Plasma Arachidonic Acid Levels Research Articles

Gender-related and PUFA-related differences in lipoprotein-associated phospholipase A2 levels in patients with type 2 diabetes and atherosclerotic cardiovascular disease.

Lipoprotein-associated phospholipase A2 (Lp-PLA2) may play an important role in the development of atherosclerotic cardiovascular disease (ASCVD). Increased plasma levels of Lp-PLA2 may predict future cardiovascular (CV) events in type 2 diabetes (T2D). The potential beneficial effects of polyunsaturated fatty acids (PUFA) on ASCVD have been widely investigated. However, the impact of different PUFA concentrations on Lp-PLA2 remains uncertain. We sought to determine the intergender differences in a population of patients with both T2D and ASCVD regarding Lp-PLA2 mass and the association between Lp-PLA2 mass and plasma levels of PUFA. In this cross-sectional study, we measured the Lp-PLA2 mass, PUFA concentrations and inflammatory markers in 74 patients (49 males and 25 females) with T2D and ASCVD. In this very high-risk population, males had, on average, 33.6% higher levels of Lp-PLA2 than females. The Lp-PLA2 mass was positively associated with interleukin 6 (IL-6) (r = 0.27, p = 0.019), creatinine (r = 0.29, p = 0.03) and triglyceride levels (r = 0.41, p = 0.002). Additionally, male gender and higher levels of triglycerides, leptin, oxidized low-density lipoprotein (oxLDL), and intercellular adhesion molecule 1 (ICAM-1) were independent predictors for an increased Lp-PLA2. Moreover, arachidonic acid (AA) negatively correlated with Lp-PLA2 (r = -0.26, p = 0.024), which was especially apparent in the female subgroup. In the population of patients with ASCVD and T2D, males present with higher plasma levels of Lp-PLA2 than females. Additionally, higher plasma levels of AA were associated with lower Lp-PLA2 levels. Our findings support the utilization of Lp-PLA2 as a novel biomarker in ASCVD risk assessment in a very high CV risk population.

Protective role of arachidonic acid against diabetic myocardial ischemic injury: a translational study of pigs, rats, and humans

AimPatients with diabetes mellitus have poor prognosis after myocardial ischemic injury. However, the mechanism is unclear and there are no related therapies. We aimed to identify regulators of diabetic myocardial ischemic injury.Methods and resultsMass spectrometry-based, non-targeted metabolomic approach was used to profile coronary sinus blood from diabetic and non-diabetic Bama-mini pigs at 0.5-h post coronary artery ligation. Six metabolites had a |log2 (Fold Change)|> 1.3. Among them, the most changed is arachidonic acid (AA), levels of which were 32 times lower in diabetic pigs than in non-diabetic pigs. The AA-derived products, PGI2 and 6-keto-PGF1α, were also significantly reduced. AA treatment of cultured cardiomyocytes protected against cell death by 30% at 48 h of high glucose and oxygen deprivation, which coincided with increased mitophagic activity (as indicated by increased LC3II/LC3I, decreased p62 and increased parkin & PINK1), improved mitochondrial renewal (upregulation of Drp1 and FIS1), reduced ROS generation and increased ATP production. These cardioprotective effects were abolished by PINK1(a crucial mitophagy protein) knockdown or the autophagy inhibitor 3-Methyladenine. The protective effect of AA was also inhibited by indomethacin and Cay10441, a prostacyclin receptor antagonist. Furthermore, diabetic Sprague Dawley rats were subjected to coronary ligation for 40 min and AA treatment (10 mg/day per animal gavaged) decreased myocardial infarct size, cell apoptosis index, inflammatory cytokines and improved heart function. Scanning electron microscopy showed more intact mitochondria in the border zone of infarcted myocardium in AA treated rats. Lastly, diabetic patients after myocardial infarction had lower plasma levels of AA and 6-keto-PGF1α and reduced cardiac ejection fraction, compared with non-diabetic patients after myocardial infarction. Plasma AA level was inversely correlated with fasting blood glucose.ConclusionsAA protects against diabetic ischemic myocardial damage by promoting mitochondrial autophagy and renewal, which is related to AA derived PGI2 signaling. AA may represent a new strategy to treat diabetic myocardial ischemic injury.

Essential Fatty Acid Associated with Heart Rate Variability in Highly Trained Male Cross-Country Skiers: A Pilot Study

