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Differential and shared effects of eicosapentaenoic acid and docosahexaenoic acid on serum metabolome in subjects with chronic inflammation.

ABSTRACT: The omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) affect cell function and metabolism, but the differential effects of EPA and DHA are not known. In a randomized, controlled, double-blind, crossover study, we assessed the effects of 10-week supplementation with EPA-only and DHA-only (3 g/d), relative to a 4-week lead-in phase of high oleic acid sunflower oil (3 g/day, defined as baseline), on fasting serum metabolites in 21 subjects (9 men and 12 post-menopausal women) with chronic inflammation and some characteristics of metabolic syndrome. Relative to baseline, EPA significantly lowered the tricarboxylic acid (TCA) cycle intermediates fumarate and α-ketoglutarate and increased glucuronate, UDP-glucuronate, and non-esterified DHA. DHA significantly lowered the TCA cycle intermediates pyruvate, citrate, isocitrate, fumarate, α-ketoglutarate, and malate, and increased succinate and glucuronate. Pathway analysis showed that both EPA and DHA significantly affected the TCA cycle, the interconversion of pentose and glucuronate, and alanine, and aspartate and glutamate pathways (FDR < 0.05) and that DHA had a significantly greater effect on the TCA cycle than EPA. Our results indicate that EPA and DHA exhibit both common and differential effects on cell metabolism in subjects with chronic inflammation and some key aspects of metabolic syndrome.

SUBMITTER: Chang WC

PROVIDER: S-EPMC8357808 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Chronic Arachidonic Acid Administration Decreases Docosahexaenoic Acid- and Eicosapentaenoic Acid-Derived Metabolites in Kidneys of Aged Rats.

Project description:Arachidonic acid (ARA) metabolites produced by cyclo-oxygenase and lipoxygenase are important mediators maintaining physiological renal function. However, the effects of exogenous ARA on kidney function in vivo remain unknown. This study examined the effects of long-term oral ARA administration on normal renal function as well as inflammation and oxidative stress in aged rats. In addition, we measured levels of renal eicosanoids and docosanoids using liquid chromatography-tandem mass spectrometry. Control or ARA oil (240 mg/kg body weight/day) was orally administered to 21-month-old Wistar rats for 13 weeks. Levels of plasma creatinine, blood urea nitrogen, inflammatory and anti-inflammatory cytokines, reactive oxygen species, and lipid peroxidation were not significantly different between the two groups. The ARA concentration in the plasma, kidney, and liver increased in the ARA-administered group. In addition, levels of free-form ARA, prostaglandin E2, and 12- and 15-hydroxyeicosatetraenoic acid increased in the ARA-administered group, whereas renal concentration of docosahexaenoic acid and eicosapentaenoic acid decreased in the ARA-administered group. Levels of docosahexaenoic acid-derived protectin D1, eicosapentaenoic acid-derived 5-, and 18-hydroxyeicosapentaenoic acids, and resolvin E2 and E3 decreased in the ARA-administered group. Our results indicate that long-term ARA administration led to no serious adverse reactions under normal conditions and to a decrease in anti-inflammatory docosahexaenoic acid- and eicosapentaenoic acid-derived metabolites in the kidneys of aged rats. These results indicate that there is a possibility of ARA administration having a reducing anti-inflammatory effect on the kidney.

| S-EPMC4618288 | biostudies-literature

Differential effects of high dose omega-3 fatty acids on metabolism and inflammation in patients with obesity: eicosapentaenoic and docosahexaenoic acid supplementation.

Project description:BackgroundObesity is complicated by low-grade chronic inflammation characterised by increases in inflammatory proteins and cells in peripheral blood. It has been known that omega-3 fatty acids (FA) like eicosapentaenoic (EPA) and docosahexaenoic (DHA) could modulate the inflammatory process and improve metabolic markers.ObjectiveThis study aimed to determine the effect of high-dose omega-3 FA on metabolic and inflammatory markers among patients with obesity and healthy volunteers.MethodsThis prospective study included 12 women with obesity (body mass index [BMI] ≥ 35.0 kg/m2) and 12 healthy women (BMI < 24.0 kg/m2) who were supplemented with a dose of 4.8 g/day (3.2 g EPA plus 1.6 g DHA) for 3 months followed by no treatment for 1 month. Plasma metabolic and inflammatory markers and levels of mRNA transcripts of CD4+ T lymphocyte subsets were determined monthly.ResultsNone of the participants exhibited changes in weight or body composition after study completion. EPA and DHA supplementation improved metabolic (insulin, Homeostatic Model Assessment of Insulin Resistance [HOMA-IR], triglyceride [TG]/ high-density lipoprotein [HDL] ratio, TG, and arachidonic acid [AA]/EPA ratio) and tumor necrosis factor-alpha (TNF-α). Moreover, the levels of mRNA transcripts of T CD4+ lymphocyte subsets (TBX21, IFNG, GATA-3, interleukin [IL]-4, FOXP3, IL-10 IL-6, and TNF-α), were down-regulated during the intervention phase. After 1 month without supplementation, only insulin, HOMA-IR and the mRNA transcripts remained low, whereas all other markers returned to their levels before supplementation.ConclusionSupplementation with high-dose omega-3 FAs could modulate metabolism and inflammation in patients with obesity without weight loss or changes in body composition. However, these modulatory effects were ephemeral and with clear differential effects: short-duration on metabolism and long-lasting on inflammation.

