Long-chain Metabolites Research Articles

Long-chain polyunsaturated fatty acids in a diabetic teenager during and after nine repeated episodes of diabetic ketoacidosis

Type 1 diabetes is often accompanied with acute hypoinsulinemia that may theoretically inhibit the conversion of essential fatty acids to their longer-chain metabolites. Previously, we found significant reduction in plasma arachidonic (C20:4n-6) and docosahexaenoic (C22:6n-3) acid values in a group of diabetic children during diabetic ketoacidosis. Here we report data on the changes of fatty acids in plasma phospholipids in a diabetic teenager during and after nine subsequent episodes of diabetic ketoacidosis (DKA). Plasma phospholipid linoleic acid (C18:2n-6) values significantly decreased [23.05 (1.05) versus 19.22 (3.22), % w/w, median (IQR), p < 0.01], while values of dihomo-gamma-linolenic acid (C20:3n-6) and docosatetraenoic acid (C22:4n-6) significantly increased [1.72 (0.44) versus 1.80 (0.63) and 0.40 (0.01) versus 0.45 (0.07), respectively, p < 0.05]. Values of alpha-linolenic acid (C18:3n-3) did not change, while values of docosahexaenoic acid were significantly higher after than during the ketoacidosis [1.57 (0.67) versus 1.87 (0.32), p < 0.05). These data obtained in the same patient during repeated episodes of diabetic ketoacidosis support the concept that hypoinsulinemia plays an important role in disturbances of essential fatty acid metabolism in diabetes.

Update on alpha-linolenic acid

Consumption of omega 3 fatty acids is known to have health benefits. For many years, the importance of the only member of the omega 3 family considered to be essential, alpha-linolenic acid (ALA), has been overlooked. Current research indicates that ALA, along with its longer chain metabolites, may play an important role in many physiological functions. Potential benefits of ALA include cardioprotective effects, modulation of the inflammatory response, and a positive impact on both central nervous system function and behavior. Recommended levels for ALA intake have been set, yet the possible advantages of its consumption are just being revealed.

Essential fatty acids and their metabolites could function as endogenous HMG-CoA reductase and ACE enzyme inhibitors, anti-arrhythmic, anti-hypertensive, anti-atherosclerotic, anti-inflammatory, cytoprotective, and cardioprotective molecules.

Lowering plasma low density lipoprotein-cholesterol (LDL-C), blood pressure, homocysteine, and preventing platelet aggregation using a combination of a statin, three blood pressure lowering drugs such as a thiazide, a β blocker, and an angiotensin converting enzyme (ACE) inhibitor each at half standard dose; folic acid; and aspirin-called as polypill- was estimated to reduce cardiovascular events by ~80%. Essential fatty acids (EFAs) and their long-chain metabolites: γ-linolenic acid (GLA), dihomo-GLA (DGLA), arachidonic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) and other products such as prostaglandins E1 (PGE1), prostacyclin (PGI2), PGI3, lipoxins (LXs), resolvins, protectins including neuroprotectin D1 (NPD1) prevent platelet aggregation, lower blood pressure, have anti-arrhythmic action, reduce LDL-C, ameliorate the adverse actions of homocysteine, show anti-inflammatory actions, activate telomerase, and have cytoprotective properties. Thus, EFAs and their metabolites show all the classic actions expected of the "polypill". Unlike the proposed "polypill", EFAs are endogenous molecules present in almost all tissues, have no significant or few side effects, can be taken orally for long periods of time even by pregnant women, lactating mothers, and infants, children, and adults; and have been known to reduce the incidence cardiovascular diseases including stroke. In addition, various EFAs and their long-chain metabolites not only enhance nitric oxide generation but also react with nitric oxide to yield their respective nitroalkene derivatives that produce vascular relaxation, inhibit neutrophil degranulation and superoxide formation, inhibit platelet activation, and possess PPAR-γ ligand activity and release NO, thus prevent platelet aggregation, thrombus formation, atherosclerosis, and cardiovascular diseases. Based on these evidences, I propose that a rational combination of ω-3 and ω-6 fatty acids and the co-factors that are necessary for their appropriate action/metabolism is as beneficial as that of the combined use of a statin, thiazide, a β blocker, and an angiotensin converting enzyme (ACE) inhibitor, folic acid, and aspirin. Furthermore, appropriate combination of ω-3 and ω-6 fatty acids may even show additional benefits in the form of protection from depression, schizophrenia, Alzheimer's disease, and enhances cognitive function; and serve as endogenous anti-inflammatory molecules; and could be administered from childhood for life long.

