Lower Levels Of Arachidonic Acid Research Articles

Unique lipid composition maintained by extracellular blockade leads to prooncogenicity

Lipid-mediated inflammation is involved in the development and malignancy of cancer. We previously demonstrated the existence of a novel oncogenic mechanism utilizing membrane lipids of extracellular vesicles in Epstein–Barr virus (EBV)-positive lymphomas and found that the lipid composition of lymphoma cells is skewed toward ω-3 fatty acids, which are anti-inflammatory lipids, suggesting an alteration in systemic lipid composition. The results showed that arachidonic acid (AA), an inflammatory lipid, was significantly reduced in the infected cells but detected at high levels in the sera of EBV-positive patients lead to the finding of the blockade of extracellular AA influx by downregulating FATP2, a long-chain fatty acid transporter that mainly transports AA in EBV-infected lymphoma cells. Low AA levels in tumor cells induced by downregulation of FATP2 expression confer resistance to ferroptosis and support tumor growth. TCGA data analysis and xenograft models have demonstrated that the axis plays a critical role in several types of cancers, especially poor prognostic cancers, such as glioblastoma and melanoma. Overall, our in vitro, in vivo, in silico, and clinical data suggest that several cancers exert oncogenic activity by maintaining their special lipid composition via extracellular blockade.

Metabolomic Effects of Folic Acid Supplementation in Adults: Evidence from the FACT Trial

BackgroundFolic acid (FA) is the oxidized form of folate found in supplements and FA-fortified foods. Most FA is reduced by dihydrofolate reductase to 5-methyltetrahydrofolate (5mTHF); the latter is the form of folate naturally found in foods. Ingestion of FA increases the plasma levels of both 5mTHF and unmetabolized FA (UMFA). Limited information is available on the downstream metabolic effects of FA supplementation, including potential effects associated with UMFA. ObjectiveWe aimed to assess the metabolic effects of FA-supplementation, and the associations of plasma 5mTHF and UMFA with the metabolome in FA-naïve Bangladeshi adults. MethodsSixty participants were selected from the Folic Acid and Creatine Trial; half received 800 μg FA/day for 12 weeks and half placebo. Plasma metabolome profiles were measured by high-resolution mass spectrometry, including 170 identified metabolites and 26,541 metabolic features. Penalized regression methods were used to assess the associations of targeted metabolites with FA-supplementation, plasma 5mTHF, and plasma UMFA. Pathway analyses were conducted using Mummichog. ResultsIn penalized models of identified metabolites, FA-supplementation was associated with higher choline. Changes in 5mTHF concentrations were positively associated with metabolites involved in amino acid metabolism (5-hydroxyindoleacetic acid, acetylmethionine, creatinine, guanidinoacetate, hydroxyproline/n-acetylalanine) and 2 fatty acids (docosahexaenoic acid and linoleic acid). Changes in 5mTHF concentrations were negatively associated with acetylglutamate, acetyllysine, carnitine, propionyl carnitine, cinnamic acid, homogentisate, arachidonic acid, and nicotine. UMFA concentrations were associated with lower levels of arachidonic acid. Together, metabolites selected across all models were related to lipids, aromatic amino acid metabolism, and the urea cycle. Analyses of nontargeted metabolic features identified additional pathways associated with FA supplementation. ConclusionIn addition to the recapitulation of several expected metabolic changes associated with 5mTHF, we observed additional metabolites/pathways associated with FA-supplementation and UMFA. Further studies are needed to confirm these associations and assess their potential implications for human health. Trial registration numberThis trial was registered at https://clinicaltrials.gov as NCT01050556.

Effects of Hot Arid Environments on the Production Performance, Carcass Traits, and Fatty Acids Composition of Breast Meat in Broiler Chickens.