Polyunsaturated fatty acid (PUFA) metabolites play important roles in the modulation of vascular tone, heart rate variability (HRV), and cardiovascular diseases. This study was undertaken to examine the relationship between HRV and the plasma levels of essential acids. Methods: Highly trained cross-country skiers participated in the study (n = 19). Time-domain and frequency-domain HRV analyses were performed. The plasma levels of fatty acids were determined using gas–liquid chromatography. Results: Plasma eicosapentaenoic acid and docosahexaenoic acid were found to be negatively correlated with resting heart rate (HR) (p = 0.026). The plasma levels of alpha-linolenic acid (ALA) were positively associated with the relative value of high-frequency power (rs = 0.465, p = 0.045) and negatively correlated with the sympathovagal balance ratio (rs = −0.493, p = 0.032) and the absolute and relative values of low-frequency power (rs = −0.490, p = 0.028). The plasma levels of arachidonic acid (ARA) were positively associated with the relative value of high-frequency power (rs = 0.59, p = 0.006) and negatively correlated with the sympathovagal balance ratio (rs = −0.54, p = 0.017) and the relative values of low-frequency power (rs = −0.52, p = 0.022). No correlation was found between n6/n3 and HRV parameters except for HR and pNN50. Conclusions: n-3 PUFAs and ARA play an important role in the autonomic regulation of heart rate in highly trained skiers. Athletes with substantial deficiencies in plasma ALA and excess levels of ARA had increased sympathetic and decreased parasympathetic activity.

Impact of FADS gene variation and dietary fatty acid exposure on biochemical and anthropomorphic phenotypes in a Hispanic/Latino cohort.

Polyunsaturated fatty acids (PUFA) and highly unsaturated fatty acid (HUFA) synthetic products and their signaling metabolites play vital roles in immunity, inflammation, and brain development/function. Frequency differences of variants within the fatty acid desaturase (FADS) gene cluster affect levels of HUFAs, their biologically active products, and numerous physiological phenotypes. Fundamental questions remain regarding the impact of this genetic variation on the health of Hispanic/Latino populations. Data and biospecimens (plasma, red blood cells, buffy coat-derived DNA) from 135 participants (83.7% female) were used to assess the relationship(s) between dietary PUFA levels, a FADS haplotype tagging SNP, rs174537, and the capacity of Hispanic/Latino populations to generate HUFAs in plasma and RBC as well as its potential impact on anthropomorphic phenotypes. The dietary habits of the cohort showed that participant diets contained a high ratio (9.3 ± 0.2, mean ± SEM) of linoleic acid (n-6) to alpha-linolenic acid (n-3) and also contained extremely low levels of n-3 HUFAs (eicosapentaenoic acid, EPA and docosahexaenoic acid, DHA), both features of the Modern Western Diet. Compared to African and European American cohorts, the frequency of the TT rs174537 genotype was highly enriched (53% of subjects) in this Hispanic/Latino cohort and was strongly associated with lower circulating HUFA levels. For example, plasma levels of arachidonic acid (ARA: 20:4, n-6) and EPA (20:5, n-3) were 37% and 23%, respectively, lower in the TT versus the GG genotype. HUFA biosynthetic efficiency, as determined by metabolic product to precursor ratios, was highly dependent (p < 0.0001) on the rs174537 genotype (GG > GT > TT) for both circulating n-6 and n-3 HUFAs. In contrast, the RBC Omega-3 Index (EPA + DHA) was extremely low (2.89 ± 1.65, mean ± sd) in this population and independent of rs174537 genotype. Importantly, the rs174537 genotype was also related to female height with TT genotype participants being 4.5 cm shorter (p = 0.0001) than the GG + GT participants. Taken together, this study illustrates that dietary PUFA + HUFA × FADS gene- interactions place a large proportion (>50%) of Hispanic/Latino populations at high risk of a deficiency in both circulating and cellular levels of n-3 HUFAs.

N-Acetylcysteine Decreases Myocardial Content of Inflammatory Mediators Preventing the Development of Inflammation State and Oxidative Stress in Rats Subjected to a High-Fat Diet.

Arachidonic acid (AA) is a key precursor for proinflammatory and anti-inflammatory derivatives that regulate the inflammatory response. The modulation of AA metabolism is a target for searching a therapeutic agent with potent anti-inflammatory action in cardiovascular disorders. Therefore, our study aims to determine the potential preventive impact of N-acetylcysteine (NAC) supplementation on myocardial inflammation and the occurrence of oxidative stress in obesity induced by high-fat feeding. The experiment was conducted for eight weeks on male Wistar rats fed a standard chow or a high-fat diet (HFD) with intragastric NAC supplementation. The Gas-Liquid Chromatography (GLC) method was used to quantify the plasma and myocardial AA levels in the selected lipid fraction. The expression of proteins included in the inflammation pathway was measured by the Western blot technique. The concentrations of arachidonic acid derivatives, cytokines and chemokines, and oxidative stress parameters were determined by the ELISA, colorimetric, and multiplex immunoassay kits. We established that in the left ventricle tissue NAC reduced AA concentration, especially in the phospholipid fraction. NAC administration ameliorated the COX-2 and 5-LOX expression, leading to a decrease in the PGE2 and LTC4 contents, respectively, and augmented the 12/15-LOX expression, increasing the LXA4 content. In obese rats, NAC ameliorated NF-κB expression, inhibiting the secretion of proinflammatory cytokines. NAC also affected the antioxidant levels in HFD rats through an increase in GSH and CAT contents with a simultaneous decrease in the levels of 4-HNE and MDA. We concluded that NAC treatment weakens the NF-κB signaling pathway, limiting the development of myocardial low-grade inflammation, and increasing the antioxidant content that may protect against the development of oxidative stress in rats with obesity induced by an HFD.