Do polyunsaturated fatty acids behave like an endogenous “polypill”?

Lowering plasma low density lipoprotein-cholesterol (LDL-C), blood pressure, homocysteine, and preventing platelet aggregation using a combination of a statin, three blood pressure lowering drugs such as a thiazide, a beta blocker, and an angiotensin converting enzyme (ACE) inhibitor each at half standard dose; folic acid; and aspirin - called as polypill - was estimated to reduce cardiovascular events by approximately 80%. Essential fatty acids (EFAs) and their long-chain metabolites and other products prevent platelet aggregation, lower blood pressure, reduce LDL-C, and ameliorate the adverse actions of homocysteine. Thus, EFAs and their metabolites show all the actions expected of the "polypill". Unlike the proposed "polypill", EFAs are endogenous molecules, have no significant side effects, can be taken orally for long periods of time even by pregnant women, lactating mothers, and children; and have been shown to reduce the incidence cardiovascular diseases. I propose that a rational combination of omega-3 and omega-6 fatty acids is as beneficial as that of the "polypill"; and may even show additional benefit in the prevention of depression, schizophrenia, Alzheimer's disease, and enhance cognitive function.

Competition between 24:5n-3 and ALA for Δ6 desaturase may limit the accumulation of DHA in HepG2 cell membranes

The use of Delta 6 desaturase (D6D) twice in the conversion of alpha-linolenic acid (ALA; 18:3n-3) to docosahexaenoic acid (DHA; 22:6n-3) suggests that this enzyme may play a key regulatory role in the synthesis and accumulation of DHA from ALA. We examined this using an in vitro model of fatty acid metabolism to measure the accumulation of the long-chain metabolites of ALA in HepG2 cell phospholipids. The accumulation of ALA, eicosapentaenoic acid (20:5n-3), docosapentaenoic acid (22:5n-3), and 24:5n-3 in cell phospholipids was linearly related to the concentration of supplemented ALA over the range tested (1.8-72 microM). The accumulation of the post-D6D products of 22:5n-3, 24:6n-3 and DHA, in cell phospholipids was saturated at concentrations of >18 microM ALA. Supplementation of HepG2 cells with preformed DHA revealed that, although the accumulation of DHA in cell phospholipids approached saturation, the level of DHA in cell phospholipids was significantly greater compared with the accumulation of DHA from ALA, indicating that the accumulation of DHA from ALA was not limited by incorporation. The parallel pattern of accumulation of 24:6n-3 and DHA in response to increasing concentrations of ALA suggests that the competition between 24:5n-3 and ALA for D6D may contribute to the limited accumulation of DHA in cell membranes.

Identification and quantitation of novel vitamin E metabolites, sulfated long-chain carboxychromanols, in human A549 cells and in rats

The metabolism of vitamin E involves oxidation of the phytyl chain to generate the terminal metabolite 7,8-dimethyl-2-(beta-carboxyethyl)-6-hydroxychroman (CEHC) via intermediate formation of 13'-hydroxychromanol and long-chain carboxychromanols. Conjugated (including sulfated) metabolites were reported previously but were limited to CEHCs. Here, using electrospray and inductively coupled plasma mass spectrometry, we discovered that gamma-tocopherol (gamma-T) and delta-T were metabolized to sulfated 9'-, 11'-, and 13'-carboxychromanol (9'S, 11'S, and 13'S) in human A549 cells. To further study the metabolites, we developed a HPLC assay with fluorescence detection that simultaneously analyzes sulfated and nonconjugated intermediate metabolites. Using this assay, we found that sulfated metabolites were converted to nonconjugated carboxychromanols by sulfatase digestion. In cultured cells, approximately 45% long-chain carboxychromanols from gamma-T but only 10% from delta-T were sulfated. Upon supplementation with gamma-T, rats had increased tissue levels of 9'S, 11'S, and 13'S, 13'-hydroxychromanol, 13'-carboxychromanol, and gamma-CEHC. The plasma concentrations of combined sulfated long-chain metabolites were comparable to or exceeded those of CEHCs and increased proportionally with the supplement dosages of gamma-T. Our study identifies sulfated long-chain carboxychromanols as novel vitamin E metabolites and provides evidence that sulfation may occur parallel with beta-oxidation. In addition, the HPLC fluorescence assay is a useful tool for the investigation of vitamin E metabolism.

