Docosahexaenoic acid, eicosapentaenoic acid, arachidonic acid, and neural tube defects in Tunisian population.

OBJECTIVE: To determine the effect of maternal status in (plasma and red blood cell) folate, vitamin B12, homocysteine, and vitamin D, as well as their interaction with MTHFR (C677T and A1298C) and MTRR A66G polymorphisms, on maternal plasma docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and arachidonic acid (ARA) levels and the risk of neural tube defects (NTDs). METHODS: ARA, EPA, and DHA composition was assessed using capillary gas chromatography. RESULTS: ARA and DHA levels were higher in controls than in case mothers for low plasma folate status. For low red blood cell folate status, DHA levels were higher in controls than in case mothers. For high homocysteine levels, ARA and DHA levels were higher in controls than in case mothers. NTD mothers had lower EPA and DHA levels for low vitamin B12 levels. NTD mothers had lower DHA levels for low vitamin D levels. For low plasma folate status, DHA levels in the MTHFR C677T gene and ARA and EPA levels in MTHFR A1298C gene were different among the three genotypes in case mothers. DHA levels in the MTHFR C677T gene were different among the three genotypes in case mothers for both low and high homocysteine levels. For low vitamin B12 levels, ARA and DHA levels were different among the three genotypes of the MTHFR C677T gene in case mothers. In the MTHFR C677T gene, ARA and DHA levels were different among the three genotypes in case mothers for low vitamin D levels. CONCLUSIONS: More advanced research is required to verify a suitable biochemical parameter status in relation to the genotypes in pregnant women.

Changes in the Fatty Acid Profile in Erythrocytes in High-Level Endurance Runners during a Sports Season.

Fatty acids (FAs) are an essential component of the erythrocyte membrane, and nutrition and physical exercise are two variables that affect their structure and function. The aim of this study was to evaluate the erythrocyte profile in a group of high-level endurance runners, as well as the changes in different FAs, throughout a sports season in relation to the training performed. A total of 21 high-level male endurance runners (23 ± 4 years; height: 1.76 ± 0.05) were evaluated at four different times throughout a sports season. The athletes had at least 5 years of previous experience and participated in national and international competitions. The determination of the different FAs was carried out by gas chromatography. The runners exhibited low concentrations of docosahexaenoic acid (DHA) and omega-3 index (IND ω-3), as well as high values of stearic acid (SA), palmitic acid (PA), and arachidonic acid (AA), compared to the values of reference throughout the study. In conclusion, training modifies the erythrocyte FA profile in high-level endurance runners, reducing the concentrations of polyunsaturated fatty acids (PUFAs) such as DHA and AA and increasing the concentrations of saturated fatty acids (SFAs) such as SA and the PA. High-level endurance runners should pay special attention to the intake of PUFAs ω-3 in their diet or consider supplementation during training periods to avoid deficiency.

Sex-dependent differences in tissue and blood n-3 PUFA levels following ALA or ALA + DHA feeding of liver-specific Elovl2-KO and control mice.

Docosahexaenoic acid (DHA, 22:6n-3) must be consumed from the diet or synthesized from polyunsaturated fatty acid (PUFA) precursors, such as α-linolenic acid (ALA, 18:3n-3). Elongase 2 (encoded by Elovl2 gene) catalyzes two elongation reactions in the PUFA biosynthesis pathway and may be important in regulating the observed sex differences in n-3 PUFA levels. Our aim was to determine how targeted knockout of liver Elovl2 affects tissue and blood n-3 PUFA levels in male and female C57BL/6J mice. Twenty-eight-day old male and female liver Elovl2-KO and control mice were placed onto one of two dietary protocols for a total of 8 weeks (4-8 mice per genotype, per diet, per sex): 1) an 8-week 2 % ALA in total fat diet or 2) a 4-week 2 % ALA diet followed by a 4-week 2 % ALA + 2 % DHA diet. Following this 8-week feeding period, 12-week-old mice were sacrificed and serum, red blood cells (RBC), liver, heart and brain were collected and fatty acid levels measured. Significant interaction effects (p < 0.05, sex x genotype) for serum, RBC, liver and heart DHA levels were identified. In serum and liver, DHA levels were significantly different (p < 0.01) between all groups with male controls > female controls > female KO > male KO in serum and female controls > male controls > female KO > male KO in liver. In RBCs and the heart, female controls = male controls > female KO > male KO (p < 0.001). The addition of DHA to diet removed the interaction effects on DHA levels in the serum, liver and heart, yielding a significant sex effect in serum, liver (female > male, p < 0.01) and brain (male > female, p < 0.05) and genotype effect in serum and heart (control > KO, p < 0.05). Ablation of liver Elovl2 results in significantly lower blood and tissue DHA in a sex-dependent manner, suggesting a role for Elovl2 on sex differences in n-3 PUFA levels.