The high environmental temperature is one of the main factors challenging the broiler industry during the hot seasons due to it causing more thermal stress. This study aimed to find the effects of heat stress under hot arid environments on the growth performance, carcass traits, and nutritional composition of breast meat in broiler chickens. A total of 240 broiler chickens were allocated into two groups: (1) a control group (thermoneutral environment (TN); 24 ± 0.17 °C) and (2) a heat stress (HS) group, with 30 replicates in each environment. From d 25 to 35 of age, the broiler chickens in the HS group were exposed to 8 h/day of thermal stress (34 ± 0.71 °C) from 8:00 am to 4:00 pm, while the actual recorded value of ambient temperature was 31 °C on average with a relative air humidity (RH) between 48 and 49% for 10 consecutive days (d 25-35 of age). The live body weight (BW), weight gain, and feed intake significantly deteriorated (p < 0.05), and the feed conversion ratio tended to deteriorate (p = 0.055) in the HS group. The hot and cold carcass yields increased (p < 0.05), while the relative heart and liver weights decreased (p < 0.05) in the broiler chickens exposed to HS. The breast meat yield tended to decrease (p = 0.057), while wing meat yields increased significantly (p = 0.050) in heat-stressed broiler chickens. The shrinkage of the carcass percentage increased during chilling (p < 0.001) in the HS group. The ultimate pH values; cooking loss; and contents of moisture, crude protein, and fat of breast meat showed no response (p > 0.05) between the TN and HS groups. The heat-stressed broiler chickens presented lower levels of arachidonic acid (C20:4 (n-6)) (p = 0.01) and eicosadienoic acid (C20:2 (n-6)) (p = 0.050) in the breast meat, while the variations in n-3 polyunsaturated fatty acid were insignificant (p > 0.05) between the groups. In conclusion, our findings confirmed that the hot arid environments could reduce the production performance of broiler chickens and increase carcass shrinkage during chilling, but did not compromise the n-3 polyunsaturated fatty acid and cooking loss in the breast meat.

Reproductive management of the mugilid Liza aurata and characterization of proximate and fatty acid composition of broodstock tissues and spawnings

The golden grey mullet (Liza aurata) is a promising species for aquaculture's sustainable expansion. However, the lack of sustainable juvenile provision, mainly related to the lack of reproductive control, is one of the most significant bottlenecks for further expanding the culture of this species. In many cases, mullet broodstock management needs the application of hormone treatments to induce gonadal maturation or spawning. However, no works are directly related to the broodstock collection, acclimation, and reproductive management of Liza aurata. On the other hand, the knowledge of essential fatty acids (EFA) requirements and mobilization patterns by the broodstock is a first step to designing appropriate feeding protocols and formulas, which are crucial for the success of reproduction and larval development.For these reasons, this study aimed 1) to describe for the first time the reproductive management of Liza aurata broodstock under controlled conditions and 2) to offer a first approach to the reproductive lipid metabolism of the former species.A selection of 22 Liza aurata broodstock from wild origin was acclimated in open seawater conditions. Additionally, the proximate and fatty acid composition of body tissues (gonads, liver, and muscle) of the initial wild population were evaluated, to be later compared with the profile of the eggs obtained after one year from the selected broodstock, for the first time described under cultured conditions.The results highlighted the feasibility for the obtention of natural spawnings from broodstock with a mean weight of 787 g and 604 g (females and males, respectively), at a sex ratio of 2:1 (females/males), under natural photoperiod and marine water conditions with temperatures decreasing from 20.4 ± 0.3 °C to 18.8 ± 0.4 °C.On the other hand, it was evidenced the crucial role of HUFA (highly unsaturated fatty acids) precursors for the gonadal development of Liza aurata, primarily for females. Additionally, the wild males' gonads presented a remarkable high content of HUFA, predominantly DHA (docosahexaenoic acid) (34% of the total fatty acids). In the eggs, significant variations appeared under captivity conditions, with lower levels of ARA (arachidonic acid) and EPA (eicosapentaenoic acid) and higher EPA/ARA and DHA/ARA ratios than the wild female gonad. Additionally, it was evidenced the significant role of the liver as a physiological reservoir of HUFA, which seem to be mobilized to the gonad during the maturation process.Present results may help obtain a better insight to adjust broodstock management conditions and feeds, contributing to a more sustainable aquaculture growth.

Reduced Endocannabinoid Tone in Saliva of Chronic Orofacial Pain Patients.