Low contribution of n-3 polyunsaturated fatty acids to plasma and erythrocyte membrane lipids in diabetic young adults

Hypoinsulinemia characteristic to type 1 diabetes may theoretically inhibit the conversion of essential fatty acids to their longer-chain metabolites. Fatty acids were determined in plasma and erythrocyte membrane lipids in young diabetic adults ( n=34) and in age-matched healthy controls ( n=36). Values of linoleic acid (56.01 [5.02] versus 51.05 [7.32], % by wt, median [range from the first to the third quartile], P<0.00l) and arachidonic acid (AA) (11.17 [2.98] versus 9.69 [1.95] P<0.001) were significantly higher in diabetic subjects than in controls. However, α-linolenic acid values did not differ, and docosahexaenoic acid (0.43 [0.12] versus 0.57 [0.29], P<0.01) values were significantly lower in diabetic than in control subjects. Significant inverse correlations were found between AA and hemoglobin A 1c values in the phospholipid ( r=−0.40, P<0.05) and sterol ester ( r=−0.40, P<0.05) fractions. The data obtained in the present study suggest that the availability of n-3 long-chain polyunsaturated fatty acid may be reduced in young diabetic adults.

Maternal and fetal fatty acid composition in ovine muscle tissues

In species characterized by a cotyledonary placenta, as sheep, the relative contribution of maternally derived and placenta synthesized fatty acids is not fully understood. For this reason, the FA composition of mother muscle and the deposition of FA in the fetal muscle were studied by gas-chromatography. Five pregnant Sarda ewes were slaughtered at approximately 145 days of pregnancy. Semitendinosus, semimembranosus and femoral biceps muscles were immediately removed from ewes and fetuses. Data were analyzed by a paired t-test, to detect differences in FA composition between fetus and mother tissues. Results showed that FA profile of fat muscle differed markedly between fetus and mother. The intramuscular fat content were 6.38% and 11.79% on DM basis in fetus and mother muscle, respectively. Linoleic (LA; 18:2n-6), and linolenic (ALA; 18:3n-3) acid were found at smaller concentrations in fetus (0.77 and 0.01 mg/100 mg total FA for LA and ALA, respectively) than in maternal muscle (5.55 and 1.04 for LA and ALA, respectively). On the contrary, a higher proportion of their long-chain polyunsaturated metabolites, like arachidonic (AA; 20:4n-6) and docoexadienoic (DHA; 22:6n-3) acid in fetus compared to mother tissue (AA, 2.32 vs 1.30; DHA, 0.83 vs 0.09 mg/100 mg total FA) indicates a preferential fetal accumulation of those FA which are important for fetuses growth and central nervous system development. The c9,t11 Conjugated linoleic acid (CLA) isomer concentration in mother tissue was 0.72 mg/100 mg FA. It was found also in fetus muscle (0.11 mg/100 mg total FA) suggesting a transplacental fatty acid passage to fetal tissues or a desaturation activity on vaccenic acid (VA; 18:1 t11) in the placental or in the fetal tissue. Surprisingly, the c9,t11-CLA was not the most abundant CLA isomer found in fetus fat. Others CLA isomers, separated but not identified, were found in concentration of 0.17, 0.15 and 0.53 mg/100 mg of FA. Concentrations of these CLA isomers were lower in mother tissue (0.12, 0.05 and 0.10 mg/100 mg of FA). The concentration of VA was 0.46 and 0.90 in fetus and mother muscle, respectively. Correlation analysis between FA profile of mothers and fetuses evidenced a close relationship only for odd-numbered long-chain fatty (r = -0.72 for C15:0 and r = -0.88 for C17:0). The results suggested a different FA metabolism in the muscle tissue of mother and fetus in dairy sheep.