Effects of omega-3 supplementation on components of the endocannabinoid system and metabolic and inflammatory responses in adipose and liver of peripartum dairy cows

BackgroundDietary supplementation of omega-3 fatty acids can reduce the activation of the endocannabinoid system (ECS) by decreasing the availability of arachidonic acid, thus lowering endocannabinoids (eCBs) levels. The ECS is a modulator of energy metabolism, stress response and inflammation in mammals, yet there is little information on the roles of the ECS in transition dairy cows. During the periparturient period, the adipose tissue and liver are the main metabolic organs that participate in the adaptations of dairy cows to onset of lactation; however, exceeded adipose tissue lipolysis and accumulation of lipids in the liver have adverse effects on cows’ physiology. Here we aimed to examine whether omega-3 supplementation during the transition period will modulate ECS activation and affect metabolic and inflammatory indices in postpartum dairy cows, by supplementing twenty-eight transition Holstein dairy cows with either saturated fat (CTL) or encapsulated flaxseed oil (FLX). Components of the ECS, metabolic and inflammatory markers were measured in blood, liver, and subcutaneous adipose tissue.ResultsFLX supplementation reduced feed intake by 8.1% (P < 0.01) and reduced plasma levels of arachidonic acid (by 44.2%; P = 0.02) and anandamide (by 49.7%; P = 0.03) postpartum compared to CTL. The mRNA transcription levels of the cannabinoid receptor 1 (CNR1/CB1) tended to be lower (2.5 folds) in white blood cells of FLX than in CTL (P = 0.10), and protein abundance of ECS enzyme monoacylglycerol lipase was higher in peripheral blood mononuclear cells of FLX than in CTL (P = 0.04). In adipose tissue, palmitoylethanolamide levels were lower in FLX than in CTL (by 61.5%; P = 0.02), relative mRNA transcription of lipogenic genes were higher, and the protein abundance of cannabinoid receptor 2 (P = 0.08) and monoacylglycerol lipase (P = 0.10) tended to be higher in FLX compared to CTL. Hepatic 2-arachidonoylglycerol tended to be higher (by 73.1%; P = 0.07), and interlukin-6 mRNA transcription level was 1.5 folds lower in liver of FLX than in CTL (P = 0.03).ConclusionsNutritional supplementation of omega-3 fatty acids seems to partly modulate ECS activation, which could be related to lower feed intake. The altered ECS components in blood, adipose tissue and liver are associated with moderate modulations in lipid metabolism in the adipose and inflammation in liver of peripartum dairy cows.

Effect of Metabolite Levels on Type 2 Diabetes Mellitus and Glycemic Traits: A Mendelian Randomization Study.

To assess the causal associations of plasma levels of metabolites with type 2 diabetes mellitus (T2DM) and glycemic traits. Two-sample mendelian randomization (MR) was conducted to assess the causal associations. Genetic variants strongly associated with metabolites at genome-wide significance level (P < 5 × 10-8) were selected from public genome-wide association studies, and single-nucleotide polymorphisms of outcomes were obtained from the Diabetes Genetics Replication and Meta-analysis consortium for T2DM and from the Meta-Analyses of Glucose and Insulin-related Traits Consortium for fasting glucose, insulin, and glycated hemoglobin (HbA1c). The Wald ratio and inverse-variance weighted methods were used for analyses, and MR-Egger was used for sensitivity analysis. The β estimates per 1-SD increase of arachidonic acid (AA) level was 0.16 (95% CI, 0.078-0.242; P < 0.001). Genetic predisposition to higher plasma AA levels were associated with higher fasting glucose levels (β 0.10 [95% CI, 0.064-0.134], P < 0.001), higher HbA1c levels (β 0.04 [95% CI, 0.027-0.061]), and lower fasting insulin levels (β -0.025 [95% CI, -0.047 to -0.002], P = 0.033). Besides, 2-hydroxybutyric acid (2-HBA) might have a positive causal effect on glycemic traits. Our findings suggest that AA and 2-HBA may have causal associations on T2DM and glycemic traits. This is beneficial for clarifying the pathogenesis of T2DM, which would be valuable for early identification and prevention for T2DM.