Background: the endocannabinoid system (ECS) participates in many physiological and pathological processes including pain generation, modulation, and sensation. Its involvement in chronic orofacial pain (OFP) in general, and the reflection of its involvement in OFP in salivary endocannabinoid (eCBs) levels in particular, has not been examined. Objectives: to evaluate the association between salivary (eCBs) levels and chronic OFP. Methods: salivary levels of 2 eCBs, anandamide (AEA), 2-arachidonoylglycerol (2-AG), 2 endocannabinoid-like compoundsN-palmitoylethanolamine (PEA), N-oleoylethanolamine (OEA), and their endogenous precursor and breakdown product, arachidonic acid (AA), were analyzed using liquid chromatography/tandem mass spectrometry in 83 chronic OFP patients and 43 pain-free controls. The chronic OFP patients were divided according to diagnosis into musculoskeletal, neurovascular/migraine, and neuropathic pain types. Results: chronic OFP patients had lower levels of OEA (p = 0.02) and 2-AG (p = 0.01). Analyzing specific pain types revealed lower levels of AEA and OEA in the neurovascular group (p = 0.04, 0.02, respectively), and 2-AG in the neuropathic group compared to controls (p = 0.05). No significant differences were found between the musculoskeletal pain group and controls. Higher pain intensity was accompanied by lower levels of AA (p = 0.028), in neuropathic group. Conclusions: lower levels of eCBs were found in the saliva of chronic OFP patients compared to controls, specifically those with neurovascular/migraine, and neuropathic pain. The detection of changes in salivary endocannabinoids levels related to OFP adds a new dimension to our understanding of OFP mechanisms, and may have diagnostic as well as therapeutic implications for pain.

Plasma Oxylipins and Their Precursors Are Strongly Associated with COVID-19 Severity and with Immune Response Markers.

COVID-19 is characterised by a dysregulated immune response, that involves signalling lipids acting as mediators of the inflammatory process along the innate and adaptive phases. To promote understanding of the disease biochemistry and provide targets for intervention, we applied a range of LC-MS platforms to analyse over 100 plasma samples from patients with varying COVID-19 severity and with detailed clinical information on inflammatory responses (>30 immune markers). The second publication in a series reports the results of quantitative LC-MS/MS profiling of 63 small lipids including oxylipins, free fatty acids, and endocannabinoids. Compared to samples taken from ward patients, intensive care unit (ICU) patients had 2–4-fold lower levels of arachidonic acid (AA) and its cyclooxygenase-derived prostanoids, as well as lipoxygenase derivatives, exhibiting negative correlations with inflammation markers. The same derivatives showed 2–5-fold increases in recovering ward patients, in paired comparison to early hospitalisation. In contrast, ICU patients showed elevated levels of oxylipins derived from poly-unsaturated fatty acids (PUFA) by non-enzymatic peroxidation or activity of soluble epoxide hydrolase (sEH), and these oxylipins positively correlated with markers of macrophage activation. The deficiency in AA enzymatic products and the lack of elevated intermediates of pro-resolving mediating lipids may result from the preference of alternative metabolic conversions rather than diminished stores of PUFA precursors. Supporting this, ICU patients showed 2-to-11-fold higher levels of linoleic acid (LA) and the corresponding fatty acyl glycerols of AA and LA, all strongly correlated with multiple markers of excessive immune response. Our results suggest that the altered oxylipin metabolism disrupts the expected shift from innate immune response to resolution of inflammation.

85 What Does the Vaginal Lipidome Tell Us?

Abstract Increasing reproductive efficiency in the breeding herd is a fundamental goal of modern swine production systems that depends on a multitude of factors, some of which begin at or before birth. Of particular interest, previous research has identified a link between colostrum consumption in the first 24h of the piglet’s life with survival, growth, and fertility through adulthood. Thus, the ingestion of colostrum appears to set the developmental trajectory of health and fertility in swine. However, the mechanism that link colostrum to long-term growth, health and fertility are not fully understood. Exploratory analysis of vaginal lipidome collected from three-week-old neonates that were followed prospectively to determine fertility found infertile sows had lower levels of arachidonic acid (AHA) and docosahexaenoic acid (DHA), and a greater abundance of two very long chain fatty acids (VLCFA: cerotic and ximenic). We surmise that AHA and DHA are markers of colostrum intake as additional studies found that AHA was increased in vaginal lipidome of gilts that consumed colostrum versus being fed milk replacer. We also surmise that high levels of VLCFA in the infertile animals was indicative of a buildup of these fatty acids in the tissue, similar to individuals with peroxisomal disorders with resulting alterations in lipid homeostasis linked to infertility. Taken together, our hypothesis is that differing levels of colostrum intake stimulate differing rates of peroxisomal biogenesis in neonates which in turn affects the development of the reproductive system and long-term fertility.

Plasma and Red Blood Cell PUFAs in Home Parenteral Nutrition Paediatric Patients-Effects of Lipid Emulsions.

