Relationship between the niacin skin flush response and essential fatty acids in schizophrenia

The skin flush response to niacin is selectively mediated by the release of vasodilatory prostaglandins from the skin. The normal skin flush response to niacin is attenuated in many individuals with schizophrenia (SCZ). This finding suggests abnormal prostaglandin signaling in SCZ. Since prostaglandins are derived from arachidonic acid (AA), the finding of an abnormal skin flush response is consistent with biochemical data suggesting relative depletion of AA, and other essential fatty acids (EFAs), in a substantial portion of people with SCZ. This paper will describe the mechanism of the skin flush response to niacin, and will review evidence that the response to niacin is abnormal in SCZ, that this abnormality is not related to psychotropic medications, and that it may be a marker of the EFA deficiency which has been documented to be present in many patients with SCZ.     

Effect of essential fatty acids on circulating T cell subsets in patients with colorectal cancer

The effect of essential fatty acids (EFA), given orally as dietary supplements, on the responsiveness in vitro of peripheral blood lymphocytes (PBL), to the mitogen concanavalin A have been studied in 10 patients with localized and 14 patients with advanced colorectal cancer. The degree of lymphocyte activation was assessed by measuring the amount of tritiated [³H]thymidine incorporated into newly synthesised lymphocyte DNA. The results were expressed as stimulation indices. T cell responses to concanavalin A stimulation showed a significant reduction of stimulation indices following EFA supplementation, in both the localized (P=0.026) and advanced (P=0.016) tumour groups, when compared with pretreatment activity in vitro. Mixing experiments, using EFA-supplemented and non-EFA-supplemented lymphocytes with concanavalin A, suggest no enhancement of T suppressor cell activity. Cell surface marker analysis (fluorescence-activated cell sorting for CD phenotyping) revealed a reduction of absolute numbers of CD4⁺ and CD8⁺ lymphocytes following EFA supplementation. The stimulation indices returned to presupplementation values 3 months following cessation of EFA intake. There was no significant change of these indices in the control (no EFA supplementation) advanced tumour group tested. This study suggests that EFA supplementation in patients with colorectal cancer selectively reduces circulating PBL. and T cell subset (including suppressor cells) numbers and/or activity. Such effects may have an important outcome in patients with malignant disease.This work was supported by grants from the Grampian Health Broad, the Royal College of Surgeons of Edinburgh, and Scottish Hospital Endownment Research Trust     

Omega-3 and omega-6 fatty acid concentrations in red blood cell membranes relate to schizotypal traits in healthy adults

Reduced omega-3 and omega-6 fatty acids in red blood cell (RBC) membranes are often found in patients with schizophrenia. Here we investigated whether membrane concentrations of these fatty acids might vary as a function of schizotypal traits in non-psychotic individuals. Twenty-five healthy adults completed the O-LIFE schizotypal trait inventory and fatty acid composition of their venous blood samples was analysed via gas-liquid chromatography. Correlations between schizotypy measures and RBC fatty acids were examined and comparisons made between groups high and low on fatty acid measures and schizotypy scores. The omega-6 fatty acids arachidonic, adrenic and docosapentaenoic acid were directly related to positive schizotypal trait measures, as were most omega-3 fatty acids, but none were related to a negative, withdrawn form of schizotypy. Our findings of high RBC concentrations of omega-3 and omega-6 fatty acids in healthy adults with positive schizotypal traits clearly contrast with the low levels often found in schizophrenia, but are quite consistent with evidence that omega-3 fatty acids (notably EPA) can be useful in the treatment of schizophrenic illness.     