Induction of Beneficial Changes in Glucose Homeostasis, Lipid Profile, Inflammation, Retinopathy, Bile Acids and Gut Microbiota in Streptozotocin-Induced Type 1 Diabetes Mellitus by Essential Fatty Acids

Background: Essential fatty acids (EFAs) n3 alpha-linolenic acid (ALA) and n6 linoleic acid (LA) have been shown to improve lipid metabolism, promote nervous system development, suppress inflammation, and are of benefit in diabetes mellitus and cancer. But the exact mechanism of their action(s) is not clear. In the present study, we evaluated the effects of ALA and LA on glucose homeostasis, circulating lipid profile, inflammatory markers, gut microbiome, and bile acids in streptozotocin (STZ)-induced type 1 diabetes with retinopathy in rats. We also measured vitreal LXA4 levels in patients with diabetic retinopathy since arachidonic acid (AA), the precursor of LXA4, is derived from LA. Methods: The study was performed in male Sprague Dawley rats. Type 1 DM was induced by intraperitoneal injection of STZ. The type 1 DM animals received LA or ALA 100 ug/day via intraperitoneal route on alternate days till the end of the study (21 days after the DM onset). In these animals, glucose homeostasis and lipid profile were evaluated. Plasma and retinal fatty acid profile by gas chromatography (GC), retinal histology by H&E staining, activities of desaturases in the retina and liver tissues and inflammatory markers by qRT-PCR, and composition of the gut microbiota by 16S rDNA sequencing technology of the fecal samples were performed. In addition, short-chain fatty acids (SCFAs) and bile acids (BAs) in the feces and liver of rats were assayed by GC and liquid chromatography coupled with tandem mass spectrometry (UHPLC–MS/MS), respectively. Human vitreal samples obtained from patients with proliferative diabetic retinopathy (PDR) were analyzed for their fatty acids profile and LXA4 levels and compared with those with macular hole (control). Findings: LA and ALA-treated STZ-induced type 1 DM animals showed significant reduction in their plasma glucose levels, pro-inflammatory cytokines (IL-6 and TNF-α), changes in the composition of gut microbiome in the form of an increase in the abundance of Ruminococcaceae (ALA-treated group), Alloprevotella, Prevotellaceae_Ga6A1_group, Ruminococcaceae_UCG_010 and Ruminococcus_1 (in LA-treated group) , an increase in acetic acid and butyric acid, and an increase in the fecal concentrations of CA, CDCA and TUDCA and a decrease in GCA. Concentrations of hepatic CDCA, TCDCA, and TUDCA were significantly increased in ALA treated animals while CDCA were elevated in those with LA treatment. STZ-treated animals showed significant decrease in plasma LA, GLA, and AA and ALA levels with no significant changes in retinal fatty acid composition. All these changes reverted to normal in LA and ALA treated group. The changes in the plasma fatty acid composition were accompanied by significant alterations in the expression of desaturases, COX-2 and 5-LOX and 12-LOX enzymes and pro- and anti-inflammatory cytokines. In addition, retinal LXA4 levels were found to be decreased in patients with PDR. Interpretation: The results of the present study suggest that ALA and LA administration can improve plasma glucose levels, suppress inflammation, and produce significant beneficial alterations in the gut microbiota, plasma lipid profile and EFAs metabolism. Decrease in retinal LXA4 levels in those with PDR agree with the suggestion that EFAs metabolism is altered in T1DM and DR. These results imply a significant role for EFAs and their metabolites in the pathobiology of type 1 DM and diabetic retinopathy. Funding Information: The project was funded by the National Natural Science Foundation of China (No. 82000886), and Natural Science Foundation of Zhejiang Province (No.LQ20H120011). Declaration of Interests: Authors have no conflicts of interest to declare. Ethics Approval Statement: This study was approved by the animal ethics committee of the Second Affiliated Hospital of Zhejiang University school of medicine. All experimental procedures using animals were performed in accordance with the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research. This study was approved by the Clinical Ethical Research Committee of the Second Affiliated Hospital of Zhejiang University school of medicine. The study was performed as per the tenets of Helsinki declaration. Informed consent obtained from all the participating patients.

Circulating plasma fatty acids and risk of pancreatic cancer: Results from the Golestan Cohort Study

Pancreatic cancer (PC) with a dismal prognosis is considered as a fatal malignancy, attracting the scientists' attention to study its causes and pathogenesis pathways. Given the lack of enough evidence and conflicting findings about the association of PC risk with plasma fatty acids, we aimed to explore the associations of circulating plasma fatty acids with the risk of PC in a cohort study. From about 50,000 subjects participated in this cohort study in 2004-2008, fifty incident cases of PC were recruited and 150 controls matched by age, sex and residence place (urban/rural) were randomly selected. The plasma fatty acids composition was measured by gas chromatography with Flame Ionization Detector (GC-FID) in plasma samples collected at the baseline of cohort study. Multivariable conditional logistic regression was used to estimate OR (with 95% CI) of PC risk associated with plasma levels of fatty acids considering known potential risk factors for PC. Our findings showed that total saturated fatty acids and total industrial trans fats were not associated with the risk of PC; whereas, statistically significant inverse associations were found between high plasma levels of total mono-unsaturated fatty acids (MUFAs), omega-3 and ruminant trans fatty acids with the risk of PC [ORQ1-Q4=0.31 (0.11-0.89), OR Q2-Q1=0.30 (0.10-0.91) and ORQ2-Q1=0.15 (0.04-0.49), respectively]. Omega-6 fatty acids especially high plasma levels of Arachidonic acid was positively associated with the risk of PC [ORQ1-Q3=11.07 (3.50-35.02)]. Except for the plasma circulating whole fats, the levels of different classes of fats may significantly change pancreatic cancer susceptibility. Unsaturated fatty acids including omega-3-PUFA and MUFA are considered as protective biomarkers in PC prevention. On the contrary, omega-6-fatty acids are positively associated with the risk of PC.