Background: Mixed lipid emulsions (LE) containing fish oil present several advantages compared to the sole soybean oil LE, but little is known about the safety of essential fatty acids (EFA) profile in paediatric patients on long-term Parenteral Nutrition (PN). Aim of the study: to assess glycerophosfolipid polyunsaturated fatty acids (PUFA) levels on plasma and red blood cell (RBC) membrane of children on long term PN with composite LE containing fish oil (SMOF), and to compare it with a group receiving olive oil LE (Clinoleic®) and to the reference range for age, previously determined on a group of healthy children. Results: A total of 38 patients were enrolled, median age 5.56 (0.9–21.86) years, 15 receiving Clinoleic®, 23 receiving SMOF. Patients on SMOF showed significantly higher levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), lower levels of arachidonic acid (ARA) and Mead acid (MEAD)/ARA ratio in plasma and RBC compared with patients on Clinoleic® and with healthy children. Triene:tetraene (T:T) ratio of both groups of patients did not differ from that of healthy children-median plasma (MEAD/ARA: 0.01, interquartile rage (IQR) 0.01, p = 0.61 and 0.02, IQR 0.02, p = 0.6 in SMOF and Clinoleic® patients, respectively), and was considerably lower than Holman index (>0.21). SMOF patients showed no statistically significant differences in growth parameters compared with Clinoleic® patients. Patients of both groups showed stiffness class F0-F1 of liver stiffness measure (LSM) 5.6 (IQR 0.85) in SMOF patients and 5.3 (IQR 0.90) in Clinoleic® patients, p = 0.58), indicating absence of liver fibrosis. Conclusions: Fatty acids, measured as concentrations (mg/L), revealed specific PUFA profile of PN patients and could be an accurate method to evaluate nutritional status and eventually to detect essential fatty acid deficiency (EFAD). SMOF patients showed significantly higher EPA, DHA and lower ARA concentrations compared to Clinoleic® patients. Both LEs showed similar hepatic evolution and growth.

Spleen Oxylipin and Polyunsaturated Fatty Acid Profiles are Altered by Dietary Source of Polyunsaturated Fatty Acid and by Sex.

As the largest secondary lymphoid organ, the spleen plays an important role in immune responses. The role of arachidonic acid (ARA) and its 20-carbon eicosanoids in modulating immune function has long been of interest. However, recent advances have enabled the identification of numerous other n-6 and n-3 polyunsaturated fatty acid (PUFA)-derived oxylipins. Here, we investigate the effects of diet and sex on the spleen nonesterified oxylipin profiles and phospholipid and neutral lipid PUFA composition in Sprague-Dawley rats supplemented with oils rich in α-linolenic acid (ALA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), or linoleic acid. Dietary ALA, EPA, and DHA resulted in lower levels of ARA and ARA oxylipins. Oxylipins derived from other n-6 PUFA were also reduced despite no or opposite effect on their PUFA levels. Each diet also resulted in higher levels of oxylipins almost exclusively derived from the supplemented PUFA, despite PUFA in the same biosynthetic pathway also often being increased. Further, while oxylipin differences often reflected changes to phospholipid PUFA, there were instances where they corresponded more closely to changes in neutral lipid PUFA. With respect to sex effects, >50% of lipoxygenase ARA-derived oxylipins were higher in males in at least one diet group, while multiple DHA oxylipins were lower in males only in rats provided the DHA diet. This fundamental description of oxylipin composition in the spleen, including the influence of diet and sex and the relationship to PUFA composition, will help inform future studies examining the functions of these oxylipins under physiological and pathological conditions.

Arachidonic acid effects on the overall performance, fatty acid profile, hepatopancreas morphology and lipid-relevant genes in Litopenaeus vannamei juveniles

The effect of arachidonic acid (ARA) was evaluated on Litopenaeus vannamei juveniles. Growth performance; hepatopancreas and muscle fatty acid compositions; hepatopancreatic cells morphology; and expression of lipid-relevant genes were estimated after six-week experiment. A basal fat-reduced diet was manufactured and subsequently coated with different fatty acids sources, distinct levels of ARA (0, 0.3, and 0.6%), fish and soybean oil (50:50 Control diet). L. vannamei juveniles (1.10 ± 0.22 g) were randomly divided into twelve tanks with thirty animals each. The animals were fed three times per day, with 8% of the total biomass. The results showed that animals fed with diet containing 0.3% of ARA presented a lower final weight compared to the Control. Different levels of ARA inclusion in the experimental diets directly influenced in the tissues fatty acid profile with lower ARA levels in Control and 0% followed by 0.3% and 0.6%. In muscle and hepatopancreas tissues, a higher accumulation of docosahexaenoic acid (DHA) was revealed in the Control compared to the rest of the experimental treatments. The expression pattern of lipoxygenase (alox5), prostaglandin E synthase (pges2), sterol regulatory element-binding protein-1 (srebp1) and cycloxygenase (cox2) were significantly affected by the ARA inclusion, showing the highest expression in the Control treatment with a decrease according to the increasing levels of dietary ARA. It is concluded that ARA inclusion in shrimp diets result in a negative impact on the overall performance, probably modulated by a differential gene expression related to the eicosanoids synthesis, lipolytic and lipogenic pathways. Besides, the lipid deposition on the hepatopancreatic cells was reduced.

