linoleic-acid and nervonic-acid

Two recent meta-analyses showed decreased red blood cell (RBC) polyunsaturated fatty acids (FA) in schizophrenia and related disorders. However, both these meta-analyses report considerable heterogeneity, probably related to differences in patient samples between studies. Here, we investigated whether variations in RBC FA are associated with psychosis, and thus may be an intermediate phenotype of the disorder.. For the present study, a total of 215 patients (87% outpatients), 187 siblings, and 98 controls were investigated for multiple FA analyses. Based on previous studies, we investigated docosahexaenoic acid (DHA), docosapentaenoic acid (DPA), arachidonic acid (AA), linoleic acid (LA), nervonic acid (NA), and eicasopentaenoic acid (EPA). On an exploratory basis, a large number of additional FA were investigated. Multilevel mixed models were used to compare the FA between the 3 groups.. Compared to controls, both patients and siblings showed significantly increased DHA, DPA, AA, and NA. LA was significantly higher in siblings compared to controls. EPA was not significantly different between the 3 groups. Also the exploratory FA were increased in patients and siblings.. We found increased RBC FA DHA, DPA, AA, and NA in patients and siblings compared to controls. The direction of change is similar in both patients and siblings, which may suggest a shared environment and/or an intermediate phenotype. Differences between patient samples reflecting stage of disorder, dietary patterns, medication use, and drug abuse are possible modifiers of FA, contributing to the heterogeneity in findings concerning FA in schizophrenia patients.

Topics: Adult; Arachidonic Acid; Docosahexaenoic Acids; Eicosapentaenoic Acid; Erythrocytes; Fatty Acids, Monounsaturated; Fatty Acids, Unsaturated; Female; Healthy Volunteers; Humans; Linoleic Acid; Male; Psychotic Disorders; Schizophrenia; Siblings; Young Adult

The obese lipid profile is associated with increased free fatty acids and triacylglycerides. Currently, little is known about the plasma lipid species associated with obesity. In this study, we compared plasma lipid fatty acid (FA) profiles as a function of BMI. Profiling phospholipid (PL) FAs and their respective oxylipids could predict which obese individuals are more likely to suffer from diseases associated with chronic inflammation or oxidative stress. We investigated the relationship between BMI and plasma PL (PPL) FA composition in 126 men using a quantitative gas chromatography analysis. BMI was inversely associated with both PPL nervonic and linoleic acid (LA) but was positively associated with both dihomo-γ-linolenic and palmitoleic acid. Compared to lean individuals, obese participants were more likely to have ω-6 FAs, except arachidonic acid and LA, incorporated into PPLs. Obese participants were less likely to have EPA and DHA incorporated into PPLs compared to lean participants. Non-esterified plasma PUFA and oxylipid analysis showed ω-6 oxylipids were more abundant in the obese plasma pool. These ω-6 oxylipids are associated with increased angiogenesis (i.e. epoxyeicosatrienoates), reactive oxygen species (i.e. 9-hydroxyeicosatetraenoate), and inflammation resolution (i.e. Lipoxin A4). In summary, BMI is directly associated with specific PPL FA and increased ω-6 oxylipids.

Topics: 8,11,14-Eicosatrienoic Acid; Aged; Body Mass Index; Chromatography, Gas; Fatty Acids, Monounsaturated; Fatty Acids, Unsaturated; Humans; Linoleic Acid; Male; Middle Aged; Obesity; Triglycerides

