Dihomo-gamma-linolenic Acid Research Articles

Altered serum mono- and polyunsaturated fatty acid levels in adults with ADHD

Other than in children diagnosed with attention deficit hyperactivity disorder (ADHD), the connection between ADHD and lipids has not been sufficiently investigated so far in adults. Blood serum lipoproteins and fatty acids (FA) composition were measured and analyzed by colorimetry and gaschromatography in eight male and seven female adults diagnosed with ADHD as well as in 15 age- and gender-matched healthy control subjects. In ADHD patients, polyunsaturated FAs [docosahexaenoic, arachidonic and dihomogammalinolenic acid (p = 0.048; 0.003; 0.012)] showed lower concentrations, while monounsaturated acids (palmitoleic and oleic acid) as well as total and LDL cholesterol showed higher concentrations (p = 0.011; 0.005). ADHD scores positively correlated with palmitoleic (R = -0.56; p = 0.032), stearic (R = 0.53; p = 0.044), eicosapentaenoic (R = 0.62; p = 0.014), docosahexaenoic (R = 0.51; p = 0.050), gammalinolenic (R = 0.62; p = 0.018) and alphalinolenic acid (R = 0.56; p = 0.031) concentration. Even though the total and LDL cholesterol concentrations in blood serum were significantly higher among the ADHD patients than in controls, none of the ADHD symptom scores were significantly associated with any of the lipoproteine measures. We could demonstrate that a lack of polyunsaturated FAs in blood serum of subjects with ADHD persists into adulthood. Furthermore, we could show that adult ADHD symptomatology positively correlates with elevated levels of saturated stearic and monounsaturated FAs.

The association between interpregnancy interval and birth weight: what is the role of maternal polyunsaturated fatty acid status?

BackgroundThe objective of this study was to evaluate the mediating role of maternal early pregnancy plasma levels of long chain polyunsaturated fatty acids (LCPUFAs) in the association of interpregnancy interval (IPI) with birth weight and smallness for gestational age (SGA) at birth.MethodsWe analysed a subsample of the Amsterdam Born Children and their Development (ABCD) cohort, comprising 1,659 parous pregnant women recruited between January 2003 and March 2004. We used linear and logistic regression to evaluate the associations between fatty acid status, interpregnancy interval and pregnancy outcome.ResultsLow plasma phospholipids concentrations of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and dihomo-gamma-linolenic acid (DGLA), and high concentrations of arachidonic acid (AA) during early pregnancy were associated with reduced birth weight and/or an increased risk of SGA. Short IPIs (< 6 months, with 18–23 months as a reference) were associated with a mean decrease of 207.6 g (SE: ± 73.1) in birth weight (p = 0.005) and a twofold increased risk of SGA (OR: 2.05; CI: 0.93–4.51; p = 0.074). Adjustment for maternal fatty acid concentrations did not affect these results to any meaningful extent.ConclusionsDespite the observed association of maternal early pregnancy LCPUFA status with birth weight and SGA, our study provides no evidence for the existence of an important role of maternal EPA, DHA, DGLA or AA in the association of short interpregnancy intervals with birth weight and SGA.

Effects of Statins on Serum n-3 to n-6 Polyunsaturated Fatty Acid Ratios in Patients With Coronary Artery Disease