The severity of COVID-19 upon hospital admission is associated with plasma omega-3 fatty acids.

Fatty acids are precursors of inflammatory oxylipins. In the context of COVID-19, an excessive production of pro-inflammatory cytokines is associated with disease severity. The objective was to investigate whether the baseline omega 3/omega 6 fatty acids ratio and the oxylipins were associated with inflammation and oxidative stress in unvaccinated patients with COVID-19, classified according to the severity of the disease during hospitalization. This Prospective population-based cohort study included 180 hospitalized patients with COVID-19. The patients were classified into five groups according to the severity of their disease. Group 1 was the least severe and Group 5 was the most severe. Three specific types of fatty acids-eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and arachidonic acid (AA)-as well as their enzymatic and non-enzymatic oxylipins were determined using chromatography coupled mass spectrometry. There was no difference in the ratio of omega-3 to omega-6 fatty acids between the groups (p = 0.276). However, the EPA/AA ratio was lower in Group 4 compared to Group 1 (p = 0.015). This finding was associated with an increase in both C-Reactive Protein (p < 0.001) and Interleukin-6 (p = 0.002). Furthermore, the concentration of F2-Isoprostanes was higher in Group 4 than in Group 1 (p = 0.009), while no significant changes were observed for other oxylipins among groups. Multivariate analysis did not present any standard of biomarkers, suggesting the high complexity of factors involved in the disease severity. Our hypothesis was confirmed in terms of EPA/AA ratio. A higher EPA/AA ratio upon hospital admission was found to be associated with lower concentration of C-Reactive Protein and Interleukin-6, leading to a better prognosis of hospitalized SARS-CoV-2 patients. Importantly, this beneficial outcome was achieved without any form of supplementation. The trial also provides important information that can be further applied to reduce the severity of infections associated with an uncontrolled synthesis of pro-inflammatory cytokines.Trial registration: https://clinicaltrials.gov/study/NCT04449718 -01/06/2020. ClinicalTrials.gov Identifier: NCT04449718.

Synbiotic Bacillus megaterium DSM 32963 and n-3 PUFA Salt Composition Elevates Pro-Resolving Lipid Mediator Levels in Healthy Subjects: A Randomized Controlled Study.

Beneficial health effects of omega-3 polyunsaturated fatty acids (n-3 PUFA) are partly attributed to specialized pro-resolving mediators (SPMs), which promote inflammation resolution. Strategies to improve n-3 PUFA conversion to SPMs may, therefore, be useful to treat or prevent chronic inflammatory disorders. Here, we explored a synbiotic strategy to increase circulating SPM precursor levels. Healthy participants (n = 72) received either SynΩ3 (250 mg eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA) lysine salts; two billion CFU Bacillus megaterium; n = 23), placebo (n = 24), or fish oil (300 mg EPA plus DHA; N = 25) capsules daily for 28 days in a randomized, double-blind placebo-controlled parallel 3-group design. Biomarkers were assessed at baseline and after 2 and 28 days of intervention. The primary analysis involved the comparison between SynΩ3 and placebo. In addition, SynΩ3 was compared to fish oil. The synbiotic SynΩ3 comprising Bacillus megaterium DSM 32963 and n-3 PUFA salts significantly increased circulating SPM precursor levels, including 18-hydroxy-eicosapentaenoic acid (18-HEPE) plus 5-HEPE, which was not achieved to this extent by fish oil with a similar n-3 PUFA content. Omega-3 indices were increased slightly by both SynΩ3 and fish oil. These findings suggest reconsidering conventional n-3 PUFA supplementation and testing the effectiveness of SynΩ3 particularly in conditions related to inflammation.

Omega-3 fatty acids and major depression: a Mendelian randomization study.