White matter (WM) abnormalities have been implicated in schizophrenia, yet the mechanisms underlying these abnormalities are not fully understood. Several lines of evidence suggest that polyunsaturated fatty acids (PUFAs) play a role in myelination, and there is substantial evidence documenting decreased PUFA concentrations in schizophrenia. We therefore hypothesized that lower membrane PUFA concentrations may be related to reduced WM integrity in schizophrenia and related disorders.. In 30 male patients with a recent-onset psychotic disorder, erythrocyte membrane PUFA concentrations were assessed and diffusion tensor imaging was performed with voxelwise analysis.. Lower total PUFA concentration was associated with lower fractional anisotropy (FA) throughout the corpus callosum and bilateral parietal, occipital, temporal and frontal WM (P < .05, corrected). Of the individual PUFAs, lower arachidonic acid concentration, and to a lesser extent, lower nervonic acid, linoleic acid, and docosapentaenoic acid concentration were significantly associated with lower FA. PUFA concentrations were inversely associated with radial diffusivity but showed little association with axial diffusivity. Greater severity of negative symptoms was associated with lower nervonic acid concentration and lower FA values.. Membrane PUFA concentrations appear to be robustly related to brain WM integrity in early phase psychosis. These findings may provide a basis for studies to investigate the effects of PUFA supplementation on WM integrity and associated symptomatology in early psychosis.

Topics: Adult; Anisotropy; Arachidonic Acid; Cerebral Cortex; Corpus Callosum; Diffusion Tensor Imaging; Erythrocyte Membrane; Fatty Acids, Monounsaturated; Fatty Acids, Unsaturated; Humans; Image Processing, Computer-Assisted; Linoleic Acid; Male; Myelin Sheath; Nerve Fibers, Myelinated; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology; Young Adult

The binding of human DNA polymerase beta (pol beta) to DNA template-primer duplex and single-stranded DNA in the absence or presence of pol beta inhibitors has been studied using a surface plasmon resonance biosensor. Two fatty acids, linoleic acid and nervonic acid, were used as potent pol beta inhibitors. In the interaction between pol beta and DNA, pol beta could bind to ssDNA in a single binding mode, but bound to DNA template-primer duplexes in a parallel mode. Both pol beta inhibitors prevented the binding of pol beta to the single strand overhang and changed the binding from parallel to single mode. The affinities of pol beta to the template-primer duplex region in the presence of nervonic acid or linoleic acid were decreased by 20 and 5 times, respectively. The significant inhibitory effect of nervonic acid on the pol beta-duplex interaction was due to both a 2-fold decrease in the association rate and a 9-fold increase in the dissociation rate. In the presence of linoleic acid, no significant change of association rate was observed, and the decrease in binding affinity of pol beta to DNA was mainly due to 7-fold increase in the dissociation rate.

Topics: Base Sequence; DNA Polymerase beta; DNA, Single-Stranded; Fatty Acids; Fatty Acids, Monounsaturated; Humans; Kinetics; Linoleic Acid; Molecular Sequence Data; Nucleic Acid Conformation; Protein Binding

Relative increases in unsaturated fatty acids (USFA) in the diet are considered to exert beneficial effects on coronary risk factors (CRF). However, detailed analysis of the relationships between serum USFA and CRF are scanty and there is no report of the relationship between nervonic acid (NA) and CRF. The objective of the present study was to analyze the relationships between serum USFA and CRF. Body height and weight, blood pressure, fasting serum total cholesterol (TC), triacyl-glycerol (TG), HDL cholesterol (HDLc), fasting blood sugar (FBS), total fatty acid composition, leptin, and high-sensitivity C-reactive protein (CRP) were measured in 31 men (age, 41-78 years) and 11 women (age, 54-77 years). The relationships between serum USFA, and body mass index (BMI), leptin, systolic blood pressure (SBP), diastolic blood pressure (DBP), TC, TG, HDLc, FBS, and CRP were analyzed using multiple regression analysis. The final results were summarized using coronary risk factor scores (CRFS) in order to assess the correlations between USFA with CRF. Oleic acid (OA), linoleic acid (LA), and eicosapentaenoic acid (EPA) were positively related to coronary risk factors (total CRFS = 2, 3, and 4, respectively), while nervonic acid (NA) exerted negative effects on these risk factors (total CRFS = -6 ). It is concluded NA may have preventive effects on obesity-related metabolic disorders.