Association Between Fatty Acids Profile and Cerebral Blood Flow: An Exploratory fNIRS Study on Children with and without ADHD.

Polyunsaturated fatty acids (PUFAs) biostatus has been proposed as possible attention deficit hyperactivity disorder (ADHD) diagnosis biomarker. The present exploratory study aimed to investigate the association between PUFAs biostatus and cerebral cortex metabolism measured by functional Near Infrared Spectroscopy (fNIRS) in a sample of children with and without ADHD. 24 children with ADHD and 22 typically developing (TD) peers, aged 8–14, were recruited. Linoleic, arachidonic, docosahexaenoic and eicosapentaenoic acids levels were evaluated in whole blood. All children underwent fNIRS while performing an n-back working memory task. Between groups comparisons revealed lower levels of arachidonic acid in children with ADHD and stronger NIRS signal in TD participants, especially when completing more difficult tasks. Correlations conducted between fNIRS activation and PUFA biostatus revealed several associations between hemodynamic changes in the frontoparietal regions and fatty acids profile across participants. This result was also confirmed by the multiple hierarchical regression analyses that remarked an inverse effect of eicosapentaenoic acid levels on oxyhemoglobin values in right frontoparietal region. Such preliminary findings, if confirmed, would suggest that PUFAs could play a role in atypical neurodevelopment.

Why most insects have very low proportions of C20 polyunsaturated fatty acids: The oxidative stress hypothesis.

Eicosanoids, a group of C20 oxygenated polyunsaturated fatty acids (PUFAs), mediate various physiological processes, such as immunity, reproduction, excretion, and metabolism in insects. Arachidonic acid (AA) is used for the main precursor for the production of various eicosanoids. However, most terrestrial insects possess relatively low AA levels. Insects are presumed to be evolved sincethe Paleozoic era, at which oxygen levels might be much higher than current conditions. Compared with other animals, they exhibit relatively high metabolic rates with the well-developed tracheal system, which directly supply enough oxygen to active tissues like flight muscles. This might allow insects to be susceptible to reactive oxygen species (ROS) generated from high oxidative catabolism. Long-chain PUFAs including AA is usually reacted with ROS and become peroxidized. Peroxidized PUFAs cause various cellular damage. Thus, we propose a hypothesis that terrestrial insects minimize AA levels to minimize oxidative stress.

The Impact of FADS Variants on Responses to Diet in Patients With ALI

Nutritional support in the intensive care unit (ICU) is a vital element of patient care. Polyunsaturated fatty acids (PUFAs) like γ‐linolenic acid (GLA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been recommended in immunomodulatory diets because of their anti‐inflammatory effects. However, clinical trials have failed to show unanimous benefit with PUFA‐rich diets. Metabolic conversion of these PUFAs are dependent on fatty acid desaturase (FADS) and elongase (ELOVL) enzymes, which are unequal across humans. In fact, several genetic variants within FADS and ELOVL genes have been shown to impact PUFA metabolism. Select variants are also differentially expressed in African Americans. We hypothesize that these genetic variants may help explain the differential responses to PUFA‐rich diets. In this study, we aimed to investigate gene‐diet interactions in patients with acute lung injury (ALI).Banked DNA and plasma samples from the OMEGA randomized clinical trial (NCT00609180) were used to conduct a secondary analysis on genetic variants within FADS and ELOVL regions; 43 SNPs were genotyped. Plasma PUFA levels were quantified using gas chromatography. Of the 272 enrolled, 143 received omega‐rich vs. 129 placebo diets. All statistical analyses were stratified by race and adjusted for age and gender.Several SNPs were associated with PUFA levels. Notably, SNP rs174537 had a significant impact on arachidonic acid (ARA). Caucasian T allele carriers on the omega‐rich diet had lower ARA levels (p=0.022, Fig. 1). Interestingly, this SNP had a major impact on PUFAs within African Americans on both placebo and omega‐rich diets. ARA levels were significantly higher and DHA levels were low (p=0.0007) in African Americans. Genotype at rs174537 was associated with patient outcomes; Caucasians with the T allele had significantly more VENT‐free and ICU‐free days (~&gt;12%) than GGs, but this was not observed within African Americans. Instead, a significant interaction between gender and diet was seen, with African American women on placebo diet having 40% fewer VENT‐free (p=0.009) and ICU‐free days (p=0.022) than African American men. Mortality was highest in GGs receiving omega‐rich diets in both races, however this was not statistically significant. These data suggest strong ethnic, gender and genetic factors influencing the response to omega‐rich diets. Further investigation on other gene‐gene interactions (e.g. between FADS and ELOVL variants), and epigenetic modifications are needed to understand the underlying mechanisms regulating PUFA metabolism and biosynthesis in critically injured and ill patients.Support or Funding InformationNIH K25 HL133611This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Identification of a functional FADS1 3′UTR variant associated with erythrocyte n-6 polyunsaturated fatty acids levels