A low n-3 to n-6 polyunsaturated fatty acids (PUFAs) ratio is reported to be associated with cardiovascular events. However, the effects of statins on this ratio have not been fully examined. A total of 101 patients with coronary artery disease, who were not receiving lipid-lowering therapy were randomly assigned to receive either 4 mg/day of pitavastatin or 20 mg/day of pravastatin. Serum PUFA levels were measured at baseline and 8 months after treatment with statins. Pitavastatin was used to treat 51 patients and the remaining 50 patients were treated using pravastatin. A significant positive correlation was observed between the percent change in low-density lipoprotein cholesterol and that in dihomogamma-linolenic acid (r = .376, P = .007), arachidonic acid (AA; r = .316, P = .02), eicosapentaenoic acid (EPA; r = .408, P = .003), or docosahexaenoic acid (DHA; r = .270, P = .056) in the pitavastatin group. However, these correlations were not observed in the pravastatin group. The DHA/AA ratio decreased significantly in the pitavastatin group only (from 0.96 to 0.83, P = .0002) and the DHA/AA ratio was significantly lower in the pitavastatin group at 8 months (0.83 vs 0.96, P = .03). The EPA/AA ratio did not show significant changes in either group. Pitavastatin decreased the serum DHA/AA ratio, whereas pravastatin had no effect on this ratio. Neither pitavastatin nor pravastatin had an effect on the serum EPA/AA ratio in patients with coronary artery disease.

Serum Paraoxonase 1 Activity Is Associated with Fatty Acid Composition of High Density Lipoprotein

Introduction. Cardioprotective effect of high density lipoprotein (HDL) is, in part, dependent on its related enzyme, paraoxonase 1 (PON1). Fatty acid composition of HDL could affect its size and structure. On the other hand, PON1 activity is directly related to the structure of HDL. This study was designed to investigate the association between serum PON1 activity and fatty acid composition of HDL in healthy men. Methods. One hundred and forty healthy men participated in this research. HDL was separated by sequential ultracentrifugation, and its fatty acid composition was analyzed by gas chromatography. PON1 activity was measured spectrophotometrically using paraxon as substrate. Results. Serum PON1 activity was directly correlated with the amount of stearic acid and dihomo-gamma-linolenic acid (DGLA). PON1/HDL-C was directly correlated with the amount of miristic acid, stearic acid, and DGLA and was inversely correlated with total amount of ω6 fatty acids of HDL. Conclusion. The fatty acid composition of HDL could affect the activity of its associated enzyme, PON1. As dietary fats are the major determinants of serum lipids and lipoprotein composition, consuming some special dietary fatty acids may improve the activity of PON1 and thereby have beneficial effects on health.

Stress response pathways protect germ cells from omega-6 polyunsaturated fatty acid-mediated toxicity in Caenorhabditis elegans

Polyunsaturated fatty acids serve both structural and functional roles as membrane components and precursors for a number of different factors involved in inflammation and signaling. These fatty acids are required in the human diet, although excess dietary intake of omega-6 fatty polyunsaturated fatty acids may have a negative influence on human health. In the model nematode, Caenorhabditis elegans, dietary exposure to dihomo-gamma-linolenic acid (DGLA), an omega-6 fatty acid, causes the destruction of germ cells and leads to sterility. In this study we used genetic and microscopic approaches to further characterize this phenomenon. We found that strains carrying mutations in genes involved in lipid homeostasis enhanced sterility phenotypes, while mutations reducing the activity of the conserved insulin/IGF signaling pathway suppressed sterility phenotypes. Exposure to a mild heat stress prior to omega-6 fatty acid treatment led to an adaptive or hormetic response, resulting in less sterility. Mutations in skn-1 and knockdown of genes encoding phase II detoxification enzymes led to increased sterility in the presence of dietary DGLA. Thus, detoxification systems and genetic changes that increase overall stress responses protect the germ cells from destruction. Microscopic analyses revealed that dietary DGLA leads to deterioration of germ cell membranes in the proliferative and transition zones of the developing germ line. Together, these data demonstrate that specific omega-6 polyunsaturated fatty acids, or molecules derived from them, are transported to the germ line where they disrupt the rapidly expanding germ cell membranes, leading to germ cell death.