Essential Fatty Acids - A Review

Essential fatty acids (EFAs): cis-linoleic acid (LA) and alpha-linolenic acid (ALA) are essential for humans and their deficiency is rare in humans due to their easy availability in diet. EFAs are metabolized to their respective long-chain metabolites: 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 form precursors to respective prostaglandins (PGs), thromboxanes (TXs), and leukotrienes (LTs), lipoxins (LXs) and resolvins. EFAs and their metabolites may function as endogenous angiotensin converting enzyme and HMG-CoA reductase inhibitors, nitric oxide enhancers, anti-hypertensives, and anti-atherosclerotic molecules. EFAs react with nitric oxide (NO) to yield respective nitroalkene derivatives that have cell-signaling actions via ligation and activation of peroxisome proliferator-activated receptors (PPARs). In several diseases such as obesity, hypertension, diabetes mellitus, coronary heart disease, alcoholism, schizophrenia, Alzheimer's disease, atherosclerosis, and cancer the metabolism of EFAs is altered. Thus, EFAs and their derivatives have significant clinical implications.

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.

Metabolic modulation of myocardial ischemia

The metabolic pathways of the heart during normoxia and ischemia have been well studied. High plasma fatty acid concentrations and the myocardial accumulation of long-chain fatty acyl metabolites during ischemia correlate with increased morbidity and mortality. However, enhanced glucose use can maintain cell homeostasis, diminish ischemic injury, and be clinically beneficial. Metabolic modulators represent a new class of drugs with the potential to treat myocardial ischemia. They are ideal as adjunctive anti-ischemic therapy because they lack the hemodynamic consequences of traditional therapy and treat the underlying metabolic dysfunction that leads to contractile failure and arrhythmias. Clinical studies have demonstrated their efficacy in acute and chronic settings. It is anticipated that there will be greater utilization of this new class of agents in the near future.

160 Fatty Acid Composition of Human Milk in a Portuguese Urban Population:Prospective Study from 7 Days to 16 Weeks of Lactation

Fat in human milk varies during a feed, during the day and throughout the period of lactation. Fatty acid (FA) composition varies over the course of the day and during lactation. Aim: To evaluate FA composition in human milk, from 7 days (transitional milk) to 16 weeks of lactation (mature milk) and to assess the composition stability of these FA throughout this period. Methods: Mothers living in urban area of Porto who accepted to participate in the study were selected according to inclusion criteria (healthy term newborn exclusively breast-feeding). Pooled human milk was collected from all feedings over 24 hours at the following times: 7 days and 4, 8, 12 and 16 weeks of lactation. FA were analysed through capillary gas chromatography. Comparisons were made (Oneway ANOVA). Correlations between FA were made through Pearson and Spearman correlation coefficient. Results: 31 mothers completed the follow-up period. Total saturated fatty acids (SFA) progressively increased from 40.50 ± 3.72 (% wt/wt) at 7th day up to 43.08 ± 4.61 at the 16th week of lactation, whereas total monounsaturated fatty acid decreased from 33.04 ± 2.58 (% wt/wt) to 31.48 ± 3.32, in the same period. Arachidonic acid (AA) markedly decreases with the stage of lactation. Docosahexaenoic acid (DHA) content decreases lightly from the 7th day to the 4th week of lactation, remaining stable throughout the rest of the lactation period. No significant correlation was found between the levels of linonleic and a-linolenic acid, and their long-chain metabolites AA and DHA. Conclusions: Despite fluctuations in the contents of AA and DHA, the ratio AA/DHA did not significantly change throughout the period of lactation. The ratio AA/DHA remained constant during the study, suggesting a protective mechanism, as AA and DHA are essential structural components of all tissues and particularly of retina and neuronal tissues.

Polyunsaturated fatty acids in plasma lipids of diabetic children during and after diabetic ketoacidosis