| S-EPMC10196397 | biostudies-literature

Ratios of serum eicosapentaenoic acid to arachidonic acid and docosahexaenoic acid to arachidonic acid were inversely associated with serum resistin levels: The Hisayama Study.

Project description:Aims/introductionResistin is an adipocyte-derived polypeptide that leads to the progression of insulin resistance and subsequent atherosclerosis. Some studies have reported an association between self-reported intake of n-3 polyunsaturated fatty acids (PUFAs) and serum resistin levels. However, no studies have investigated the association between the ratio of serum levels of n-3 to serum n-6 PUFAs and the serum resistin concentration in the general population.Materials and methodsWe carried out a cross-sectional study of 3,200 community-dwelling Japanese individuals aged ≥40 years in 2002-2003. The ratios of serum eicosapentaenoic acid or docosahexaenoic acid to arachidonic acid (AA) were categorized into quartiles. The associations of serum eicosapentaenoic acid/AA and docosahexaenoic acid/AA with the serum resistin concentration were assessed using linear regression models with adjustment for potential confounding factors.ResultsThe geometric mean of serum resistin was 10.3 ng/mL. The age- and sex-adjusted geometric mean of serum resistin decreased significantly with increased levels of serum eicosapentaenoic acid/AA (quartile 1: 11.3 ng/mL; quartile 2: 10.6 ng/mL; quartile 3: 10.3 ng/mL; quartile 4: 9.3 ng/mL; P for trend <0.001). A similar association was observed for serum docosahexaenoic acid/AA (quartile 1: 11.1 ng/mL; quartile 2: 10.6 ng/mL; quartile 3: 10.1 ng/mL; quartile 4: 9.7 ng/mL; P for trend <0.001). An adjustment for potential confounding factors did not change these associations.ConclusionsHigher ratios of serum n-3 to n-6 PUFAs were associated with lower serum resistin levels. Consumption of a large amount of n-3 PUFAs might have desirable effects on resistin-mediated diseases.

| S-EPMC7078098 | biostudies-literature

Common and differential effects of docosahexaenoic acid and eicosapentaenoic acid on helper T-cell responses and associated pathways.

Project description:Our understanding of the differential effects between specific omega-3 fatty acids is incomplete. Here, we aimed to evaluate the effects of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) on T-helper type 1 (Th1) cell responses and identify the pathways associated with these responses. Naïve CD4+ T cells were co-cultured with bone marrow-derived dendritic cells (DCs) in the presence or absence of palmitate (PA), DHA, or EPA. DHA or EPA treatment lowered the number of differentiated IFN-γ-positive cells and inhibited the secretion of IFN-γ, whereas only DHA increased IL-2 and reduced TNF-α secretion. There was reduced expression of MHC II on DCs after DHA or EPA treatment. In the DC-independent model, DHA and EPA reduced Th1 cell differentiation and lowered the cell number. DHA and EPA markedly inhibited IFN-γ secretion, while only EPA reduced TNF-α secretion. Microarray analysis identified pathways involved in inflammation, immunity, metabolism, and cell proliferation. Moreover, DHA and EPA inhibited Th1 cells through the regulation of diverse pathways and genes, including Igf1 and Cpt1a. Our results showed that DHA and EPA had largely comparable inhibitory effects on Th1 cell differentiation. However, each of the fatty acids also had distinct effects on specific cytokine secretion, particularly according to the presence of DCs. [BMB Reports 2021; 54(5): 278-283].

| S-EPMC8167247 | biostudies-literature

Fish and Meat Intake, Serum Eicosapentaenoic Acid and Docosahexaenoic Acid Levels, and Mortality in Community-Dwelling Japanese Older Persons.