Association of plasma omega-3 and omega-6 lipids with burden of disease measures in bipolar subjects

Omega-3 (n-3) fatty acids have been implicated in mood disorders, yet clinical trials supplementing n-3 fats have shown mixed results. However, the predominant focus of this research has been on the n-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). We used an unbiased approach to assay plasma n-3 and omega-6 (n-6) species that interact at the level of biosynthesis and down-stream processing, to affect brain function and, potentially, mood. We used lipomic technology to assay plasma levels of n-3 and n-6 fatty acids from 40 bipolar and 18 control subjects to investigate differences in plasma levels and associations with the burden of disease markers, neuroticism and global assessment of function (GAF) and mood state (Hamilton Depression Scale (HAM-D)). Most significantly, we found the levels of dihomo-gamma-linolenic acid (DGLA) to positively correlate with neuroticism and HAM-D scores and negatively correlate with GAF scores; and HAM-D to negatively correlate with linoleic acid (LA) and positively correlate with fatty acid desaturase 2 (FADS2) activity, an enzyme responsible for converting LA to gamma-linolenic acid (GLA). These associations remained significant following Bonferroni multiple testing correction. These data suggest that specific n-6 fatty acids and the enzymes that control their biosynthesis may be useful biomarkers in measurements of depressive disorders and burden of disease, and that they should be considered when investigating the roles of n-3s.

Effect Of Epa Ethyl Ester On Fatty Acid Profile In Hemodialysis Patients With Low Epa/Aa Ratio

Large amounts of n-3 polyunsaturated fatty acids are known to lower the risk of cardiovascular events (CVE). Serum eicosapentaenoic acid (EPA) / arachidonic acid (AA) ratio may potentially be a predictor of CVE which is the most common cause of death in hemodialysis (HD) patients. Therefore, we estimated the effect of EPA ethyl ester on fatty acid profile in HD patients. Fatty acid profile and high sensitivity CRP (hs-CRP) were measured in 131 patients receiving maintenance HD. Among these, 64 patients (F:M=25:39) with both low EPA/AA ratio (≦0.4) and negative CRP were enrolled in this randomized study (Group A, EPA administrated group, n=30; Group B, EPA non-administrated group, n=34). The mean age of the patients was 66.5 ± 11.9 years old and the duration of HD was 8.4 ± 7.9 years. The serum levels of EPA, AA, docosahexaenoic acid (DHA), and dihomogammalinolenic acid (DHL-A) were measured by gas chromatography (SRL, Tokyo, Japan). The mean levels of EPA/AA ratio, DHA/AA ratio, DHL-A, non HDL-C and GNRI (Geriatric Nutritional Risk Index) were 0.28±0.13, 0.62±0.15, 22.7±8.4 μg/ml, 112.2±31.0 mg/dl and 93.6±5.5, respectively. After one month of treatment with EPA in group A, EPA/AA ratio was significantly increased (0.30±0.15 vs. 0.95±0.45, p<0.0001) and DHL-A significantly decreased (22.7±7.4 vs. 15.7±6.8, p= 0.0003), but DHA/AA ratio, serum non HDL-C and phosphate levels did not change. EPA/AA ratio was significantly higher and DHL-A lower in group A compared with group B after one month of the start of study. Medication of EPA for one month increases EPA/AA ratio, and decreases DHL-A level without the change of serum phosphate level in HD patients with low EPA/AA ratio.

Association of Changes in Body Fatness and Fatty Acid Composition of Plasma Phospholipids During Early Puberty in Japanese Children

Plasma fatty acid composition can change with age, reflecting diet and levels of desaturating enzymes such as stearoyl-CoA desaturase (SCD), delta-6 desaturase (D6D) and delta-5 desaturase (D5D), which contribute to the development of insulin resistance. This study analyzed longitudinal changes in fatty acid composition in Japanese children during early puberty and the association between changes in desaturase indices and changes in body fatness and insulin resistance. The study included 77 children (38 boys and 39 girls) aged 9.6±0.5 years. Relative weight (RW) and waist-to-height ratio (WHtR) were determined. The fatty acid composition of plasma phospholipids was analyzed by gas chromatography, and the desaturase indices were calculated: SCD (16:1n-7/16:0: SCD16 and 18:1n-9/18:0: SCD18), D6D (20:3n-6/18:2n-6) and D5D (20:4n-6/20:3n-6) in 2006 and 2009. Obese children showed higher dihomo-gamma linolenic acid (DGLA; 20:3n-6), a higher D6D index and lower D5D index than non-obese children. Longitudinal changes in fatty acid com-position were generally similar in both sexes. Increased D6D index and DGLA and decreased D5D index were significantly associated with increased WHtR in boys and girls. In addition, increased D6D index was associated with an increased homeostasis model of assessment ratio (HOMA-R) only in girls. The change in abdominal adiposity is a determinant of longitudinal changes in D6D and D5D indices and DGLA during early puberty.