Omega-3 fatty acids have been implicated in the aetiology of depressive disorders, though trials supplementing omega-3 to prevent major depressive disorder (MDD) have so far been unsuccessful. Whether this association is causal remains unclear. We used two sample Mendelian randomization (MR) to investigate causality. Genetic variants associated with circulating omega-3 and omega-6 fatty acids in UK Biobank (UKBB, n = 115,078) were selected as exposures. The Psychiatric Genomics Consortium (PGC) genome-wide association studies (GWAS) of MDD (n = 430,775; cases = 116,209; controls = 314,566) and recurrent depression (rMDD, n = 80,933; cases = 17,451; controls = 62,482), were used as outcomes. Multivariable MR (MVMR) models were used to account for biologically correlated lipids, such as high- and low-density cholesterol and triglycerides, and to explore the relative importance of longer-chain omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) using data from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE, n = 8866). Genetic colocalization analyses were used to explore the presence of a shared underlying causal variant between traits. Genetically predicted total omega-3 fatty acids reduced the odds of MDD (ORIVW 0.96 per standard deviation (SD, i.e. 0.22 mmol/l) (95% CIs 0.93-0.98, p = 0.003)). The largest point estimates were observed for eicosapentaenoic acid (EPA), a long-chain omega-3 fatty acid (OREPA 0.92; 95% CI 0.88-0.96; p = 0.0002). The effect of omega-3 fatty acids was robust to MVMR models accounting for biologically correlated lipids. 'Leave-one-out' analyses highlighted the FADS gene cluster as a key driver of the effect. Colocalization analyses suggested a shared causal variant using the primary outcome sample, but genomic confounding could not be fully excluded. This study supports a role for omega-3 fatty acids, particularly EPA, in the aetiology of depression, although pleiotropic mechanisms cannot be ruled out. The findings support guidelines highlighting the importance of EPA dose and ratio for MDD and question whether targeted interventions may be superior to universal prevention trials, as modest effect sizes will limit statistical power.

Lipidomic and Fatty Acid Biomarkers in Whole Blood Can Predict the Dietary Intake of Eicosapentaenoic and Docosahexaenoic Acids in a Danish Population.

BACKGROUND: The intake of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been associated with health benefits. Blood levels of these fatty acids, measured by gas chromatography (GC), are associated with their dietary intake, but the relationships with lipidomic measurements are not well defined. OBJECTIVES: This study aimed to determine the lipidomic biomarkers in whole blood that predict intakes of EPA + DHA and examine the relationship between lipidomic and GC-based n-3 polyunsaturated fatty acid (n-3 PUFA) biomarkers. METHODS: Lipidomic and fatty acid analyses were completed on 120 whole blood samples collected from Danish participants. Dietary intakes were completed using a web-based 7-d food diary. Stepwise multiple linear regression was used to identify the fatty acid and lipidomic variables that predict intakes of EPA + DHA and to determine lipidomic species that predict commonly used fatty acid biomarkers. RESULTS: Stepwise regression selected lipidomic variables with an R2 = 0.52 for predicting EPA + DHA intake compared to R2 = 0.40 for the selected fatty acid GC-based variables. More predictive models were generated when the lipidomic variables were selected for females only (R2 = 0.62, n = 68) and males only (R2 = 0.72, n = 52). Phosphatidylethanolamine plasmalogen species containing EPA or DHA tended to be the most predictive lipidomic variables. Stepwise regression also indicated that selected lipidomic variables can predict commonly used fatty acid GC-based n-3 PUFA biomarkers as the R2 values ranged from 0.84 to 0.91. CONCLUSIONS: Both fatty acid and lipidomic data can be used to predict EPA + DHA intakes, and fatty acid GC-based biomarkers can be emulated by lipidomic species. Lipidomic-based biomarkers appear to be influenced by sex differences, probably in n-3 PUFA and lipoprotein metabolism. These results improve our ability to understand the relationship between novel lipidomic data and GC fatty acid data and will increase our ability to apply lipidomic methods to fatty acid and lipid nutritional research.

Resolvin D1 level during different trimesters of pregnancy for predicting the risk of fetal growth retardation in elderly pregnancy.

Resolvin D1 (RvD1) is potentially associated with fetal growth retardation (FGR) through alleviating maternal inflammation and its linkage with several pregnancy complications. Thus, this study detected RvD1 levels at different trimesters of pregnancy, aiming to investigate its role in predicting FGR risk of elderly pregnant women. This prospective, observational cohort study enrolled 165 elderly pregnant women aged ≥35 years. Serum RvD1 was detected at 10-13 weeks (early pregnancy), 20-23 weeks (middle pregnancy), and 30-33 weeks (late pregnancy) of gestational week by enzyme-linked immunosorbent assay. RvD1 was varied among different trimesters of pregnancy in elderly pregnant women (p < 0.001). FGR occurred in 25 (15.2%) women in this study. RvD1 at early (p = 0.009), middle (p = 0.002), and late (p = 0.003) pregnancy was decreased in women with FGR versus those without. By multivariate analysis, RvD1 at middle pregnancy (odds ratio (OR): 0.477, p < 0.001), pre-pregnancy body mass index (OR: 0.763, p = 0.025), and gestational diabetes mellitus (yes versus no) (OR: 0.071, p = 0.031) were independently correlated with declined FGR risk. While age (OR: 1.382, p = 0.009) was independently associated with elevated risk of FGR. Furthermore, the combination of these independent factors as a predictive model exhibited a good potential for assessing FGR risk (area under the curve: 0.802, 95% confidence interval: 0.711-0.894). In conclusion, RvD1 at different trimesters of pregnancy is negatively linked with the risk of FGR, whose level at middle pregnancy serves as an independent factor for FGR risk in elderly pregnant women.