Environmental factors and membrane polyunsaturated fatty acids in schizophrenia

There is accumulating evidence of reductions in red blood cell membrane essential fatty acids in patients with schizophrenia. The mechanisms that may underlie these reductions have yet to be determined. It is possible that the observed membrane fatty acid deficits are associated with the development of schizophrenia. Alternatively, the membrane fatty acid deficits may be due to environmental factors, such as smoking and variations in diet, which may not be associated specifically with the pathophysiology of schizophrenia. Patients with schizophrenia smoke cigarettes at very high rates. Cigarette smoke contains many pro-oxidants that contribute directly to oxidative stress. Polyunsaturated fatty acids (PUFAs) are very susceptible to oxidative effects of free radicals. Thus, smoke-induced oxidative stress could plausibly account for reductions in membrane fatty acid in schizophrenia. Recent studies provide conflicting evidence for smoking effects on membrane fatty acid deficits. Likewise, the effects of diet on membrane PUFAs in schizophrenia are not entirely clear. Essential PUFAs need to be consumed in diet. Thus, differences in membrane PUFAs observed between patients and control subjects may be due to dietary variation. Few studies that have examined dietary effects differ in their interpretation of the effects of diet on membrane PUFAs. Thus, the jury is still out whether smoking or dietary effects are the primary causes of membrane PUFA deficits in patients with schizophrenia. Future studies will need to systematically examine the potential effects of smoking and diet, as well as other environmental factors such exercise, to definitively establish whether or not PUFA abnormalities are inherent to schizophrenia.     

Shifts in membrane fatty acid profiles associated with acid adaptation of Streptococcus mutans

Cells of Streptococcus mutans UA159 physiologically adapted to acidification during growth at pH 5 in glucose-limited chemostat cultures were enriched in mono-unsaturated and longer chain fatty acids compared with unadapted cells grown under the same conditions but at pH 7. Ratios of unsaturated to saturated fatty acids in the cells were, respectively, 1.2 and 0.3. Cyclopropane fatty acids were not detected. Streptococcus sobrinus 6715, which is known to have minimal acid-adaptive capacity, showed only minimal change in membrane fatty acids.     

Postnatal development of phospholipids and their fatty acid profile in rat heart

The aim of this study was to determine the concentration of phospholipids (PL), plasmalogen components of choline (PC) and ethanolamine (PE) phosphoglycerides (PLPC, PLPE) and fatty acid profile of PL and triacylglycerols (TAG) in developing rat left ventricular myocardium between postnatal day (d) 2 and 100. The steepest increase of total PL (TPL) concentration occurs between d2 and d5, followed by a further slower increase between d20 and d40. Similar developmental changes were observed in PC and PE. The PLPE concentration rises by d10, whereas PLPC does not change during the whole period investigated, except for the transient decline on d5. The concentration of diphosphatidylglycerol (DPG) increases by d60; the steepest rise occurs between d20 and d40. Phosphatidylinositol (PI) concentration rises only by d5. The concentration of phosphatidylserine (PS) decreases between d5 and d10 and then it does not change. Sphingomyelin (SM) concentration is maintained till d10, it declines on d20 and does not change thereafter. The proportion of saturated fatty acids (SFA) increases by d5 in PC, PE, PS and TAG, and by d10 in DPG and PI. After d20 the SFA proportion gradually decline in all lipids. Monounsaturated FA (MUFA) proportion decreases in PC, PE, PI and PS from d2 till d10, and in the weaning period it tends to rise again. In contrast, in DPG and TAG the proportion of MUFA declines during the whole postnatal period. N-6 polyunsaturated FA (PUFA) decrease in all PL by d20 and rise again thereafter; in TAG they decline between d2 and d10 and return to the initial level by d100. N-3 PUFA increase in all PL during the suckling period and decline after weaning; in TAG they increase only by d5 and then they decline. This remodeling of myocardial PL and TAG composition during postnatal development may affect membrane properties and contribute to developmental changes in the function of membrane proteins and cell signaling.     