İskenderun Körfezi (Kuzeydoğu Akdeniz) Kıyısalında Dağılım Gösteren Bazı Kahverengi ve Kırmızı Makroalg Türlerinin Protein, Lipit ve Yağ Asiti İçerikleri

Five seaweed species belonging to Phaeophyta and Rhodophyta were analyzed to determine the proximate composition and fatty acid profiles. Seaweeds were collected from ?skenderun Bay, the northeastern Mediterranean coast of Turkey. The Brown seaweeds (Sargassum acina-rum, Halopteris scoparia, Taonia atomaria, Dictyota dichotoma) and only one red seaweed (Liagora sp.) were used for the analysis. The highest protein content was obtained for D. di-chotoma (15.41 % dry wt) followed by T.atomaria (12.57 % dry wt). Lipid contents of sea-weeds ranged from 12.7 % for D. dichotoma to 0.02 % dry weight for H. scoparia. The ash contents of all algae species were found to be in the range of 15.15% and 63.55 % on a dry we-ight basis. The fatty acid compositions of seaweed species were in the range of 18.51-63.96 % saturated (SFA), 15.25-23.02 % monounsaturated (MUFAs) and 14.62-29.04 % polyunsatu-rated fatty acids (PUFAs). The highest dihomogammalinolenic acid (C20:3 n6, DGLA) content (.76) were determined in the brown seaweed, S. acinarum.

Maternal α-linolenic acid availability during gestation and lactation alters the postnatal hippocampal development in the mouse offspring

The availability of ω-3 polyunsaturated fatty acids is essential for perinatal brain development. While the roles of docosahexaenoic acid (the most abundant ω-3 species) were extensively described, less is known about the role of α-linolenic acid (ALA), which is the initial molecular species undergoing elongation and desaturation within the ω-3 pathways. This study describes the association between maternal ALA availability during gestation and lactation, and alterations in hippocampal development (dentate gyrus) in the mouse male offspring, at the end of lactation (postnatal day 19, P19). Postnatal ALA supplementation increased cell proliferation (36% more proliferating cells compared to a control group) and early neuronal differentiation, while postnatal ALA deficiency increased cellular apoptosis within the dentate gyrus of suckling pups (61% more apoptotic cells compared to a control group). However, maternal ALA deficiency during gestation prevented the increased neurogenesis induced by postnatal supplementation. Fatty acid analysis revealed that ALA supplementation increased the concentration of the ω-3 species in the maternal liver and serum, but not in the brain of the offspring, excepting for ALA itself. Interestingly, ALA supplementation also increased the concentration of dihomo γ-linolenic acid (a ω-6 species) in the P19 brains, but not in maternal livers or serum. In conclusion, postnatal ALA supplementation enhances neurogenesis in the dentate gyrus of the offspring at postnatal day 19, but its beneficial effects are offset by maternal ALA deficiency during gestation. These results suggest that ALA is required in both fetal and postnatal stages of brain development.