Association between plasma maresin 1 and the risk of atherosclerotic cardiovascular disease in Chinese adults: A community-based cohort study.

BACKGROUND AND AIMS: It has been reported that maresin 1 (MaR1) is able to protect against the development of atherogenesis in cellular and animal models. This study was performed to investigate whether plasma MaR1 is associated with the risk of atherosclerotic cardiovascular disease (ASCVD) at the population level. METHODS AND RESULTS: The study included 2822 non-ASCVD participants from a community-based cohort who were followed for about 8 years. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) for ASCVD events according to baseline MaR1 quartiles were calculated using the Cox proportional hazards model. During follow-up, a total of 290 new ASCVD cases were identified. The restricted cubic spline analysis indicated a linear dose-response association between plasma MaR1 and incident ASCVD. In addition, the adjusted-HR (95% CI) for ASCVD events associated with one standard deviation increase in MaR1 was 0.79 (0.68-0.91). Moreover, the adjusted-HRs (95% CIs) for ASCVD events associated with the second, third and fourth quartiles versus the first quartile of plasma MaR1 were 1.00, 1.04 (0.76, 1.42), 0.88 (0.64, 1.22) and 0.58 (0.41, 0.84), respectively. Mediation analyses showed that the association between MaR1 and incident ASCVD was partially mediated by small dense low-density lipoprotein cholesterol, with a mediation proportion of 9.23%. Further, the net reclassification improvement and integrated discrimination improvement of ASCVD risk were significantly improved when MaR1 was added to basic model established by conventional risk factors (all p < 0.01). CONCLUSIONS: Elevated plasma MaR1 concentrations are associated with a lower risk of ASCVD development.

Omega-3 Status Evaluation in Australian Female Rugby League Athletes: Ad Libitum Fish Oil Provision Results in a Varied Omega-3 Index.

Optimal omega-3 status, influenced by increased intake of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), is vital for physiological health. This study investigated the impact of ad libitum fish oil supplementation on the omega-3 status of female athletes in a professional rugby league team during a competitive season. Twenty-four (n = 24) athletes participated, and their omega-3 status was assessed using the Omega-3 Index (O3I) and arachidonic acid (AA) to EPA ratio through finger-prick blood samples taken at the start and end of the season. They were given access to a fish oil supplement (PILLAR Performance, Australia) with a recommended daily dose of four capsules per day (2,160 mg EPA and 1,440 mg docosahexaenoic acid). At the beginning of the season, the group mean O3I was 4.77% (95% confidence interval [CI: 4.50, 5.04]) and the AA to EPA ratio was 14.89 (95% CI [13.22, 16.55]). None of the athletes had an O3I exceeding 8%. By the season's end, the O3I was a significantly increased to 7.28% (95% CI [6.64, 7.93], p < .0001) and AA to EPA ratio significantly decreased to a mean of 6.67 (95% CI [5.02, 8.31], p < .0001), driven primarily by the significant increase in EPA of +1.14% (95% CI [0.77, 1.51], p < .0001). However, these changes were varied between the athletes and most likely due to compliance. This study has demonstrated that using the objective O3I feedback scale is possible with elite female rugby athletes, but individual strategies will be required to achieve daily intake targets of EPA + DHA.

Arachidonic acid and docosahexaenoic acid levels correlate with the inflammation proteome in extremely preterm infants.