Role of collagen tripeptide fragment GER on activation of adhesion and modification of fatty acid composition in membrane phospholipids of CHO-K1 cells

It has been found that the multiply repeated tripeptide fragment GER (Gly-Glu-Arg) from different collagen types stimulates the nonspecific adhesion of CHO-K1 cells. Activation of cell adhesion is accompanied by modifications to the fatty acid composition in the phospholipids of the cell membrane. Cell incubation with the synthetic GER peptide increases the unsaturation index of phosphatidylcholin (PC), phosphatidylethanolamine (PEA), and phosphatidylinositol (PI). Arachidonic (C20:4ω6) acid is mainly contributed to the increased index of PI. Not only arachidonic acid but other unsaturated fatty acids, such as docosatetraenoic (C22:4ω6), docosapentaenoic (C22:5ω3), and docosahexaenoic (C22:6ω3), are responsible for the increased index of PC and PEA. In addition, the elevation of the relative content of polyenoic fatty acids in PI is concomitant with a reduced amount of monoenoic fatty acids, mainly due to decline in the oleic (C18:1) acid level. The role of GER peptide in (1) the activation of cell adhesion as a regulator of active or inactive states of integrin receptors; (2) modification of fatty acid composition in major classes of phospholipids as a modulator of the fluidity in annular lipid zones surrounding to the adhesive molecules is discussed.     

N-3 and n-6 fatty acid metabolism in undifferentiated and differentiated human intestine cell line (Caco-2)

Metabolism of n-6 and n-3 fatty acids in the undifferentiated and differentiated human adenocarcinoma colon cell line (Caco-2) was studied. In cells incubated with either 182n-6 or 183n-3, no significant amounts of long chain n-6 and n-3 metabolites were found. Incubation with either 183n-6 or 184n-3 raised significantly the levels of 203n-6 and 204n-3, respectively. In the undifferentiated cells, significant proportions of 203n-6 and 204n-3 were further 5-desaturated to form 204n-6 and 205n-3, respectively. Incubation with either 204n-6 or 205n-3 raised the levels of their direct elongation products, 224n-6 and 225n-3, respectively. Incubation with 224n-6 or 225n-3 increased the levels of 204n-6 and 205n-6. These results suggest that 6-desaturation in the Caco-2 cells is less active in comparision with elongation, 5-desaturation and retro-conversion. These enzymes were modulated by the state of differentiation, and appeared to be non-specific to n-3 and n-6 fatty acids. When cells were incubated with 183n-6 and 184n-3 concomitantly, the levels of incorporation of total n-6 fatty acids into cellular lipids were greater than those of the n-3 fatty acids, whereas the ratios of 20+22 carbon metabolites to 18-carbon precursor favored n-3 over n-6 fatty acids. These results suggest that n-3 and n-6 fatty acids were not metabolized identically in Caco-2 cells.     

Effect of varying levels of dietary essential fatty acid during early ontogeny of the sea scallop Placopecten magellanicus

This study investigated the biological effects of various dietary essential fatty acids levels to sea scallop larvae, Placopecten magellanicus. Scallop larvae were fed three diets from D-veliger to settlement. Diet A consisted of Isochrysis sp. and Pavlova lutheri, diet B was a mix of Isochrysis sp. and Chaetoceros muelleri and diet C consisted of the same two species, but C. muelleri was grown under silicate deprivation to alter the fatty acid composition. Pediveligers (28 days old) were sampled prior to settlement for fatty acid analysis, growth measurement and survival assessment. Survival and settlement success were measured at the end of the experiment (day 40). Our results show that feeding regime greatly influenced larval size, settlement and fatty acid composition. Diet A was severely deficient in arachidonic acid (20:4n-6, AA), leading to the poorest larval growth, survival and lipid content. Nevertheless, larvae fed diet A selectively accumulate AA by a factor three compared to the dietary amount. Shell size of 28-day-old larvae was positively correlated with AA content and negatively correlated with eicosapentaenoic acid (20:5n-3, EPA)-AA ratio, thus suggesting that these two variables are of major interest for the optimisation of larval growth in sea scallops. Finally, larvae fed diet C displayed 20% higher shell size at day 28 than larvae fed diet A and B, likely in relation to the dietary amount of saturated fatty acid (SFA). However, the moderate survival and settlement success of these groups of larvae might be associated with a relative deficiency in docosahexaenoic acid (22:6n-3, DHA). This study underlines that the overall balance between polyunsaturated fatty acid (PUFA) needs to be considered to adequately fed sea scallop larvae.     