Effect of maternal corticosterone on utilisation of residual yolk sac fatty acids by developing broiler embryo

1. Increased concentrations of maternal corticosterone are deposited into egg yolk under stress conditions. This experiment investigated the effect of maternal corticosterone on yolk and yolk sac fatty acid profiles of eggs and developing broiler embryos. 2. At 42 weeks of age, 200 broiler breeder females were randomly divided into two groups: maternal corticosterone (MC): 2 mg/hen/d of corticosterone dissolved in 1 mL of 99% ethanol and mixed in the individual daily feed for a 14 d period, and control: 1 mL of ethanol added to the individual daily feed. Hens were inseminated, and eggs were collected daily from d 3 of corticosterone feeding to d 14 and incubated. Fatty acid profiles of egg yolk and yolk sac were analysed before incubation and at 12, 14, 18 and 21 d of incubation. 3. Yolk corticosterone concentrations were greater in MC eggs. Before incubation, eggs from MC had lower DHA (22 : 6 n-3) but higher stearic (18 : 0) and dihomo-gamma linolenic (20 : 3 n-6 Cis 8,11,14) acid content compared with the control. 4. Higher concentrations of stearic (18 : 0), elaidic (18 : 1 tr n-9), eicosenoic (20 : 1 n-9), eicosadienoic (20 : 2 n-6), dihomo-gamma linoleic (20 : 3 n-6) and arachidonic (20 : 4 n-6) acids and lower concentrations of myristic (14 : 0), palmitoleic (16 : 1 n-7), linoleic (18 : 2 n-6) and DHA (22 : 6 n-3) were found at different periods of incubation in the residual yolk sac of MC than from controls. 5. The results suggest that the preferentially selective absorption of fatty acids is related to specific tissue requirements.

Insulin induces fatty acid desaturase expression in human monocytes

Increasing evidence suggests that fatty acid desaturases, rate-limiting enzymes in unsaturated fatty acid biosynthesis, are important factors in the pathogenesis of lipid-induced insulin resistance. The conversion of dihomogamma linolenic acid (DGLA) into arachidonic acid (AA) in human plasma phospholipids has been shown to be regulated by insulin, suggesting a role for insulin in fatty acid desaturase 1 regulation. However insulin's role in monocyte inflammation associated with obesity and lifestyle disease development is uncertain. We therefore investigated if insulin is able to induce expression of stearoyl-CoA desaturase (SCD, Δ9 desaturase), fatty acid desaturase 1 (FADS1, Δ5 desaturase), and fatty acid desaturase 2 (FADS2, Δ6 desaturase), as well as the sterol regulatory element binding transcription factor 1-c (SREBP-1c) in monocytes. Here, for the first time, we demonstrate that THP-1 monocytes are insulin-responsive in inducing expression of SCD, FADS1, and FADS2 in a time- and dose-dependent manner. Understanding secondary consequences of postprandial hyperinsulinemia may open up new strategies for prevention and/or treatment of obesity-related metabolic complications.

The impact of FADS genetic variants on ω6 polyunsaturated fatty acid metabolism in African Americans

BackgroundArachidonic acid (AA) is a long-chain omega-6 polyunsaturated fatty acid (PUFA) synthesized from the precursor dihomo-gamma-linolenic acid (DGLA) that plays a vital role in immunity and inflammation. Variants in the Fatty Acid Desaturase (FADS) family of genes on chromosome 11q have been shown to play a role in PUFA metabolism in populations of European and Asian ancestry; no work has been done in populations of African ancestry to date.ResultsIn this study, we report that African Americans have significantly higher circulating levels of plasma AA (p = 1.35 × 10-48) and lower DGLA levels (p = 9.80 × 10-11) than European Americans. Tests for association in N = 329 individuals across 80 nucleotide polymorphisms (SNPs) in the Fatty Acid Desaturase (FADS) locus revealed significant association with AA, DGLA and the AA/DGLA ratio, a measure of enzymatic efficiency, in both racial groups (peak signal p = 2.85 × 10-16 in African Americans, 2.68 × 10-23 in European Americans). Ancestry-related differences were observed at an upstream marker previously associated with AA levels (rs174537), wherein, 79-82% of African Americans carry two copies of the G allele compared to only 42-45% of European Americans. Importantly, the allelic effect of the G allele, which is associated with enhanced conversion of DGLA to AA, on enzymatic efficiency was similar in both groups.ConclusionsWe conclude that the impact of FADS genetic variants on PUFA metabolism, specifically AA levels, is likely more pronounced in African Americans due to the larger proportion of individuals carrying the genotype associated with increased FADS1 enzymatic conversion of DGLA to AA.

