0.46 respectively (p < 0.001). There was no change in eicosatrienoic fatty acid percentage. Supplementation with fish oil reverted the decrease in omega-6 and omega-3 fatty acid percentage of pregnant and lactating rats. CONCLUSIONS: Pregnancy and lactation decrease the capacity to transform precursors of essential fatty acids in long chain polyunsaturated fatty acids.

Animals↗

Essential fatty acid deficiency in four adult patients during total parenteral nutrition.

Four undernourished adults (15%-37% below idealll body weight) received fat-free total parenteral nutrition for a period of 6 to 8 weeks. Chemical evidence of essential fatty acid deficiency (triene:tetraene ratio greater than 0.4) appeared in all patients during the first 3 weeks of treatment. Deficiency developed more rapidly in the two patients who were younger (ages 16 and 36) and more severely undernourished (26% and 37% below ideal body weight) than in the two older patients (62 and 76) who were less undernourished (15% and 16% below idea body weight). All patients continued to gain weight and maintain positive nitrogen balance throughout the course of total parenteral nutrition and developing essential fatty acid deficiency. Hepatomegaly and increased serum liver enzyme activities occurred in the two patients with evidence of the most severe essential fatty acid deficiency. Liver biopsy, in the cases with hepatomegaly, showed hepatocytes containing fat and what appeared to be enlarged, spherical mitochondria. There was no cellular infiltrate or significant degree of necrosis. Supplementation with oral linoleic acid (as safflower oil) reversed the essential fatty acid deficiency and the elevation of serum liver enzymes.

Adolescent↗

The effect of hyperoxia on the lungs of rats deficient in essential fatty acids.

Morphological alterations in the lungs of rats deficient in either or both of vitamin E and essential fatty acids were investigated after exposure to hyperoxia for 48 h. In rats deficient in both vitamin E and essential fatty acids, there was damage to type-2 alveolar cells observed as swollen mitochondria and bleb formation in the cytoplasm. None of these changes was found in rats deficient in only one of these substances. Hyperoxia in rats deficient in both substance also caused destruction of the capillary endothelial cells and edema in the interstitium. The lungs of rats deficient in only one of the substances showed some edema in the capillary endothelial cells, but not destruction, and less interstitial edema. These findings suggest that simultaneous deficiency in vitamin E and essential fatty acids facilitates lung damage in rats exposed to hyperoxia.

Journal Article↗

The association of lipid abnormalities with tissue pathology in human osteoarthritic articular cartilage.

Articular cartilage is one of very few body tissues uniquely characterized as having substantial stores of lipid deposits. Lipid droplets are naturally accumulated by chondrocytes and individual fatty acids have been shown to have protective as well as deleterious effects on cartilage degradation in animal models of degenerative joint disease. As a means to better assess the role of lipids in human joint pathology, a comparative analysis of fatty acids was undertaken in small segments of osteoarthritic articular cartilage. The data were assessed in terms of chondrocyte synthetic activity and histological determination of disease severity. The distribution profile of individual fatty acids in normal and osteoarthritic specimens remained constant, with palmitic, oleic, and linoleic acids representing 85% of the total fatty acids. In contrast, levels of total fatty acids were markedly increased in association with increasing degree of lesion severity. Compared with tissue from normal-aged joints, grade 0 to 1 mild lesions had elevated levels of total fatty acids, essential fatty acids, and chondrocyte synthetic activity of 80%, 312%, and 393%, respectively. More severe tissue involvement (grade 6 to 9), was associated with even greater increases of 440%, 1,100%, and 1,150%, respectively. No change was noted in cholesterol content in any tissue. The accumulation of arachidonic acid was greater than the proportional increase in total fatty acid content and was primarily distributed into the neutral lipid fraction, where it constituted almost 62% of the fatty acid level in tissues of moderate lesion severity. There was an association of lipid accumulation in general and arachidonic acid in particular with histological severity.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗

Studies on the accumulation of serum proteins in zymosan-induced inflammation in mouse peritoneum.

Inflammatory responses were induced in mice by intraperitoneal (i.p.) injection of zymosan. This resulted in a rapid accumulation of protein in the peritoneum that was dependent on the time of the injection and concentration of zymosan used. Though other stimuli, e.g., phorbol myristate acetate, lipopolysaccharide, carrageenan and latex beads, caused the accumulation of proteins, the maximum response was obtained only with zymosan. Injection of free fatty acids were unable to induce protein accumulation in peritoneum. Factors which decreased leukotriene production in mouse peritoneum, i.e., dietary n-3 fatty acids essential fatty acid deficient diets, did not affect protein accumulation. Direct injection of leukotrienes also failed to induce protein accumulation. Analyses revealed that the proteins were similar to serum proteins, indicating that zymosan causes the leakage of serum proteins into peritoneum.

Animals↗

Can tumour cell drug resistance be reversed by essential fatty acids and their metabolites?

Tumour cell drug resistance is a major problem in cancer chemotherapy. Essential fatty acids have been shown to be cytotoxic to a variety of tumour cells in vitro. But, the effect of these fatty acids on tumour cell drug resistance has not been well characterized. Gamma-linolenic acid (GLA) of the n-6 series and eicosapentaenoic acid (EPA) of the n-3 series potentiated the cytotoxicity of anti-cancer drugs: vincristine, cis-platinum and doxorubicin on human cervical carcinoma (HeLa) cells in vitro. Alpha-linolenic acid (ALA), GLA, EPA and docosahexaenoic acid (DHA) enhanced the uptake of vincristine by HeLa cells. In addition, DHA, EPA, GLA and DGLA were found to be cytotoxic to both vincristine-sensitive (KB-3-1) and -resistant (KB-ChR-8-5) human cervical carcinoma cells in vitro. Pre-incubation of vincristine-resistant cells with sub-optimal doses of fatty acids enhanced the cytotoxic action of vincristine. GLA, DGLA, AA, EPA and DHA enhanced the uptake and inhibited the efflux of vincristine and thus, augmented the intracellular concentration of the anti-cancer drug(s). Fatty acid analysis of KB-3-1 and KB-ChR-8-5 cells showed that the latter contained low amounts of ALA, GLA, 22:5 n-3 and DHA in comparison to the vincristine-sensitive cells. The concentrations of GLA and DHA were increased 10-15 fold in the phospholipid, free fatty acid and ether lipid cellular lipid pools of GLA and DHA treated cells. These results coupled with the observation that various fatty acids can alter the activity of cell membrane bound enzymes such as sodium-potassium-ATPase and 5'-nucleotidase, levels of various anti-oxidants, p53 expression and the concentrations of protein kinase C suggest that essential fatty acids and their metabolites can reverse tumour cell drug-resistance at least in vitro.

5'-Nucleotidase↗