BACKGROUND & AIM: Clinical trials supplementing the long-chain polyunsaturated fatty acids (LCPUFAs) docosahexaenoic acid (DHA) and arachidonic acid (AA) to preterm infants have shown positive effects on inflammation-related morbidities, but the molecular mechanisms underlying these effects are not fully elucidated. This study aimed to determine associations between DHA, AA, and inflammation-related proteins during the neonatal period in extremely preterm infants. METHODS: A retrospective exploratory study of infants (n = 183) born below 28 weeks gestation from the Mega Donna Mega trial, a randomized multicenter trial designed to study the effect of DHA and AA on retinopathy of prematurity. Serial serum samples were collected after birth until postnatal day 100 (median 7 samples per infant) and analyzed for phospholipid fatty acids and proteins using targeted proteomics covering 538 proteins. Associations over time between LCPUFAs and proteins were explored using mixed effect modeling with splines, including an interaction term for time, and adjusted for gestational age, sex, and center. RESULTS: On postnatal day one, 55 proteins correlated with DHA levels and 10 proteins with AA levels. Five proteins were related to both fatty acids, all with a positive correlation. Over the first 100 days after birth, we identified 57 proteins to be associated with DHA and/or AA. Of these proteins, 41 (72%) related to inflammation. Thirty-eight proteins were associated with both fatty acids and the overall direction of association did not differ between DHA and AA, indicating that both LCPUFAs similarly contribute to up- and down-regulation of the preterm neonate inflammatory proteome. Primary examples of this were the inflammation-modulating cytokines IL-6 and CCL7, both being negatively related to levels of DHA and AA in the postnatal period. CONCLUSIONS: This study supports postnatal non-antagonistic and potentially synergistic effects of DHA and AA on the inflammation proteome in preterm infants, indicating that supplementation with both fatty acids may contribute to limiting the disease burden in this vulnerable population. CLINICAL REGISTRATION NUMBER: ClinicalTrials.gov (NCT03201588).

Placental MFSD2A expression in fetal growth restriction and maternal and fetal DHA status.

INTRODUCTION: Fetal growth restriction (FGR) may affect placental transfer of key nutrients to the fetus, such as the fatty acid docosahexaenoic acid (DHA). Major facilitator superfamily domain containing 2A (MFSD2A) has been described as a specific DHA carrier in placenta, but its expression has not been studied in FGR. The aim of this study was to evaluate for the first time the placental MFSD2A levels in late-FGR pregnancies and the maternal and cord plasma DHA. METHODS: 87 pregnant women from a tertial reference center were classified into late-FGR (N = 18) or control (N = 69). Fatty acid profile was determined in maternal and cord venous plasma, as well as placental levels of MFSD2A and of insulin mediators like phospho-protein kinase B (phospho-AKT) and phospho-extracellular regulated kinase (phospho-ERK). RESULTS: Maternal fatty acid profile did not differ between groups. Nevertheless, late-FGR cord vein presented higher content of saturated fatty acids than control, producing a concomitant decrease in the percentage of some unsaturated fatty acids. In the late-FGR group, a lower DHA fetal/maternal ratio was observed when using percentages, but not with concentrations. No alterations were found in the expression of MFSD2A in late-FGR placentas, nor in phospho-AKT or phospho-ERK. DISCUSSION: MFSD2A protein expression was not altered in late-FGR placentas, in line with no differences in cord DHA concentration between groups. The increase in the saturated fatty acid content of late-FGR cord might be a compensatory mechanism to ensure fetal energy supply, decreasing other fatty acids percentage. Future studies are warranted to elucidate if altered saturated fatty acid profile in late-FGR fetuses might predispose them to postnatal catch-up and to long-term health consequences.

Sex, Body Mass Index, and APOE4 Increase Plasma Phospholipid-Eicosapentaenoic Acid Response During an ω-3 Fatty Acid Supplementation: A Secondary Analysis.

BACKGROUND: The brain is concentrated with omega (ω)-3 (n-3) fatty acids (FAs), and these FAs must come from the plasma pool. The 2 main ω-3 FAs, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), must be in the form of nonesterified fatty acid (NEFA) or esterified within phospholipids (PLs) to reach the brain. We hypothesized that the plasma concentrations of these ω-3 FAs can be modulated by sex, body mass index (BMI, kg/m2), age, and the presence of the apolipoprotein (APO) E-ε4 allele in response to the supplementation. OBJECTIVES: This secondary analysis aimed to determine the concentration of EPA and DHA within plasma PL and in the NEFA form after an ω-3 FA or a placebo supplementation and to investigate whether the factors change the response to the supplement. METHODS: A randomized, double-blind, placebo-controlled trial was conducted. Participants were randomly assigned to either an ω-3 FA supplement (DHA 0.8 g and EPA 1.7 g daily) or to a placebo for 6 mo. FAs from fasting plasma samples were extracted and subsequently separated into PLs with esterified FAs and NEFAs using solid-phase extraction. DHA and EPA concentrations in plasma PLs and as NEFAs were quantified using gas chromatography. RESULTS: EPA and DHA concentrations in the NEFA pool significantly increased by 31%-71% and 42%-82%, respectively, after 1 and 6 mo of ω-3 FA supplementation. No factors influenced plasma DHA and EPA responses in the NEFA pool. In the plasma PL pool, DHA increased by 83%-109% and EPA by 387%-463% after 1 and 6 mo of ω-3 FA supplementation. APOE4 carriers, females, and individuals with a BMI of ≤25 had higher EPA concentrations than noncarriers, males, and those with a BMI of >25, respectively. CONCLUSIONS: The concentration of EPA in plasma PLs are modulated by APOE4, sex, and BMI. These factors should be considered when designing clinical trials involving ω-3 FA supplementation. This trial was registered at clinicaltrials.gov as NCT01625195.