Blood polyunsaturated fatty acid (PUFA) levels are determined by diet and by endogenous synthesis via Δ5- and Δ6-desaturases (encoded by the FADS1 and FADS2 genes, respectively). Genome-wide association studies have reported associations between FADS1-FADS2 polymorphisms and the plasma concentrations of PUFAs, HDL- and LDL-cholesterol, and triglycerides. However, much remains unknown regarding the molecular mechanisms explaining how variants affect the function of FADS1-FADS2 genes. Here, we sought to identify the functional variant(s) within the FADS gene cluster. To address this question, we (1) genotyped individuals (n=540) for the rs174547 polymorphism to confirm associations with PUFA levels used as surrogate estimates of desaturase activities and (2) examined the functionality of variants in linkage disequilibrium with rs174547 using bioinformatics and luciferase reporter assays. The rs174547 minor allele was associated with higher erythrocyte levels of dihomo-γ-linolenic acid and lower levels of arachidonic acid, suggesting a lower Δ5-desaturase activity. In silico analyses suggested that rs174545 and rs174546, in perfect linkage disequilibrium with rs174547, might alter miRNA binding sites in the FADS1 3'UTR. In HuH7 and HepG2 cells transfected with FADS1 3'UTR luciferase vectors, the haplotype constructs bearing the rs174546T minor allele showed 30% less luciferase activity. This relative decrease reached 60% in the presence of miR-149-5p and was partly abolished by cotransfection with an miR-149-5p inhibitor. This study identifies FADS1 rs174546 as a functional variant that may explain the associations between FADS1-FADS2 polymorphisms and lipid-related phenotypes.

Effects on Fatty Acid Metabolism of a New Powdered Human Milk Fortifier Containing Medium-Chain Triacylglycerols and Docosahexaenoic Acid in Preterm Infants.

Preterm infants require fortification of human milk (HM) with essential fatty acids (FA) to ensure adequate post-natal development. As part of a larger randomized controlled study, we investigated FA metabolism in a subset of 47 clinically stable preterm infants (birth weight ≤1500 g or gestational age ≤32 weeks). Infants were randomized to receive HM supplemented with either a new HM fortifier (nHMF; n = 26) containing 12.5 g medium-chain FA (MCFA), 958 mg linoleic acid (LA), 417 mg α-linolenic acid (ALA), and 157 mg docosahexaenoic acid (DHA) per 100 g of powder (in compliance with the latest guidelines) or a fat-free HMF (cHMF; n = 21). Plasma phospholipid (PL) and triacylglycerol (TAG), and red blood cell phosphatidylcholine (RBC-PC) and phosphatidylethanolamine (RBC-PE) FA profiles were assessed before and after 21 days of feeding. In the nHMF group, significantly increased levels of n-9 monounsaturated fatty acids were observed, formed most likely by elongation and desaturation of dietary saturated fatty acids present in HM. ALA fortification increased ALA assimilation into plasma TAG. Similarly, DHA fortification enriched the DHA content in RBC-PE, which, in this compartment, was not associated with lower arachidonic acid levels as observed in plasma TAG and phospholipids. RBC-PE, a reliable indicator of FA metabolism and accretion, was the most sensitive compartment in this study.