Effect of polyunsaturated fatty acids on drug-sensitive and resistant tumor cells in vitro

Previous studies showed that γ-linolenic acid (GLA, 18: 3 ω-6), arachidonic acid (AA, 20:4 ω -6), eicosapentaenoic acid (EPA, 20: 5 ω -3) and docosahexaenoic acid (DHA, 22:6 ω -3) have selective tumoricidal action. In the present study, it was observed that dihomo-gamma-linolenic acid (DGLA) and AA, EPA and DHA have cytotoxic action on both vincristine-sensitive (KB-3-1) and resistant (KB-ChR-8-5) cancer cells in vitro that appeared to be a free-radical dependent process but not due to the formation of prostaglandins, leukotrienes and thromboxanes. Uptake of vincristine and fatty acids was higher while their efflux was lower in KB-3-1 cells compared with KB-ChR-8-5 cells, suggesting that drug resistant cells have an effective efflux pump. GLA, DGLA, AA, EPA and DHA enhanced the uptake and decreased efflux in both drug-sensitive and drug-resistant cells and augmented the susceptibility of tumor cells especially, of drug-resistant cells to the cytotoxic action of vincristine. These results suggest that certain polyunsaturated fatty acids have tumoricidal action and are capable of enhancing the cytotoxic action of anti-cancer drugs specifically, on drug-resistant cells by enhancing drug uptake and reducing its efflux. Thus, polyunsaturated fatty acids either by themselves or in combination with chemotherapeutic drugs have the potential as anti-cancer molecules.

Coxibs strike back

Coxibs strike back

FADS genetic variants and ω-6 polyunsaturated fatty acid metabolism in a homogeneous island population

Long-chain polyunsaturated fatty acids (PUFA) orchestrate immunity and inflammation through their capacity to be converted to potent inflammatory mediators. We assessed associations of FADS gene cluster polymorphisms and fasting serum PUFA concentrations in a fully ascertained, geographically isolated founder population of European descent. Concentrations of 22 PUFAs were determined by gas chromatography, of which ten fatty acids and five ratios defining FADS1 and FADS2 activity were tested for genetic association against 16 single nucleotide polymorphisms (SNP) in 224 individuals. A cluster of SNPs in tight linkage disequilibrium in the FADS1 gene (rs174537, rs174545, rs174546, rs174553, rs174556, rs174561, rs174568, and rs99780) were strongly associated with arachidonic acid (AA) (P = 5.8 x 10(-7) - 1.7 x 10(-8)) among other PUFAs, but the strongest associations were with the ratio measuring FADS1 activity in the omega-6 series (P = 2.11 x 10(-13) - 1.8 x 10(-20)). The minor allele across all SNPs was consistently associated with decreased omega-6 PUFAs, with the exception of dihomo-gamma-linoleic acid (DHGLA), where the minor allele was consistently associated with increased levels. Our findings in a geographically isolated population with a homogenous dietary environment suggest that variants in the Delta-5 desaturase enzymatic step likely regulate the efficiency of conversion of medium-chain PUFAs to potentially inflammatory PUFAs, such as AA.