Previously we reported significantly higher plasma values of the essential fatty acids but significantly lower values of their longer-chain metabolites in diabetic children than in healthy controls. Here, we report data on the acute effect of diabetic ketoacidosis (DKA) on the fatty acid composition of plasma lipids. Diabetic children (n=9; age: 16.1 [3.3] y; duration of diabetes: 5.0 [5.3.] y; daily insulin dose: 0.87 [0.66] unit/kg body weight/d; glycated haemoglobin: 13.4 [2.8] %; median [IQR]) were investigated at admission for DKA (during DKA) and at the end of the treatment of DKA (after DKA). Fatty acid composition of plasma lipid classes was determined by high-resolution capillary gas-liquid chromatography. Blood glucose (27.0 [8.5] vs 6.5 [1.6] mmol/l), pH (7.28 [0.35] vs 7.36 [0.06]) and base excess (-8.9 [15.1] vs -2.2 [6.3] mmol/l) were grossly abnormal during but not after DKA. Values of linoleic acid were significantly lower after than during DKA (non-esterifed fatty acids (NEFA): 15.55 [1.47] vs 12.27 [5.74] % wt/wt; triacylglycerols (TG): 20.84 [9.23] vs 17.40 [5.78]; p<0.05). In contrast, values of gamma-linolenic acid (NEFA: 0.87 [0.54] vs 2.34 [1.85]; p<0.05) and arachidonic acid (TG: 1.37 [0.71] vs 1.74 [0.57]; p<0.05) were significantly lower during than after DKA. The product/substrate ratios for delta-6 desaturation were significantly lower during than after DKA. Successful treatment of diabetic ketoacidosis is associated with a significant increase of long-chain polyunsaturated fatty acid values in blood plasma in diabetic children. This observation suggests that disturbances of essential fatty acid metabolism in diabetic children are related not only to diet but to hypoinsulinaemia as well.

Changes of Fatty Acid Composition of Human Milk during the First Month of Lactation: A Day-to-Day Approach in the First Week

Background: Fatty acid composition of human milk (HM) is known to change considerably during lactation. However, we were unable to find data on changes of fatty acid composition of HM during the very early phase of lactation, i.e. in the first week of life. Subjects and Methods: HM samples were obtained from 18 healthy lactating women every day during the first week and thereafter on the 14th and 28th days of lactation. Fatty acid composition of colostrum and mature HM samples was determined by high-resolution capillary gas-liquid chromatography. Results: Values of the n-6 essential fatty acid, linoleic acid, in HM did not change significantly during the first month of lactation, whereas values of the n-3 essential fatty acid, α-linolenic acid, showed significant increases during the first 2 weeks of lactation (1st day: 0.49 [0.12], % weight/weight, median [ranges from the 1st to the 3rd quartile], 14th day: 0.69 [0.31], p < 0.05). In contrast, values of the n-6 long-chain metabolites, eicosadienoic-, dihomo-γ-linolenic- and arachidonic acid, as well as the values of the n-3 long-chain metabolites, eicosatrienoic-, and eicosapentaenoic acid exhibited significant decreases during the entire period investigated. The principal n-3 long-chain metabolite, docosahexaenoic acid, showed a significant increase between the 3rd and 14th days, but a significant decrease between the 14th and 28th days (3rd day: 0.15 [0.13], 14th day: 0.28 [0.11], p < 0.05, 28th day: 0.19 [0.12], p < 0.01). There were statistically significant positive correlations between arachidonic and docosahexaenoic acid values on the 1st (r = 0.67, p < 0.01), 5th (r = 0.56, p < 0.05) and the 6th (r = 0.53, p < 0.05) days of lactation. Conclusion: Fatty acid composition of HM changes significantly even during the first week of lactation. The lack of positive correlation between essential fatty acids and their long-chain metabolites suggests that it is not only the availability of essential fatty acids that influences the fatty acid composition of human colostrum.

Depression and adipose polyunsaturated fatty acids in the survivors of the seven countries study population of Crete

The purpose of the present study was to investigate the relation between adipose tissue polyunsaturated fatty acids, an index of long-term or habitual fatty acid dietary intake and depression. The sample consisted of 150 elderly males from the island of Crete. The subjects were survivors of the Greek Seven Countries Study group. The mean age was 84 years. The number of subjects with complete data on all variables studied was 63. Subjects were examined by the Preventive Medicine and Nutrition Clinic of the University of Crete. Depression was assessed through the use of the short form of the Geriatric Depression Scale (GDS-15). Depression correlated negatively with adipose tissue alpha-linolenic acid (C18:3n-3). Depressed subjects had significantly reduced (−10.5%) adipose tissue C18:3n-3 levels than non-depressed subjects. The observed negative relation between adipose tissue C18:3n-3 and depression, in the present study, appears to indicate increasing long-term dietary C18:3n-3 intakes with decreasing depression. This agrees with findings of other studies indicating an inverse relation between depression and consumption of fish and n-3 polyunsaturated fatty acids. This is the first literature report of a relation between adipose tissue C18:3n-3 and depression. Furthermore, this is the first report of a relation between adipose PUFA and depression in an elderly sample. Depression has been reported to be associated with elevated cytokines, such as, IL-1, IL-2, IL-6, INF- γ and INF- α. Fish oil and omega-3 fatty acids, on the other hand, have been reported to inhibit cytokine production. The observed negative relation between adipose C18:3n-3 and depression, therefore, may stem from the inhibiting effect of C18:3n-3 or its long-chain metabolites on cytokine synthesis.