Lipoprotein(a) concentration is associated with plasma arachidonic acid in subjects with familial hypercholesterolaemia.

Elevated lipoprotein(a) (Lp(a)) is associated with CVD and is mainly genetically determined. Studies suggest a role of dietary fatty acids (FA) in the regulation of Lp(a); however, no studies have investigated the association between plasma Lp(a) concentration and n-6 FA. We aimed to investigate whether plasma Lp(a) concentration was associated with dietary n-6 FA intake and plasma levels of arachidonic acid (AA) in subjects with familial hypercholesterolaemia (FH). We included FH subjects with (n 68) and without (n 77) elevated Lp(a) defined as ≥75 nmol/l and healthy subjects (n 14). Total FA profile was analysed by GC-flame ionisation detector analysis, and the daily intake of macronutrients (including the sum of n-6 FA: 18 : 2n-6, 20 : 2n-6, 20 : 3n-6 and 20 : 4n-6) were computed from completed FFQ. FH subjects with elevated Lp(a) had higher plasma levels of AA compared with FH subjects without elevated Lp(a) (P = 0·03). Furthermore, both FH subjects with and without elevated Lp(a) had higher plasma levels of AA compared with controls (P < 0·001). The multivariable analyses showed associations between dietary n-6 FA intake and plasma levels of AA (P = 0·02) and between plasma levels of Lp(a) and AA (P = 0·006). Our data suggest a novel link between plasma Lp(a) concentration, dietary n-6 FA and plasma AA concentration, which may explain the small diet-induced increase in Lp(a) levels associated with lifestyle changes. Although the increase may not be clinically relevant, this association may be mechanistically interesting in understanding more of the role and regulation of Lp(a).

430-P: Plasma Delta-5 Desaturase Index Is Associated with Arterial Stiffness in Type 2 Diabetes

Decreased plasma n-3 polyunsaturated fatty acid (PUFA) levels or n-3/n-6 PUFA ratio is well known to be associated with the risk of cardiovascular diseases. The n-6 arachidonic acid (AA) to dihomo-γ-linolenic acid (DGLA) ratio in plasma, an indirect measure of delta-5 desaturase activity (D5D index), has been reported to be associated with insulin resistance, diabetes, and cardiovascular diseases. In this cross-sectional study, we investigated the association between plasma D5D index and arterial stiffness in patients with type 2 diabetes (T2D). This study included 382 patients with T2D and 118 healthy controls. Fasting plasma AA, DGLA, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) levels were measured by capillary gas chromatography. Arterial stiffness was assessed by measuring the heart-femoral pulse wave velocity (PWV). In patients with T2D, plasma AA levels (138.1 vs. 101.8 μg/mL, p&amp;lt;0.001) and plasma D5D index (5.85 vs. 4.49, p&amp;lt;0.001) were higher than the controls, while plasma DGLA levels were comparable to the controls (23.8 vs. 22.3 μg/mL, p=0.073). Patients with T2D had greater PWV than the controls (1141 vs. 935 cm/s, p&amp;lt;0.001). In the total population, the presence of T2D was independently associated with increased D5D index after adjusting for age, sex, and other metabolic parameters (β=0.311, p&amp;lt;0.001). Multivariate analysis in patients with T2D showed that D5D index was an independent determinant of PWV after adjusting for age, sex, (EPA+DHA)/AA ratio, and other cardiovascular risk factors (β=0.108, p=0.009). On the other hand, no significant association was found between D5D index and PWV in the controls. These data indicate that plasma n-6 AA/DGLA ratio, an estimate of D5D activity, is increased in patients with T2D and is associated with increased PWV, independently of classical cardiovascular risk factors and n-3 PUFAs. This study suggests that abnormal n-6 PUFA metabolism plays a role in advanced arterial stiffness in T2D. Disclosure T. Morioka: Research Support; Self; Eli Lilly and Company, Merck &amp; Co., Inc., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Sanofi K.K., Takeda Pharmaceutical Company Limited. Speaker's Bureau; Self; Astellas Pharma Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Merck &amp; Co., Inc., Novo Nordisk Inc., Roche Diagnostics K.K., Sanofi K.K., Sumitomo Dainippon Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. Other Relationship; Self; Ono Pharmaceutical Co., Ltd. M. Emoto: Research Support; Self; Ono Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd. Speaker's Bureau; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Eli Lilly and Company, Kowa Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Taisho Toyama Pharmaceutical CO., Ltd., Takeda Pharmaceutical Company Limited. Y. Kakutani: None. Y. Yamazaki: None. K. Mori: Speaker's Bureau; Self; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical Co., Ltd. S. Fukumoto: Research Support; Self; Astellas Pharma Inc., Chugai Pharmaceutical Co., Ltd., Kowa Pharmaceutical Europe Co. Ltd., Mitsubishi Tanabe Pharma Corporation, Taisho Toyama Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. Speaker's Bureau; Self; Novo Nordisk Inc., Sanofi K.K. A. Shioi: None. T. Shoji: Research Support; Self; Bayer Yakuhin, Ltd., Chugai Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd. Speaker's Bureau; Self; Kissei Pharmaceutical Co., Ltd., Kowa, Kyowa Hakko Kirin Co., Ltd. M. Inaba: None.