Zinc and Fatty Acids in Depression

Polyunsaturated Fatty acids (PUFAs) seem to be helpful in the therapy of depression. Zinc (Zn) may be one co-factor contributing to their antidepressive effect. Zn acts lipid protective and is a constituent of fatty acid metabolism enzymes. In animals, an antidepressive effect of Zn was already demonstrated. Therefore, if and how Zn and PUFAs correlate in depressive patients or in individuals from the general population was investigated. Blood samples were collected from 88 depressive in-patients and 88 volunteers from the general population matched for age-group and gender (each 32 men and 56 women, 21-70 years) for measurement of Zn (colorimetric) and of 12 fatty acids (FAs) (by capillary gas-chromatography). Severity of depression in patients was assessed by Beck Depression Inventory (BDI) and Hamilton Depression Rating Scale (HDRS). Zn concentration was independent of age, gender and body-mass-index and significantly correlated with the severity of depression measured by BDI (r = 0.26; P = 0.034) in depressive patients,. HDRS was inversely correlated with gammalinolenic acid concentration (r = -0.24; P = 0.029). Median serum Zn concentration in depressive patients did not differ from control individuals. Zn was correlated with myristic acid concentration (r = 0.22; P < 0.05) in controls from the general population; and a negative correlation between Zn and dihomogammalinolenic acid concentration (r = -0.26; P < 0.05) was found in depressive inpatients. FA composition in serum significantly differed between depressive and healthy persons: Depressive patients had higher stearic and arachidonic acid (AA) concentration. Relative to AA, their eicosapentaenoic and docosapentaenoic acid concentration were diminished compared to the general populations group. These results do not confirm the hypothesis of a general lack of Zn in depressive disorders, but Zn concentrations differed dependent on comorbid disorders and severity of depression. In depressive patients and control persons Zn concentration is associated with different FAs indicating diverging metabolic pathways.

Polyunsaturated Fatty Acid Levels of Serum and Red Blood Cells in Apparently Healthy Japanese Subjects Living in an Urban Area

We assessed levels of polyunsaturated fatty acid (PUFA) in serum and red blood cells (RBCs) among groups stratified by generation and its clinical significance in Japanese subjects living in an urban area. We enrolled 200 apparently healthy Japanese (126 males, mean age: 50.3+/-9.2 years) living in an urban area. Levels of PUFA, including eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), arachidonic acid (AA), and dihomo-gamma-linolenic acid (DGLA) in serum and RBCs were measured for each generation (G1 <35y, G2 35y-<45y, G3 45y-<55y, G4 55y-<65y, G5>or=65y). No significant differences in EPA, DHA, AA, or EPA/AA were observed between males and females. After dividing into generations, stepwise increases in EPA and DHA, but not DGLA or AA, were observed in serum (all p<0.0001). EPA/AA ratios were stepwisely increased in serum (mean: G1:0.26, G2:0.29, G3:0.43, G4:0.58, G5:0.68, p<0.0001) and RBCs (mean: G1:0.10, G2:0.09, G3:0.15, G4:0.20, G5:0.23, p<0.0001). Positive correlations of EPA (r=0.83), DHA (r=0.55), DGLA (r=0.54), AA (r=0.29), and EPA/AA (r=0.91) were demonstrated between serum and RBCs. In addition, a significant positive correlation between EPA/AA ratios and insulin sensitivity as well as a negative correlation between those ratios and insulin resistance were observed in subjects with metabolic syndrome. Low levels of EPA/AA, which were associated with insulin resistance, were demonstrated in young Japanese adults living in an urban area.

Differential effect of maternal diet supplementation with α-Linolenic adcid or n-3 long-chain polyunsaturated fatty acids on glial cell phosphatidylethanolamine and phosphatidylserine fatty acid profile in neonate rat brains