Is Docosahexaenoic Acid (DHA) Essential? Lessons from DHA Status Regulation, Our Ancient Diet, Epidemiology and Randomized Controlled Trials

The human diet has changed considerably during the last 100 y. One of the striking changes is the tremendous increase in dietary fat. In terms of quality we have increased our intakes of saturated fatty acids (SFA), 2 linoleic acid (LA) and transfatty acids, concomitant with reduced intakes of (n-3) fatty acids. The latter comprises reduced intake of -linolenic acid (ALA) rich foods, and less consumption of long-chain PUFA of the (n-3) series [LC(n-3)P], i.e., eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids notably from fish (1). These dietary and other environmental changes are considered to be among the major causes of the rapid expansion of diet-related chronic disease (2), including cardiovascular disease (CVD) in the past century. Our genetic constitution is unlikely to have kept pace with the changing diet. Today’s nutritional habits are consequently not the same as those on which our genes are based (2). The return to basics may be indicated, but we unfortunately have no reliable knowledge of the ancient diet on which our genes evolved. In this literature study we seek to find whether LC(n-3)P, and notably DHA, are essential. Essential fatty acid (EFA) metabolism and function. The parent essential fatty acids (EFA), LA and ALA cannot be synthesized in the human body and are therefore indispensable components of our diet. Both LA and ALA may be converted by chain elongation, desaturation and chain-shortening into their respective long-chain metabolites, collectively named LCP (20 carbon atoms and 3 double bonds). The most important LCP of the (n-6) fatty acid series is arachidonic acid (AA), whereas EPA and DHA are the major LC(n-3)P. LCP may also be derived from the diet. High contents are present in meat (AA) and fish (EPA, DHA). AA and DHA are especially abundant in the brain and the retina. Both LCP and their parent precursors may serve for energy generation, but LCP are relatively protected from -oxidation compared with their parents. AA and DHA are important building blocks of structural lipids. LCP in phospholipids contribute to membrane properties like fluidity, flexibility, permeability and modulation of membrane-bound. DHA in retina and postsynaptic membranes is crucial for adequate functioning of embedded proteins, i.e., rhodopsin for vision and postsynaptic receptors for neurotransmission. AA, EPA and dihomo--linolenic acid (DGLA), liberated from membrane phospholipids, are precursors of short-lived highly potent regulatory hormones collectively named eicosanoids. These play important roles in inflammatory reactions, blood pressure control and platelet aggregation. Eicosanoids from AA are involved in vasoconstriction/platelet aggregation (TxA 2 ), inhibition of vasodilatation/platelet aggregation (prostaglandin I2), inflammation, and leukocyte che

Effects of odd-numbered medium-chain fatty acids on the accumulation of long-chain 3-hydroxy-fatty acids in long-chain L-3-hydroxyacyl CoA dehydrogenase and mitochondrial trifunctional protein deficient skin fibroblasts

The treatment for patients with genetic disorders of mitochondrial long-chain fatty acid β-oxidation is directed toward providing sufficient sources of energy for normal growth and development, and at the same time preventing the adverse effects that precipitate or result from metabolic decompensation. Standard of care treatment has focused on preventing the mobilization of lipids that result from fasting and providing medium-chain triglycerides (MCT) in the diet in order to bypass the long-chain metabolic block. MCTs that are currently available as commercial preparations are in the form of even-chain fatty acids that are predominately a mixture of octanoate and decanoate. Recently, the use of odd-chain fatty acids has been proposed as an alternative treatment. We have shown previously that the even-numbered medium-chain fatty acids (MCFAs) that are found in MCT preparations can reduce the accumulation of potentially toxic long-chain metabolites of fatty acid oxidation (FAO). In the current study, we undertook to determine if the same is true of odd-numbered MCFAs. We found that provision of odd-chain species does decrease the build-up of long-chain FAO intermediates in our in vitro skin fibroblast model, but to a lesser extent than even-numbered MCFAs.