Red blood cell fatty acid profile of chronic renal failure patients receiving maintenance haemodialysis treatment

Increased prostaglandins (PGs) are associated with many inflammatory pathophysiological conditions; and are synthesized from arachidonic acid by either of 2 enzymes, cyclooxygenase-1 (COX-1) or -2 (COX-2). Recent epidemiologic, expression, and pharmacologic studies suggest COX-2 derived metabolites also play a functional role in the maintenance of tumor viability, growth and metastasis. Archival and/or prospectively collected human tissues were prepared for immunohistochemistry, and representative cases assayed via Western blot, RT-PCR, or TAQman analysis. Consistent overexpression of COX-2 was observed in a broad range of premalignant, malignant, and metastatic human epithelial cancers. COX-2 was detected in ca. 85% of the hyperproliferating, dysplastic, and neoplastic epithelial cells, and in the existing and angiogenic vasculature within and adjacent to hyperplastic/neoplastic lesions. These data collectively imply COX-2 may play an important role during premalignant hyperproliferation, as well as the later stages of invasive carcinoma and metastasis in various human epithelial cancers.     

Altered membrane free unsaturated fatty acid composition in human colorectal cancer tissue

Polyunsaturated free fatty acids (PUFAs) participate in normal functioning of the cell, particularly in control intracellular cell signalling. As nutritional components they compose a human diet with an indirect promoting influence on tumourogenesis. The PUFAs level depends on the functional state of the membrane. This work is focused on changes only of free unsaturated fatty acids amount (AA – arachidonic acid, LA – linoleic acid, ALA – α-linolenic acid, palmitoleic acid (PA) and oleic acid) in cell membranes of colorectal cancer of pT3 stage, G2 grade without metastasis. Qualitative and quantitative composition of free unsaturated fatty acids in the membrane was determined by high-performance liquid chromatography. It was shown that the malignant transformation was accompanied by a decrease in amount of LA and ALA while arachidonic and oleic acids increased. It is of interest that free AA levels are elevated in colon cancer, as AA is the precursor to biologically active eicosanoids.     

The role of fatty acid binding protein on the metabolism of fatty acids in isolated rat hepatocytes

In isolated rat hepatocytes flavaspidic acid, a competitor with free fatty acids for the fatty-acid-binding-protein, decreased the uptake of oleic acid and triglyceride synthesis but stimulated the formation of CO₂ and ketone bodies from oleic acid. Flavaspidic acid had no effect on the utilization of octanoic acid. Stimulation of the microsomal fatty-acid-activating enzyme by the fatty-acid-binding protein was reversed by flavaspidic acid. In contrast, the binding protein inhibited the mitochondrial fatty-acid-activating enzyme. Flavaspidic acid not only prevented this inhibition but actually stimulated the enzyme activity. The results indicate that the cytosol fatty-acid-binding protein directs the metabolism of long chain fatty acids toward esterification as well as enhancing their cellular uptake.     

Measurements of fatty acid and carbohydrate metabolism in te isolated working rat heart

The isolated working rat heart is a useful experimental model which allows contractile function to be measured in hearts perfused at physiologically relevant workloads. To maintain these high workloads the heart is required to generate a tremendous amount of energy. In vivo this energy is derived primarily from the oxidation of fatty acids. In many experimental situations it is desirable to perfuse the isolated working heart in the presence of physiologically relevant concentrations of fatty acids. This is particularly important when studying energy metabolism in the heart, or in determining how fatty acids alter the outcome of myocardial ischemic injury [1, 2]. The other major source of energy for the heart is derived from the oxidation of carbohydrates (glucose and lactate), with a smaller amount of ATP also being derived from glycolysis. Two byproducts of both fatty acid and carbohydrate metabolism are H2O and CO2. By labeling the glucose, lactate, or fatty acids in the perfusate with 3H or 14C the experimenter can quantitatively collect either 3H2O or 14CO2 produced by the heart. By using radioisotopes that are labeled at specific hydrogen or carbon molecules on the various energy substrates, and by knowing the specific activity of the radiolabeled substrate used, it is possible to determine the actual rate of flux through these individual pathways. This paper will describe the experimental protocols for directly measuring fatty acid and carbohydrate metabolism in isolated working rat hearts.     