Topics: Adult; Aged; Blood Pressure; Body Mass Index; Coronary Disease; Cross-Sectional Studies; Eicosapentaenoic Acid; Fatty Acids, Monounsaturated; Fatty Acids, Unsaturated; Female; Humans; Leptin; Linoleic Acid; Male; Middle Aged; Obesity; Oleic Acid; Regression Analysis; Risk Factors

Nutritional factors may be relative to attention-deficit hyperactive disorder (ADHD), although the pathogenic mechanism is still unknown. Based on the work of others, we hypothesized that children with ADHD have altered dietary patterns and fatty acid metabolism. Therefore, the aim of this study was to evaluate dietary patterns and the blood fatty acid composition in children with ADHD in the Taipei area of Taiwan. The present study found that 58 subjects with ADHD (average age 8.5 years) had significantly higher intakes of iron and vitamin C compared to those of 52 control subjects (average age 7.9 years) (P < 0.05). The blood total protein content in subjects with ADHD was significantly lower than that in control subjects (P < 0.05). On the other hand, children with ADHD had significantly higher blood iron levels compared to the control children (P < 0.05). Additionally, plasma gamma-linolenic acid (18:3 n-6) in children with ADHD was higher than that in control children (P < 0.05). Concerning the composition of other fatty acids in the phospholipid isolated from red blood cell (RBC) membranes, oleic acid (18:1n-9) was significantly higher, whereas nervonic acid (24:1n-9), linoleic acid (18:2n-6), arachidonic acid (20:4n-6), and docosahexaenoic acid (22:6n-3) were significantly lower in subjects with ADHD (P < 0.05). Our results suggest that there were no differences in dietary patterns of these children with ADHD except for the intake of iron and vitamin C; however, the fatty acid composition of phospholipid from RBC membranes in the ADHD children differed from that of the normal children.

Topics: Arachidonic Acid; Attention Deficit Disorder with Hyperactivity; Blood Proteins; Case-Control Studies; Child; Docosahexaenoic Acids; Eating; Erythrocytes; Fatty Acids; Fatty Acids, Monounsaturated; Fatty Acids, Omega-6; Feeding Behavior; Female; Humans; Linoleic Acid; Male; Phospholipids; Reference Values; Taiwan

We previously reported that unsaturated long-chain fatty acids were potent DNA polymerase inhibitors (Y. Mizushina et al., J. Biol. Chem. 274 (1999) 25599-25607). In those experiments, the question remained of whether metastable oil droplets (liposomal vesicles) of the unsaturated long-chain fatty acids can non-specifically inhibit the polymerase activity. We report here that only the soluble fatty acid monomers of linoleic acid or nervonic acid could affect the activities of mammalian DNA polymerases, and the metastable oil droplets could not. When we consider the facts that nuclear membranes are a kind of liposomal vesicles, that free fatty acids occur only at the moment the lipids are digested, and that the DNA polymerization possibly occurs on the nuclear membranes, the data shown here are suggestive regarding the mechanism of regulation of DNA polymerization in vivo.

Topics: Cell Cycle; Dialysis; Dimethyl Sulfoxide; DNA Repair; DNA-Directed DNA Polymerase; Fatty Acids; Fatty Acids, Monounsaturated; Humans; Linoleic Acid; Lipase; Nuclear Envelope; Nucleic Acid Synthesis Inhibitors; Particle Size; Solubility; Sonication

Unsaturated long-chain fatty acids selectively bind to the DNA binding sites of DNA polymerase beta and DNA topoisomerase II, and inhibit their activities, although the amino acid sequences of these enzymes are markedly different from each other. Computer modeling analysis revealed that the fatty acid interaction interface in both enzymes has a group of four amino acid residues in common, forming a pocket which binds to the fatty acid molecule. The four amino acid residues were Thr596, His735, Leu741 and Lys983 for yeast DNA topoisomerase II, corresponding to Thr79, His51, Leu11 and Lys35 for rat DNA polymerase beta. Using three-dimensional structure model analysis, we determined the spatial positioning of specific amino acid residues binding to the fatty acids in DNA topoisomerase II, and subsequently obtained supplementary information to build the structural model.