A perinatal strategy to prevent coronary heart disease

Objectives I investigated whether metabolism of essential fatty acids and the concentrations of their long-chain metabolites (long-chain polyunsaturated fatty acids [LCPUFAs]) are altered in fetal or perinatal growth retardation, maternal hypercholesterolemia, low-grade systemic inflammation, insulin resistance, and atherosclerosis, conditions that predispose to the development of coronary heart disease (CHD). Methods I critically reviewed the literature pertaining to the metabolism of essential fatty acids in CHD and conditions that predispose to it. Results LCPUFAs enhance endothelial nitric oxide synthesis, suppress the production of the proinflammatory cytokines tumor necrosis factor and interleukin-6, attenuate insulin resistance, and have antiatherosclerotic properties. Low-birthweight infants have decreased concentrations of LCPUFAs, especially arachidonic acid. Neonatal arachidonic acid status is related to intrauterine growth, and LCPUFAs improve fetal and postnatal growth. LCPUFAs are useful in the management of hyperlipidemia, inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase activity, and may mediate the beneficial actions of statins. Plasma concentrations of various LCPUFAs are low in diabetes mellitus, hypertension, and CHD and in populations at high risk of CHD. Breast milk is rich in LCPUFAs, and this may explain why and how adequate (6 mo to 1 y) breast feeding protects against the development of obesity, hypertension, insulin resistance, and CHD. Conclusions LCPUFAs are essential for the growth and development of the fetus and infant. LCPUFAs can prevent various conditions that predispose to the development of CHD. The low incidence of CHD seen in adequately breast-fed infants can be linked to the LCPUFA content of breast milk. Based on this evidence, I suggest that provision of LCPUFAs during critical periods of growth, especially from the second trimester of pregnancy to age 5 y, prevents CHD in adult life.

Achieving optimal essential fatty acid status in vegetarians: current knowledge and practical implications

Although vegetarian diets are generally lower in total fat, saturated fat, and cholesterol than are nonvegetarian diets, they provide comparable levels of essential fatty acids. Vegetarian, especially vegan, diets are relatively low in alpha-linolenic acid (ALA) compared with linoleic acid (LA) and provide little, if any, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Clinical studies suggest that tissue levels of long-chain n-3 fatty acids are depressed in vegetarians, particularly in vegans. n-3 Fatty acids have numerous physiologic benefits, including potent cardioprotective effects. These effects have been demonstrated for ALA as well as EPA and DHA, although the response is generally less for ALA than for EPA and DHA. Conversion of ALA by the body to the more active longer-chain metabolites is inefficient: < 5-10% for EPA and 2-5% for DHA. Thus, total n-3 requirements may be higher for vegetarians than for nonvegetarians, as vegetarians must rely on conversion of ALA to EPA and DHA. Because of the beneficial effects of n-3 fatty acids, it is recommended that vegetarians make dietary changes to optimize n-3 fatty acid status.

Effects of n-6 and n-3 Polyunsaturated Fatty Acids on Gap Junctional Intercellular Communication During Spontaneous Differentiation of the Human Colon Adenocarcinoma Cell Line Caco-2

Gap junctional intercellular communication (GJIC), which modulates cell growth and differentiation, may play an important role in tumor growth. Cancer cells have dysfunctional GJIC, but it is not known whether GJIC is mechanistically involved in the carcinogenic and anticarcinogenic effects of n-6 and n-3 polyunsaturated fatty acids (PUFAs) on colon tumor cells. Caco-2 cells were used as an in vitro model to study the effects of PUFAs on differentiated as well as undifferentiated human colon cells. The GJIC capacity of this cell line increased during spontaneous differentiation. However, no differential effects between n-6 and n-3 PUFAs on GJIC were observed. Short-term incubation with linoleic acid (18:2n-6), α-linolenic acid (18:3n-3), arachidonic acid (AA, 20:4n-6), and eicosapentaenoic acid (EPA, 20:5n-3) did not influence GJIC, while long-term incubation (>10 days) with linoleic acid and α-linolenic acid inhibited GJIC of these colon cells. Long-chain metabolites such as AA and EPA were not formed after incubation with linoleic acid and α-linolenic acid, thus excluding the involvement of prostaglandins in the observed effects. Although the exact mechanism of GJIC inhibition is unclear, cytotoxicity probably mediated by lipid peroxidation products seems to be related, because incubation with more PUFAs (AA and EPA) completely abolished GJIC.