Factors associated with plasma n-3 and n-6 polyunsaturated fatty acid levels in Tanzanian infants.

To identify factors associated with plasma polyunsaturated fatty acid (PUFA) levels among 3-month-old Tanzanian infants. Infants (n = 238) and mothers (n = 193) randomly selected from participants in the neonatal vitamin A supplementation randomized controlled trial. A cross-sectional study of maternal-infant pairs at 3 months postpartum. All infant total, n-3, n-6, and individual PUFA levels were correlated with maternal levels. Infant plasma n-3 PUFA levels were higher when maternal n-3 PUFA levels were higher (mean difference in infant % fatty acid per unit increase in maternal levels ± standard error: 0.79 ± 0.08; P < 0.01). Infant plasma docosahexaenoic acid (DHA) levels were positively associated with maternal DHA levels (0.77 ± 0.09; P < 0.01) but were lower for twin births (-0.55 ± 0.27; P = 0.03). Greater birth weight in kilograms (1.00 ± 0.43; P = 0.02) and higher maternal n-6 PUFA levels (0.20 ± 0.07; P < 0.01) were positively associated with higher infant n-6 PUFA levels, whereas maternal mono-unsaturated fatty acid (MUFA) levels (-0.26 ± 0.08; P < 0.01), maternal mid upper arm circumference (MUAC) (-0.22 ± 0.11; P = 0.04), and male sex (-0.99 ± 0.45; P = 0.03) were associated with lower infant plasma n-6 PUFA levels. Infant plasma arachidonic acid (AA) levels were positively associated with maternal plasma AA levels (0.38 ± 0.09; P < 0.01), but inversely associated with twin births (-1.37 ± 0.67; P = 0.04). Greater birth weight and higher maternal plasma PUFA levels at 3 months postpartum were significantly associated with higher infant plasma PUFA levels at 3 months age. Twin births, male sex, and higher maternal MUFA levels were associated with lower infant plasma PUFA levels. Nutrition counseling for optimal intake of PUFA-rich foods, to lactating mothers in resource-limited settings may be beneficial for improved infant health.

Carbohydrate intake attenuates post-exercise plasma levels of cytochrome P450-generated oxylipins.

IntroductionOxylipins are bioactive oxidation products derived from n-6 and n-3 polyunsaturated fatty acids (PUFAs) in the linoleic acid and α-linolenic desaturation pathways.PurposeThis study determined if carbohydrate intake during prolonged and intensive cycling countered post-exercise increases in n-6 and n-3 PUFA-derived oxylipins.MethodsThe research design utilized a randomized, crossover, counterbalanced approach with cyclists (N = 20, overnight fasted state, 7:00 am start) who engaged in four 75-km time trials while ingesting two types of bananas (Cavendish, Mini-yellow), a 6% sugar beverage, and water only. Carbohydrate intake was set at 0.2 g/kg every 15 minutes, and blood samples were collected pre-exercise and 0 h-, 0.75 h-,1.5 h-, 3 h-, 4.5 h-, 21 h-, 45 h-post-exercise. Oxylipins were measured with a targeted liquid chromatography-multiple reaction monitoring mass spectrometric method.ResultsSignificant time effects and substantial fold-increases (immediately post-exercise/pre-exercise) were measured for plasma levels of arachidonic acid (ARA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and 43 of 45 oxylipins. Significant interaction effects (4 trials x 8 time points) were found for plasma ARA (P<0.001) and DHA (P<0.001), but not EPA (P = 0.255), with higher post-exercise values found in the water trial compared to the carbohydrate trials. Significant interaction effects were also measured for 12 of 45 oxylipins. The data supported a strong exercise-induced increase in plasma levels of these oxylipins during the water trial, with carbohydrate ingestion (both bananas types and the sugar beverage) attenuating oxylipin increases, especially those (9 of 12) generated from the cytochrome P-450 (CYP) enzyme system. These trials differences were especially apparent within the first three hours of recovery from the 75-km cycling bout.ConclusionsProlonged and intensive exercise evoked a transient but robust increase in plasma levels of oxylipins, with a significant attenuation effect linked to acute carbohydrate ingestion for 28% of these, especially those generated through the CYP enzyme system.Trial registrationClinicalTrials.gov, U.S. National Institutes of Health, NCT02994628

Omega-3 and -6 fatty acid plasma levels are not associated with liver cirrhosis-associated systemic inflammation.