The Clinical Significance of Low Serum Arachidonic Acid in Sepsis Patients with Hypoalbuminemia.

Objectives Fatty acids (FAs) have various roles in pro-inflammatory and anti-inflammatory functions. Hypoalbuminemia is often observed in sepsis patients. An imbalance among these compounds formed from FAs caused by hypoalbuminemia may be related to increased mortality in sepsis patients. The purpose of this study was to investigate the correlations between serum albumin and FAs in sepsis and the outcome. Methods This study was an observational investigation. The clinical and laboratory data of sepsis patients were recorded and the Sequential Organ Failure Assessment (SOFA) score was calculated at admission. The serum arachidonic acid (AA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and dihomo-gamma-linolenic acid (DHLA) levels were also measured as FAs. The body mass index (BMI) was used to determine the general nutrition status. Results Two hundred sepsis patients were enrolled during the study period. No significant correlations were observed between the BMI and the SOFA score or the serum albumin level at admission. The FA levels of the non-survivors were significantly lower, but there were no significant differences in the EPA/AA levels of the survivors and non-survivors. A low serum albumin level was closely related to low AA (p<0.0001), EPA (p<0.0001), DHA (p=0.0003), and DHLA levels (p<0.0001). A multiple logistic-regression analysis revealed that a high SOFA score [adjusted odds ratio, 1.19; 95% confidence interval (CI), 1.02-1.39, p=0.026] and low AA (adjusted odds ratio, 0.98; 95% CI, 0.978-0.994, p=0.041) were associated with a poor outcome. Conclusion A lower AA level was an important determinant of the outcome of patients with sepsis. These findings are consistent with the findings of previous studies, which reported that hypoalbuminemia might alter the AA metabolism in sepsis patients.

Association of Retinopathy of Prematurity With Low Levels of Arachidonic Acid

Mice with oxygen-induced retinopathy fed matched diets except for ω-3 long-chain polyunsaturated fatty acids (LC-PUFAs) vs ω-6 LC-PUFAs demonstrate relative antiangiogenic and neuroprotective associations of ω-3 LC-PUFAs. However, supplementing preterm infants with LC-PUFAs has been inconsistent in reducing major preterm morbidities. However, few studies measured serum lipid levels after supplementation. To examine the associated risk of retinopathy of prematurity (ROP) from the levels of circulating ω-3 and ω-6 LC-PUFAs. This longitudinal clinical study was a further analysis of serum lipid levels from a randomized controlled trial cohort of 90 infants born at gestational age (GA) less than 28 weeks. From April 4, 2013, to September 22, 2015, cord blood samples, followed by venous blood samples, were obtained at birth and at 1, 7, 14, and 28 days after birth and then at postmenstrual age (PMA) 32, 36, and 40 weeks at the neonatal intensive care unit at Sahlgrenska University Hospital in Göteborg, Sweden. Serum phospholipid fatty acids were transmethylated and measured by gas chromatography-mass spectrometry. Mann-Whitney test, logistic regression Spearman rank correlation, and receiver operating characteristic curve analysis were used to compare differences between infants with no ROP and infants who developed ROP. Serum levels from 78 infants (43 male [55%]; mean [SD] GA, 25.5 [1.4] weeks) with a known ROP outcome were evaluated. Lower area under the curve (AUC) of arachidonic acid (AA) (20:4 ω-6) was seen in infants with a later diagnosis of ROP compared with infants with no ROP in the first month of life (mean, 34.05 [95% CI, 32.10-36.00] vs 37.15 [95% CI, 34.85-39.46]; P < .05). In addition, lower levels of AA at 32 weeks' PMA were seen in infants with later severe ROP compared with in those without ROP (mean, 7.06 [95% CI, 6.60-7.52] vs 8.74 [95% CI, 7.80-9.67]; P < .001). In logistic modeling, low postnatal serum levels of AA and GA at birth identified with a sensitivity greater than 90% of infants who developed ROP. Low postnatal levels of the ω-6 LC-PUFAs (AA) are strongly associated with ROP development. Evaluating postnatal AA fraction after birth in addition to GA may be useful for ROP prediction. clinicaltrials.gov Identifier: NCT02760472.

Low levels of linoleic acid and α-linolenic acid and high levels of arachidonic acid in plasma phospholipids are associated with hypertension.