BackgroundDietary long-chain polyunsaturated fatty acids (LC-PUFA) are of crucial importance for the development of neural tissues. The aim of this study was to evaluate the impact of a dietary supplementation in n-3 fatty acids in female rats during gestation and lactation on fatty acid pattern in brain glial cells phosphatidylethanolamine (PE) and phosphatidylserine (PS) in the neonates.MethodsSprague-Dawley rats were fed during the whole gestation and lactation period with a diet containing either docosahexaenoic acid (DHA, 0.55%) and eicosapentaenoic acid (EPA, 0.75% of total fatty acids) or α-linolenic acid (ALA, 2.90%). At two weeks of age, gastric content and brain glial cell PE and PS of rat neonates were analyzed for their fatty acid and dimethylacetal (DMA) profile. Data were analyzed by bivariate and multivariate statistics.ResultsIn the neonates from the group fed with n-3 LC-PUFA, the DHA level in gastric content (+65%, P < 0.0001) and brain glial cell PE (+18%, P = 0.0001) and PS (+15%, P = 0.0009) were significantly increased compared to the ALA group. The filtered correlation analysis (P < 0.05) underlined that levels of dihomo-γ-linolenic acid (DGLA), DHA and n-3 docosapentaenoic acid (DPA) were negatively correlated with arachidonic acid (ARA) and n-6 DPA in PE of brain glial cells. No significant correlation between n-3 and n-6 LC-PUFA were found in the PS dataset. DMA level in PE was negatively correlated with n-6 DPA. DMA were found to occur in brain glial cell PS fraction; in this class DMA level was correlated negatively with DHA and positively with ARA.ConclusionThe present study confirms that early supplementation of maternal diet with n-3 fatty acids supplied as LC-PUFA is more efficient in increasing n-3 in brain glial cell PE and PS in the neonate than ALA. Negative correlation between n-6 DPA, a conventional marker of DHA deficiency, and DMA in PE suggests n-6 DPA that potentially be considered as a marker of tissue ethanolamine plasmalogen status. The combination of multivariate and bivariate statistics allowed to underline that the accretion pattern of n-3 LC-PUFA in PE and PS differ.

Engineering of a novel hybrid enzyme: an anti-inflammatory drug target with triple catalytic activities directly converting arachidonic acid into the inflammatory prostaglandin E2

Cyclooxygenase isoform-2 (COX-2) and microsomal prostaglandin E(2) synthase-1 (mPGES-1) are inducible enzymes that become up-regulated in inflammation and some cancers. It has been demonstrated that their coupling reaction of converting arachidonic acid (AA) into prostaglandin (PG) E(2) (PGE(2)) is responsible for inflammation and cancers. Understanding their coupling reactions at the molecular and cellular levels is a key step toward uncovering the pathological processes in inflammation. In this paper, we describe a structure-based enzyme engineering which produced a novel hybrid enzyme that mimics the coupling reactions of the inducible COX-2 and mPGES-1 in the native ER membrane. Based on the hypothesized membrane topologies and structures, the C-terminus of COX-2 was linked to the N-terminus of mPGES-1 through a transmembrane linker to form a hybrid enzyme, COX-2-10aa-mPGES-1. The engineered hybrid enzyme expressed in HEK293 cells exhibited strong triple-catalytic functions in the continuous conversion of AA into PGG(2) (catalytic-step 1), PGH(2) (catalytic-step 2) and PGE(2) (catalytic-step 3), a pro-inflammatory mediator. In addition, the hybrid enzyme was also able to directly convert dihomo-gamma-linolenic acid (DGLA) into PGG(1), PGH(1) and then PGE(1) (an anti-inflammatory mediator). The hybrid enzyme retained similar K(d) and V(max) values to that of the parent enzymes, suggesting that the configuration between COX-2 and mPGES-1 (through the transmembrane domain) could mimic the native conformation and membrane topologies of COX-2 and mPGES-1 in the cells. The results indicated that the quick coupling reaction between the native COX-2 and mPGES-1 (in converting AA into PGE(2)) occurred in a way so that both enzymes are localized near each other in a face-to-face orientation, where the COX-2 C-terminus faces the mPGES-1 N-terminus in the ER membrane. The COX-2-10aa-mPGES-1 hybrid enzyme engineering may be a novel approach in creating inflammation cell and animal models, which are particularly valuable targets for the next generation of NSAID screening.