BackgroundLiver cirrhosis is associated with profound immunodysfunction, i.e. a parallel presence of chronic systemic inflammation and immunosuppression, which can result in acute-on-chronic liver failure (ACLF). Omega-3 fatty acids are precursors of pro-resolving mediators and support the resolution of inflammation.ObjectiveThe aim of this study was to determine plasma levels of omega-3 fatty acids in patients with liver cirrhosis and ACLF.MethodsPatients with liver cirrhosis with and without ACLF were enrolled in a prospective cohort study and analyzed post-hoc for the present sub-study. Clinical data and biomaterials were collected at baseline and at day 7, 28 and after 3 months of follow-up. Plasma concentrations of arachidonic acid (ARA) and docosahexaenoic acid (DHA), which represent key omega-6 and -3 fatty acids, respectively, were quantified and associated with markers of systemic inflammation and severity of liver cirrhosis.ResultsA total of 117 patients were included in the present analyses. Of those, 26 (22.2%), 51 (43.6%) and 40 (34.2%) patients had compensated or decompensated liver cirrhosis, and ACLF. Plasma levels of ARA and DHA were similar in patients with compensated cirrhosis, decompensated cirrhosis, and ACLF. Furthermore, no significant association between plasma ARA or DHA and C-reactive protein or peripheral blood leukocytes were observed (P>0.05).ConclusionIn our study plasma levels of key omega-3 and omega-6 fatty acid are neither associated with the severity of liver cirrhosis nor with liver-cirrhosis-associated systemic inflammation.

Correlation of Various Foods Intakes and Plasma Levels of Omega Fatty Acids in Healthy Japanese Old Men

Background: Trans fatty acids are considered to impair health and some ω fatty acids are protective against atherosclerosis and diabetes mellitus. Trans fatty acids are said to be formed by the partial hydrogenation of vegetable oils. Some amounts are produced in digestive organs of ruminants and present in dairy products or meat. It is important how much these intaken fatty acids influence their plasma levels. Methods: Plasma levels of fatty acids including transforms of healthy old men are measured by gas chromatography and correlations between various foods intakes and plasma levels of trans fatty acids, and ω fatty acids are examined. Results: Intake of fish resulted in increase in plasma levels of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) but intake of meat such as beef, cow and chicken meat did not increase plasma levels of arachidonic acid (AA). Intakes of oils increased plasma levels of dihomo-g-linolenic acid significantly and AA to some extent. Conclusion: Plasma levels of EPA and DHA increased upon intakes of fish in Japanese old men. Oil intake but not meat intake increased DGLA significantly. These results may explain low incidence of cardiovascular diseases in Japanese people compared with American people whose plasma levels of DHA and EPA are lower.

Determinants of Plasma Docosahexaenoic Acid Levels and Their Relationship to Neurological and Cognitive Functions in PKU Patients: A Double Blind Randomized Supplementation Study.

Children with phenylketonuria (PKU) follow a protein restricted diet with negligible amounts of docosahexaenoic acid (DHA). Low DHA intakes might explain subtle neurological deficits in PKU. We studied whether a DHA supply modified plasma DHA and neurological and intellectual functioning in PKU. In a double-blind multicentric trial, 109 PKU patients were randomized to DHA doses from 0 to 7 mg/kg&day for six months. Before and after supplementation, we determined plasma fatty acid concentrations, latencies of visually evoked potentials, fine and gross motor behavior, and IQ. Fatty acid desaturase genotypes were also determined. DHA supplementation increased plasma glycerophospholipid DHA proportional to dose by 0.4% DHA per 1 mg intake/kg bodyweight. Functional outcomes were not associated with DHA status before and after intervention and remained unchanged by supplementation. Genotypes were associated with plasma arachidonic acid levels and, if considered together with the levels of the precursor alpha-linolenic acid, also with DHA. Functional outcomes and supplementation effects were not significantly associated with genotype. DHA intakes up to 7 mg/kg did not improve neurological functions in PKU children. Nervous tissues may be less prone to low DHA levels after infancy, or higher doses might be required to impact neurological functions. In situations of minimal dietary DHA, endogenous synthesis of DHA from alpha-linolenic acid could relevantly contribute to DHA status.

Plasma n-6 Polyunsaturated Fatty Acid Levels and Survival in Renal Transplantation

The major n-6 polyunsaturated fatty acids linoleic acid (LA) and arachidonic acid (AA) play a role in inflammation and glucose metabolism, which could affect patient and renal transplant survival. In this single center cohort study of 1988 Norwegian renal transplant recipients, we assessed associations between plasma levels of LA and AA at baseline, measured by gas chromatography, and patient and graft survival, as well as inflammation and cardiovascular risk markers. During follow-up (median of 9.6years), 595 patients died and 805 renal transplants were lost, either due to recipient death or graft failure. In multivariable survival analysis, we found no associations with mortality for plasma levels of LA (hazard ratios: 0.99, 95% confidence intervals: 0.96-1.01) or AA (hazard ratios: 1.01, 95% confidence intervals: 0.96-1.06). No associations were found for cardiovascular mortality, overall graft loss, or death-censored graft loss. Plasma glucose, proglycemic marker chemerin, and proinflammatory marker growth differentiation factor 15 were inversely associated with plasma LA and positively associated with plasma AA levels in multivariable analysis. We found no associations between plasma levels of LA or AA and patient or graft survival. Plasma levels of LA and proglycemic indices were inversely associated, signaling a possible beneficial effect of LA consumption for prevention of posttransplantation diabetes mellitus.