Altered fatty acid metabolism and composition in cultured astrocytes under hyperammonemic conditions

In vitro ¹H- and ¹³C-NMR spectroscopy was used to investigate the effect of ammonia on fatty acid synthesis and composition in cultured astrocytes. Cells were incubated 3 and 24 h with 5 mM ammonia in the presence or absence of the glutamine synthetase inhibitor methionine sulfoximine. An increase of de novo synthesized fatty acids and the glycerol subunit of lipids was observed after 3 h treatment with ammonia (35% and 40% over control, respectively), the initial time point examined. Both parameters further increased significantly to 85% and 60% over control after 24 h ammonia treatment. Three hours incubation with ammonia increased the synthesis of diacylglycerides, while formation of triacylglycerides was decreased (40% over and 15% under control, respectively). The degradation of fatty acids was not affected by ammonia treatment. Furthermore, ammonia caused alterations in the composition of fatty acids, e.g. increased mono- and decreased polyunsaturated fatty acids (85% over and 15% under control concentrations, respectively). The decrease of polyunsaturated fatty acids was even more pronounced in isolated astrocytic mitochondria (39% lower than controls). Our results suggest ammonia-induced abnormalities in astrocytic membranes, which may be related to astrocytic mitochondrial dysfunction in hyperammonemic states. Most of the observed effects of ammonia on fatty acid synthesis and composition were ameliorated when glutamine synthetase was inhibited by methionine sulfoximine, supporting a pathological role of glutamine in ammonia toxicity. This study further emphasizes the importance of investigating the relative contribution of exogenous ammonia, effects of glutamine and of glutamine-derived ammonia on astrocytes and astrocytic mitochondria.     

Effect of propionyl-L-carnitine treatment on membrane phospholipid fatty acid turnover in diabetic rat erythrocytes

In this work we have examined the effect of the oral administration of propionyl-L-carnitine (PLC) on the membrane phospholipid fatty acid turnover of erythrocytes from streptozotocin-induced diabetic rats. A statistically significant reduction in radioactive palmitate, oleate, and linoleate, but not arachidonate, incorporation into membrane phosphatidylcholine (PC) of diabetic rat erythrocytes with respect to control animals was found. Changes in radioactive fatty acid incorporation were also found in diabetic red cell phosphatidylethanolamine (PE), though they were not statistically significant. Oral propionyl-L-carnitine (PLC) treatment of diabetic rats partially restored the ability of intact red cells to reacylate membrane PC with palmitate and oleate, and reacylation with linoleate was fully restored. The analysis of the membrane phospholipid fatty acid composition revealed a consistent increase of linoleate levels in diabetic rat red cells, and a modest decrease of palmitate, oleate and arachidonate. The phospholipid fatty acid composition of diabetic red blood cells was not affected by the PLC treatment. Lysophosphatidylcholine acyl-CoA transferase (LAT) specific activity measured with either palmitoyl-CoA or oleyl-CoA was significantly reduced in diabetic erythrocyte membranes in comparison to controls. In addition LAT kinetic parameters of diabetic erythrocytes were altered. The reduced LAT activity could be partially corrected by PLC treatment of diabetic rats. Our data suggest that the impaired erythrocyte membrane physiological expression induced by the diabetic disease may be attenuated by the beneficial activity of PLC on the red cell membrane phospholipid fatty acid turnover.Abbreviations LAT lysophosphatidylcholine acyl-CoA transferase - PC phosphatidylcholine - PE phosphatidylethanolamine - PLC propionyl-L-carnitine - STZ streptozotocin     

Eicosapentaenoic acid in the treatment of schizophrenia and depression: rationale and preliminary double-blind clinical trial results