Joint effects of one year of marine omega-3 fatty acid supplementation and participant dietary fish intake upon circulating lipid mediators of inflammation resolution in a randomized controlled trial.

OBJECTIVES: We assessed the joint effects of omega (n)-3 fatty acid supplementation and dietary fish intake on systemic lipid mediators of inflammation among adults. METHODS: Within VITAL, a double-blind randomized controlled trial, adults were randomized to ω-3 fatty acids (460 mg EPA + 380 mg DHA/d) or placebo. We selected participants who reported low (<1 serving/mo) baseline dietary fish intake and matched them by age, sex, race, and trial arm to participants with self-reported highest fish intake (≥3.9 servings/wk). Baseline and 1-y plasma samples were tested for 9 ω-3 fatty acid-derived lipid mediators. Multivariable linear models assessed lipid mediator changes and joint effects of ω-3 fatty acid supplementation and dietary fish intake. RESULTS: Forty-eight participants with low baseline fish intake were matched to 48 with high fish intake. Mean age was 64.6 (±7.26), 50% were female, and 85% non-Hispanic white. One-year lipid mediator changes in expected directions were observed in those receiving ω-3 fatty acids versus placebo: reductions in proinflammatory mediators, PGD2, 5-HETE, and 12-HETE; increases in proresolving mediators, EPA and DHA. Larger 1-y lipid biomarker changes were seen in those with low baseline fish intake randomized to active ω-3 fatty acids for DHA, EPA, PGD2, Resolvin D1, and Resolvin D4 were observed, although no significant multiplicative interactions were detected. DISCUSSION: Beneficial changes in circulating proresolving and proinflammatory mediators were found with 1-y of ω-3 fatty acid supplementation versus placebo for all participants, with a trend toward larger effects among those with low baseline fish intake, although interactions were not significant.

The shift in the fatty acid composition of the circulating lipidome in Alzheimer's disease.

INTRODUCTION: Fatty acids (FAs) are the building blocks of complex lipids and signaling compounds; the role of the lipidome fatty acid profile (LFA) in AD progression remains unclear. METHODS: The LFA of plasma and cerebrospinal fluid (CSF) samples from 289 participants (103 AD patients, 92 MCI patients, and 94 controls) was determined by GC-FID. The MCI subjects were followed up for 58 ± 12.5 months. RESULTS: In controls, CSF has a more neuroprotective LFA than plasma. In CSF, a higher content of docosahexaenoic acid was associated with a reduced risk of MCI-to-AD progression. In plasma, higher oleic acid content was associated with lower risk of AD, MCI, and MCI-to-AD progression, whereas higher levels of vaccenic acid and docosahexaenoic acid were associated with greater risk of AD and MCI, and higher rate of MCI-to-AD progression, respectively. DISCUSSION: The circulating LFA is involved in the pathogenesis and progression of AD. HIGHLIGHTS: The lipidome fatty acid profile in CSF and plasma was markedly different. Higher levels of vaccenic acid and lower levels of oleic acid in plasma were associated with greater risk of Alzheimer's disease. In plasma, higher levels of oleic acid were associated with a reduced risk of MCI-to-AD progression. Higher levels of docosahexaenoic acid in CSF were associated with a lower risk of MCI-to-AD progression. Higher levels of docosahexaenoic acid in plasma were associated with a greater rate of MCI-to-AD progression.

Brown Adipose Tissue Activation in Humans Increases Plasma Levels of Lipid Mediators.