Dietary fat is an important determinant in the development and progression of high blood pressure (BP), a major risk factor for cardiovascular diseases and mortality. The aim of the present study was to determine the association between plasma phospholipid fatty acids and hypertension in Japanese men. The plasma level of linoleic acid (LA) in the subjects with hypertension (systolic BP ≥140 mmHg and/or diastolic BP ≥90 mmHg) was identified to be significantly higher than that in the healthy controls. Following adjustment for age, body mass index, physical activity, smoking status, alcohol consumption, salt intake, and serum levels of glucose and hemoglobin A1c, higher plasma levels of LA and α-linolenic acid (ALA), and lower levels of arachidonic acid (AA) were significantly associated with a lower prevalence of hypertension. The odds ratio (OR) for the highest quartile (Q4) versus the lowest quartile (Q1) of LA was 0.17 (P=0.003), the OR for Q4 versus Q1 of ALA was 0.26 (P=0.042) and the OR for Q4 versus Q1 of AA was 2.04 (P=0.047). These results indicate that elevated levels of LA and ALA, and reduced levels of AA in the plasma prevent hypertension.

The profile of polyunsaturated fatty acids in juvenile idiopathic arthritis and association with disease activity

We investigated the association between dietary intake of n-3 and n-6 polyunsaturated fatty acids (PUFAs), serum profiles, and immune and inflammatory markers in juvenile idiopathic arthritis (JIA) in relation to onset, activity, and duration. A total of 66 JIA patients and 42 controls were included. Serum PUFA levels were assessed by gas-liquid chromatography-mass spectrometry, a dietary intake by 7-day dietary record method, and IL-6, IL-10, and IL-17A levels using ELISA. Dietary PUFA intake did not differ between the JIA group and controls. Intakes of n-6 and n-3 PUFA and serum levels were not associated. Levels of total n-6 PUFA and linoleic acid (LA) were higher in inactive JIA than in active JIA. Patients with active and short-lasting disease (less than 3 months from diagnosis) had significantly lower levels of arachidonic acid (AA) and docosahexaenoic acid (DHA) than the control. Serum α-linolenic acid (ALA) levels were significantly higher in poly-JIA than in oligo-JIA and in controls. We found significantly higher serum IL-10 levels in JIA than in controls. Serum n-6 and n-3 levels were significantly negatively correlated with active joint count, erythrocyte sedimentation rate, and C-reactive protein and positively with platelet count. Our study presents the low levels of AA and DHA in the active phase of short-lasting JIA, particularly poly-JIA, and the relationship between n-6 and n-3 PUFA and classic markers of inflammation. PUFAs may contribute to the pathogenesis of JIA and support a necessity to identify new targets suitable for successful interventional studies in JIA patients.

Elevated prostaglandin E metabolites and abnormal plasma fatty acids at baseline in pediatric cystic fibrosis patients: a pilot study

BackgroundAirway inflammation is a significant contributor to the morbidity of cystic fibrosis (CF) disease. One feature of this inflammation is the production of oxygenated metabolites, such as prostaglandins. Individuals with CF are known to have abnormal metabolism of fatty acids, typically resulting in reduced levels of linoleic acid (LA) and docosahexaenoic acid (DHA). MethodsThis is a randomized, double-blind, cross-over clinical trial of DHA supplementation with endpoints of plasma fatty acid levels and prostaglandin E metabolite (PGE-M) levels. Patients with CF age 6–18 years with pancreatic insufficiency were recruited. Each participant completed 3 four-week study periods: DHA at two different doses (high dose and low dose) and placebo with a minimum 4 week wash-out between each period. Blood, urine, and exhaled breath condensate (EBC) were collected at baseline and after each study period for measurement of plasma fatty acids as well as prostaglandin E metabolites. ResultsSeventeen participants were enrolled, and 12 participants completed all 3 study periods. Overall, DHA supplementation was well tolerated without significant adverse events. There was a significant increase in plasma DHA levels with supplementation, but no significant change in arachidonic acid (AA) or LA levels. However, at baseline, AA levels were lower and LA levels were higher than previously reported for individuals with CF. Urine PGE-M levels were elevated in the majority of participants at baseline, and while levels decreased with DHA supplementation, they also decreased with placebo. ConclusionsUrine PGE-M levels are elevated at baseline in this cohort of pediatric CF patients, but there was no significant change in these levels with DHA supplementation compared to placebo. In addition, baseline plasma fatty acid levels for this cohort showed some difference to prior reports, including higher levels of LA and lower levels of AA, which may reflect changes in clinical care, and consequently warrants further investigation.