It has been hypothesised that polyunsaturated fatty acids (PUFA) play an important role in the aetiology of schizophrenia and depression. Evidence supporting this hypothesis for schizophrenia includes abnormal brain phospholipid turnover shown by 31P Magnetic Resonance Spectroscopy, increased levels of phospholipase A2, reduced niacin skin flush response, abnormal electroretinogram, and reduced cell membrane levels of n-3 and n-6 PUFA. In depression, there is strong epidemiological evidence that fish consumption reduces risk of becoming depressed and evidence that cell membrane levels of n-3 PUFA are reduced. Four out of five placebo-controlled double- blind trials of eicosapentaenoic acid (EPA) in the treatment of schizophrenia have given positive findings. In depression, two placebo-controlled trials have shown a strong therapeutic effect of ethyl-EPA added to existing medication. The mode of action of EPA is currently not known, but recent evidence suggests that arachidonic acid (AA) if of particular importance in schizophrenia and that clinical improvement in schizophrenic patients using EPA treatment correlates with changes in AA.     

Identification of genes and pathways involved in the synthesis of Mead acid (20:3n − 9), an indicator of essential fatty acid deficiency

In mammals, 5,8,11-eicosatrienoic acid (Mead acid, 20:3n − 9) is synthesized from oleic acid during a state of essential fatty acid deficiency (EFAD). Mead acid is thought to be produced by the same enzymes that synthesize arachidonic acid and eicosapentaenoic acid, but the genes and the pathways involved in the conversion of oleic acid to Mead acid have not been fully elucidated. The levels of polyunsaturated fatty acids in cultured cells are generally very low compared to those in mammalian tissues. In this study, we found that cultured cells, such as NIH3T3 and Hepa1–6 cells, have significant levels of Mead acid, indicating that cells in culture are in an EFAD state under normal culture conditions. We then examined the effect of siRNA-mediated knockdown of fatty acid desaturases and elongases on the level of Mead acid, and found that knockdown of Elovl5, Fads1, or Fads2 decreased the level of Mead acid. This and the measured levels of possible intermediate products for the synthesis of Mead acid such as 18:2n − 9, 20:1n − 9 and 20:2n − 9 in the knocked down cells indicate two pathways for the synthesis of Mead acid: pathway 1) 18:1n − 9 → (Fads2) → 18:2n − 9 → (Elovl5) → 20:2n − 9 → (Fads1) → 20:3n − 9 and pathway 2) 18:1n − 9 → (Elovl5) → 20:1n − 9 → (Fads2) → 20:2n − 9 → (Fads1) → 20:3n − 9.     

Half-lives of docosahexaenoic acid in rat brain phospholipids are prolonged by 15 weeks of nutritional deprivation of n-3 polyunsaturated fatty acids

Male rat pups (21 days old) were placed on a diet deficient in n-3 polyunsaturated fatty acids (PUFAs) or on an n-3 PUFA adequate diet containing alpha-linolenic acid (alpha-LNA; 18 : 3n-3). After 15 weeks on a diet, [4,5-3H]docosahexaenoic acid (DHA; 22 : 6n-3) was injected into the right lateral cerebral ventricle, and the rats were killed at fixed times over a period of 60 days. Compared with the adequate diet, 15 weeks of n-3 PUFA deprivation reduced plasma DHA by 89% and brain DHA by 37%; these DHA concentrations did not change thereafter. In the n-3 PUFA adequate rats, DHA loss half-lives, calculated by plotting log10 (DHA radioactivity) against time after tracer injection, equaled 33 days in total brain phospholipid, 23 days in phosphatidylcholine, 32 days in phosphatidylethanolamine, 24 days in phosphatidylinositol and 58 days in phosphatidylserine; all had a decay slope significantly greater than 0 (p < 0.05). In the n-3 PUFA deprived rats, these half-lives were prolonged twofold or greater, and calculated rates of DHA loss from brain, Jout, were reduced. Mechanisms must exist in the adult rat brain to minimize DHA metabolic loss, and to do so even more effectively in the face of reduced n-3 PUFA availability for only 15 weeks.