Effects of dietary arachidonic acid on the reproductive physiology of female Atlantic cod (Gadus morhua L.)

The present study was designed to investigate potential effects of arachidonic acid (ARA) on the reproductive physiology of female Atlantic cod (Gadus morhua L.).Two-year old Atlantic cod of both sexes were equally distributed into eight sea cages after completion of their first spawning in May 2005. Four experimental groups were established and fed diets with different levels of ARA corresponding to 0.5, 1, 2 and 4% of total fatty acid. Ovarian growth and development was documented every month. Fatty acid composition was analysed in ovaries, liver and plasma at the beginning of the experiment, one month prior to spawning, and in spent fish, one month after spawning was completed. Plasma concentrations of estradiol-17β, testosterone and vitellogenin, and ovarian gene transcript levels of steroidogenic acute regulatory protein (star), P450aromatase (cyp19a1a) and 20β-hydroxy steroid dehydrogenase (20bhsd/cbr1) were monitored every month in fish fed the experimental diets and related to oocyte stage. Potential fecundity was calculated based on ovarian samples taken one month before onset of spawning.Ovarian and plasma ARA levels were highly correlated to dietary ARA levels. There was a net accumulation of ARA compared to other essential fatty acids in ovarian tissue that was reflected in a decrease in EPA:ARA ratio. Plasma concentrations of vitellogenin, estradiol-17β and testosterone and key gene transcript levels were affected by dietary ARA and stage of maturation. The results show that ARA has a significant influence on the reproductive physiology of female Atlantic cod.

Down-regulation of a signaling mediator in association with lowered plasma arachidonic acid levels in individuals with autism spectrum disorders

Previous studies have indicated that the altered composition of polyunsaturated fatty acids (PUFAs) might contribute to the pathophysiology of autism spectrum disorder (ASD). We examined the relationship between the plasma fatty acid levels, expressed as μg/ml, and the plasma levels of biomarkers of AA-related signaling mediators, such as ceruloplasmin, transferrin and superoxide dismutase, and assessed the behavioral symptoms of 30 individuals with ASD (mean age, 13.6 ± 4.3 years old) compared with 20 age- and gender-matched normal controls (mean age, 13.2 ± 5.4 years old) using Aberrant Behavior Checklists (ABC). The plasma levels of EPA and the plasma ratios of EPA/AA were significantly higher, while the plasma levels of AA and metabolites, such as 5,8,11,14-eicosatetraenoic acid, adrenic acid, and ceruloplasmin (Cp), were significantly lower in the 30 individuals with ASD compared with the 20 normal controls. The ABC scores were significantly increased in the ASD group compared with those of the control group. Thus, the results of the present study revealed that reduced plasma levels of AA and metabolites in association with high plasma EPA/AA ratios might down-regulate AA-related signaling mediators, such as Cp. Subsequently, reduced plasma Cp levels might reduce the protective capacity for brain damage, resulting in the pathophysiology underlying the behavioral symptoms in individuals with ASD. These findings suggest that reduced plasma AA levels may downregulate Cp.

Plasma arachidonic and docosahexaenoic acids in Tunisian very low birth weight infants: status and association with selected neonatal morbidities.

To study plasma arachidonic acid (AA) and docosahexaenoic acid (DHA) status in Tunisian very low birth weight (VLBW) infants and their association with selected neonatal morbidities. A total of 709 VLBW infants and 339 term infants were included. Plasma fatty acids were analyzed using capillary gas chromatography. VLBW infants had significantly (p < 0.001) lower plasma AA (9.44 ± 2.12 vs. 10.8 ± 2.10) and DHA (2.56 ± 0.89 vs. 3.46 ± 1.09) levels, but higher n-6:n-3 ratio (5.58 ± 1.22 vs. 5.17 ± 1.46) than term infants. In VLBW infants, plasma AA and DHA were related to gestational age (r = 0.156; p = 0.001 and r = 0.134; p = 0.003, respectively), birthweight (r = 0.242; p < 0.001 and r = 0.181; p < 0.001, respectively) and head circumference (r = 0.138; p = 0.005 and r = 0.108; p = 0.027, respectively). Infants with respiratory distress syndrome have decreased plasma AA and DHA and those with intraventricular hemorrhage have decreased plasma AA and n-6:n-3 ratio. Sepsis was associated with decreased DHA levels. Plasma long chain polyunsaturated fatty acids status is low in VLBW infants. These deficits may enhance the risk of common neonatal morbidities, rendering their prevention and correction greatly warranted.