CONTEXT: Activation of brown adipose tissue (BAT) thermogenesis improves insulin sensitivity and is beneficial in obesity. Emerging evidence indicates that BAT activation increases lipid mediators that play autocrine and endocrine roles to regulate metabolism and inflammation. OBJECTIVE: The goal of the study was to determine the relationship between 2 distinct approaches of BAT activation (cold exposure and mirabegron treatment) with lipid mediators in humans. METHODS: Healthy female subjects (n = 14) were treated with the ß3-adrenergic receptor agonist mirabegron (100 mg) daily for 28 days. A subset of female subjects (n = 8) was additionally exposed to cold temperatures (14-16 °C) for 2 hours using a cooling vest prior to initiating mirabegron treatment. A panel of lipid mediators was assessed in plasma using targeted liquid chromatography-tandem mass spectrometry, and their relationship to anthropometric and metabolic parameters was determined. RESULTS: Activation of BAT with cold exposure acutely increased levels of lipoxygenase and cyclooxygenase products, including 12-hydroxyeicosapentaenoic acid, 12-hydroxyeicosatetraenoic acid (HETE), 5-HETE, 14-hydroxydocosahexaenoic acid (HDHA), an isomer of maresin 2 (MaR2), 17-HDHA, protectin D1 (PD1), and prostaglandin E2. Mirabegron treatment similarly increased these products acutely, although levels of some mediators were blunted after chronic mirabegron treatment. Selected lipid mediators, including an MaR2 isomer, 17-HDHA, 5-HETE, and 15-HETE, positively correlated with nonesterified fatty acids and negatively correlated with the respiratory quotient, while PD1, 15-HETE, and 5-HETE positively correlated with adiponectin. CONCLUSION: These results indicate that selected lipid mediators may serve as biomarkers of BAT activation.

Role of polyunsaturated fatty acids in Japanese patients with coronary spastic angina.

BACKGROUND: n-3 polyunsaturated fatty acids (PUFAs) reduce the risk of ischemic heart disease. However, there are few reports of a relationship between n-3 PUFAs and coronary spastic angina (CSA). This study aimed to assess the age-dependent role of serum levels of fatty acid in patients with CSA. METHODS AND RESULTS: We enrolled 406 patients who underwent ergonovine tolerance test (ETT) during coronary angiography for evaluation of CSA. All ETT-positive subjects were diagnosed as having CSA. We categorized the patients by age and results of ETT as follows: (1) young (age ≤ 65 years) CSA-positive (n = 32), (2) young CSA-negative (n = 134), (3) elderly (age > 66 years) CSA-positive (n = 36), and (4) elderly CSA-negative (n = 204) groups. We evaluated the serum levels of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), arachidonic acid, and dihomo-gamma-linolenic acid. In the young groups, the serum levels of EPA (64.3 ±â€¯37.7 µg/mL vs. 49.4 ±â€¯28.8 µg/mL, p = 0.015) and DHA (135.7 ±â€¯47.6 µg/mL vs. 117.4 ±â€¯37.6 µg/mL, p = 0.020) were significantly higher in the CSA-positive group than in the CSA-negative group, respectively. However, this was not the case with elderly groups. In the multivariate analysis in young groups, the serum levels of EPA (p = 0.028) and DHA (p = 0.049) were independently associated with the presence of CSA, respectively. CONCLUSION: Our results suggested that the higher serum levels of EPA and/or DHA might be involved in the pathophysiology of CSA in the young population but not in the elderly population.

Evaluation of IL-10, MCP-1, IFN gamma, and protectin D1 levels in patients with Hashimoto's thyroiditis.

PURPOSE: Hashimoto's thyroiditis (HT) is one of the most prevalent autoimmune endocrine diseases and caused by the loss of immune tolerance for the thyroid gland. Many pathophysiological mechanisms were speculated about the development of HT. In our study, we aimed to reveal the relationship between HT and IL-10, MCP-1, IFNɤ, and PD1 levels and compare them with control subjects. METHODS: We collected 37 patients with HT and 25 controls referred to our outpatient clinic. The diagnosis of HT was based on the detection of circulating antibodies to thyroid antigens and decreasing echogenicity on thyroid USG in patients with appropriate clinical characteristics. Serum IL-10, MCP-1, IFNɤ, and PD1 levels were detected using an ELISA KIT (96 T) method according to the manufacturer's instructions. RESULTS: All subjects were euthyroid (median TSH level was 1.68 mU/L in HT vs 1.83 mU/L in the controls, p = 0.672). Twenty-three of 37 patients with HT were taking L-thyroxin replacement. Levels of serum IL-10, IFNɤ, and PD1 in patients with HT were higher than the controls, but the differences were not statistically significant (p = 0.393, p = 0.495, and p = 0.052 respectively). The serum levels of MCP-1 in HT patients were statistically different and higher than the controls (p = 0.018). Correlation analysis displayed significant associations between IL-10, MCP-1, IFNɤ, and PD1 levels. CONCLUSION: Our study demonstrated that serum MCP-1 levels in HT patients were significantly increased; on the other hand, significant difference was not found between HT patients and the controls in terms of serum IL-10, IFNɤ, and PD1 levels.