Topics: Amino Acid Sequence; Animals; Binding Sites; Computer Simulation; DNA; DNA Polymerase beta; DNA Topoisomerases, Type II; Fatty Acids, Monounsaturated; Fatty Acids, Unsaturated; Humans; Kinetics; Linoleic Acid; Models, Molecular; Molecular Sequence Data; Protein Binding; Protein Structure, Tertiary; Rats; Sequence Alignment; Surface Plasmon Resonance; Topoisomerase II Inhibitors; Yeasts

Receptor-mediated overexpression of H2O2-generating peroxisomal fatty acyl-CoA oxidase (AOX) has been implicated in peroxisome proliferator-induced hepatocarcinogenesis. To investigate the role of rat AOX generated H2O2 in transformation, we overexpressed this enzyme in a non-tumorigenic mouse fibroblast cell line (LM tk-) under control of mouse urinary protein promoter. The clones overexpressing rat peroxisomal AOX, when exposed to a fatty acid substrate (100 microM linoleic acid) for 6 to 96 h, demonstrated > 10-fold increase of intracellular H2O2. This increase in H2O2 concentration was associated with increased apoptosis as evidenced by DNA fragmentation, in situ terminal deoxynucleotide transferase dUTP nick end-labeling (TUNEL). These cell lines stably expressing AOX formed colonies in soft agar in proportion to the duration (1-7 weeks) of exposure to a fatty acid substrate (100 microM linoleic acid, erucic acid or nervonic acid) and these transformants developed into fibrosarcomas when injected in athymic nude mice. These results suggest that H2O2 generated by AOX overexpression in immortalized fibroblasts leads to apoptosis, and the extent and duration of H2O2 and possibly other DNA damaging reactive oxygen species generated by the overexpression of peroxisomal AOX can influence apoptosis and neoplastic transformation.

Topics: Acyl-CoA Oxidase; Animals; Apoptosis; Blotting, Northern; Blotting, Western; Cell Transformation, Neoplastic; Cells, Cultured; Colony-Forming Units Assay; DNA Primers; Erucic Acids; Fatty Acids, Monounsaturated; Fibroblasts; Fibrosarcoma; Gene Expression; Hydrogen Peroxide; In Situ Nick-End Labeling; Linoleic Acid; Male; Mice; Mice, Nude; Oxidoreductases; Polymerase Chain Reaction; Rats

We found previously that long-chain fatty acids could inhibit eukaryotic DNA polymerase activities in vitro [1,2]. The purpose of the present study was to investigate the mode of this inhibition in greater detail. Among the C18 to C24 fatty acids examined, the strongest inhibitor was a C24 fatty acid, nervonic acid (NA), and the weakest was a C18 fatty acid, linoleic acid (LA). We analyzed the inhibitory effect of these two fatty acids and their modes of action. For DNA polymerase beta (pol. beta), NA acted by competing with both the substrate- and template-primer, but for DNA polymerase alpha (pol. alpha) or human immunodeficiency virus type 1 reverse transcriptase (HIV-1 reverse transcriptase or HIV-RT), NA acted non-competitively. NA-binding to pol. beta could be stopped with a non-ionic detergent, but the binding to pol. alpha or HIV-RT could not. The inhibition mode of LA showed the same characteristics, except that the minimum inhibitory dose of the longer chain was much lower. We also tested the effects of NA and LA using pol. beta and its proteolytic fragments, as described by Kumar et al. [3,4]. Both of the fatty acids were found to bind to the 8 kDa DNA-binding domain fragment, and to suppress binding to the template-primer DNA. We found that 10,000 times more of either fatty acid was required for it to bind to the 31 kDa catalytic domain or inhibit the DNA polymerase activity. The possible modes of inhibition by these long-chain fatty acids are discussed, based on the present findings.

Topics: Animals; Cattle; DNA; DNA Polymerase beta; DNA Polymerase I; Enzyme Inhibitors; Fatty Acids, Monounsaturated; Fatty Acids, Nonesterified; Fatty Acids, Unsaturated; HIV Reverse Transcriptase; Humans; Kinetics; Linoleic Acid; Rats; Recombinant Proteins; Reverse Transcriptase Inhibitors; Structure-Activity Relationship; Thymus Gland