Associations of genetically predicted fatty acid levels across the phenome: A mendelian randomisation study.

BACKGROUND: Fatty acids are important dietary factors that have been extensively studied for their implication in health and disease. Evidence from epidemiological studies and randomised controlled trials on their role in cardiovascular, inflammatory, and other diseases remains inconsistent. The objective of this study was to assess whether genetically predicted fatty acid concentrations affect the risk of disease across a wide variety of clinical health outcomes. METHODS AND FINDINGS: The UK Biobank (UKB) is a large study involving over 500,000 participants aged 40 to 69 years at recruitment from 2006 to 2010. We used summary-level data for 117,143 UKB samples (base dataset), to extract genetic associations of fatty acids, and individual-level data for 322,232 UKB participants (target dataset) to conduct our discovery analysis. We studied potentially causal relationships of circulating fatty acids with 845 clinical diagnoses, using mendelian randomisation (MR) approach, within a phenome-wide association study (PheWAS) framework. Regression models in PheWAS were adjusted for sex, age, and the first 10 genetic principal components. External summary statistics were used for replication. When several fatty acids were associated with a health outcome, multivariable MR and MR-Bayesian method averaging (MR-BMA) was applied to disentangle their causal role. Genetic predisposition to higher docosahexaenoic acid (DHA) was associated with cholelithiasis and cholecystitis (odds ratio per mmol/L: 0.76, 95% confidence interval: 0.66 to 0.87). This was supported in replication analysis (FinnGen study) and by the genetically predicted omega-3 fatty acids analyses. Genetically predicted linoleic acid (LA), omega-6, polyunsaturated fatty acids (PUFAs), and total fatty acids (total FAs) showed positive associations with cardiovascular outcomes with support from replication analysis. Finally, higher genetically predicted levels of DHA (0.83, 0.73 to 0.95) and omega-3 (0.83, 0.75 to 0.92) were found to have a protective effect on obesity, which was supported using body mass index (BMI) in the GIANT consortium as replication analysis. Multivariable MR analysis suggested a direct detrimental effect of LA (1.64, 1.07 to 2.50) and omega-6 fatty acids (1.81, 1.06 to 3.09) on coronary heart disease (CHD). MR-BMA prioritised LA and omega-6 fatty acids as the top risk factors for CHD. Although we present a range of sensitivity analyses to the address MR assumptions, horizontal pleiotropy may still bias the reported associations and further evaluation in clinical trials is needed. CONCLUSIONS: Our study suggests potentially protective effects of circulating DHA and omega-3 concentrations on cholelithiasis and cholecystitis and on obesity, highlighting the need to further assess them as prevention treatments in clinical trials. Moreover, our findings do not support the supplementation of unsaturated fatty acids for cardiovascular disease prevention.

Identification of Resolvin D1 and Protectin D1 as Potential Therapeutic Agents for Treating Kidney Stones.

Intrarenal calcium oxalate (CaOx) crystals induce renal tubular epithelial cell (TEC) inflammatory and oxidative injury. This study is aimed at exploring potential therapeutic lipid components in kidney stones because lipids are involved in the development of several diseases and indicate the risk of kidney stones. Serum specimens were collected from 35 kidney stone patients and 35 normal controls. The lipid components in serum were measured, and differences were analyzed. The documented biological importance was comprehensively reviewed to identify lipids that differed significantly between the two groups to find potential agents associated with kidney stones. CaOx nephrocalcinosis mouse model was established to examine the therapeutic effects of specific lipids on CaOx deposition and CaOx-induced oxidative renal injury. Several lipids with significantly different levels were present in the serum of patients with stones and normal controls. Resolvin D1 (RvD1) (4.93-fold change, P < 0.001) and protectin D1 (PD1) (5.06-fold change, P < 0.001) were significantly decreased in the serum of patients with kidney stones, and an integrative review suggested that these factors might be associated with inflammatory responses, which is a crucial mechanism associated with stone damage. The administration of RvD1 and PD1 significantly inhibited kidney CaOx deposition and suppressed CaOx-induced renal tubular cell inflammatory injury and necrosis in a CaOx nephrocalcinosis mouse model. Furthermore, RvD1 and PD1 facilitated the expression of the oxidative indicator superoxide dismutase 2 (SOD2), inhibited NADPH oxidase 2 (NOX2) expression, and diminished intracellular reactive oxygen species (ROS) levels. This study preliminarily elucidated the role of lipids in kidney stones. The inhibitory effects of RvD1 and PD1 on oxidative damage induced by CaOx deposition provide a promising perspective for kidney stone treatment strategies.