Project description:The associations between meat/fish consumption, docosahexaenoic acid (DHA)/eicosapentaenoic acid (EPA) intakes, and blood DHA/EPA levels, and mortality in Japan were examined as part of the National Institute for Longevity Sciences-Longitudinal Study of Aging: 520 men and 534 women (60-79 years at baseline) were followed from 1997-2017. Nutritional intakes were assessed using a 3-day dietary record and fasting venous blood samples were collected. Serum EPA/DHA concentrations, the EPA/arachidonic acid (ARA) ratio, EPA/DHA intakes, and fish/meat intakes were examined in tertiles as indicator variables, and hazard ratios (HR) were calculated to compare the risk of death across tertiles controlling for sex, age, body mass index, smoking status, alcohol drinking, physical activity, education, employment, and history of diseases. During follow-up (mean 11.7 years), 422 subjects (40.4%) died. The multivariate-adjusted HR for all-cause mortality in subjects in the highest tertile of serum DHA and EPA/ARA ratio was 0.73 (95% confidence intervals (CI): 0.53-0.99) and 0.71 (95% CI: 0.53-0.96) compared with subjects in the lowest tertile, respectively (trend p < 0.05). There were no significant associations between mortality and serum EPA/ARA and DHA/EPA intakes. An increased serum DHA level or EPA/ARA ratio might be recommended for longevity to Japanese community dwellers.

| S-EPMC6572518 | biostudies-literature

Effect of Docosahexaenoic Acid and Eicosapentaenoic Acid Supplementation on Sleep Quality in Healthy Subjects: A Randomized, Double-Blinded, Placebo-Controlled Trial.

Project description:Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA)-omega-3 fatty acids with various functions-influence sleep in children and young adults. However, only limited studies on their effects on sleep in middle- and old-aged adults have been reported. Therefore, we investigated the effects of DHA and EPA on sleep quality in subjects aged ≥ 45 years. We performed a randomized, placebo-controlled, double-blinded, parallel-grouped study, in which we randomly assigned 66 healthy Japanese males and females. Each individual received six 480 mg capsules containing 576 mg DHA and 284 mg EPA per day (DHA/EPA group, n = 33), or corn oil (placebo group, n = 33), for 12 weeks. Before and after the intervention, the Oguri-Shirakawa-Azumi sleep inventory MA version (OSA-MA) and the sleep state test were conducted. In the DHA/EPA group, factor III (frequent dreaming) scores among the OSA-MA scores were significantly improved compared to the placebo group. Additionally, sleep state tests revealed that sleep efficiency improved in the DHA/EPA group. To our knowledge, this study is the first to report that DHA/EPA improves sleep quality in middle- and old-aged individuals, even at doses lower than those administered in previous studies.

| S-EPMC9573173 | biostudies-literature

Naturally occurring monoepoxides of eicosapentaenoic acid and docosahexaenoic acid are bioactive antihyperalgesic lipids.

Project description:Beneficial physiological effects of long-chain n-3 polyunsaturated fatty acids are widely accepted but the mechanism(s) by which these fatty acids act remains unclear. Herein, we report the presence, distribution, and regulation of the levels of n-3 epoxy-fatty acids by soluble epoxide hydrolase (sEH) and a direct antinociceptive role of n-3 epoxy-fatty acids, specifically those originating from docosahexaenoic acid (DHA). The monoepoxides of the C18:1 to C22:6 fatty acids in both the n-6 and n-3 series were prepared and the individual regioisomers purified. The kinetic constants of the hydrolysis of the pure regioisomers by sEH were measured. Surprisingly, the best substrates are the mid-chain DHA epoxides. We also demonstrate that the DHA epoxides are present in considerable amounts in the rat central nervous system. Furthermore, using an animal model of pain associated with inflammation, we show that DHA epoxides, but neither the parent fatty acid nor the corresponding diols, selectively modulate nociceptive pathophysiology. Our findings support an important function of epoxy-fatty acids in the n-3 series in modulating nociceptive signaling. Consequently, the DHA and eicosapentaenoic acid epoxides may be responsible for some of the beneficial effects associated with dietary n-3 fatty acid intake.

| S-EPMC2975720 | biostudies-literature

Biochemical and behavioral effects of decreasing dietary linoleic acid and increasing eicosapentaenoic acid and docosahexaenoic acid in a rat chronic monoarthrits model.

Project description:Clinical studies have demonstrated that decreasing linoleic acid (LA) while increasing eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in diets evokes an analgesic effect in headache sufferers. We utilized a rat chronic monoarthritis model to determine if these analgesic effects can be reproduced in rats and to and further probe potential analgesic mechanisms. We fed 8 rats a control diet (with fatty acid levels similar to standard US diets) and 8 rats a low LA diet with added EPA and DHA (H3L6 diet) and after 10 weeks, performed a unilateral intraarticular injection of Complete's Freund Adjuvant (CFA). We evaluated thermal and mechanical sensitivity as well as hind paw weight bearing prior to and at 4 and 20 days post CFA injection. At 28 days post CFA injection rats were euthanized and tissue collected. H3L6 diet fed rats had higher concentrations of EPA and DHA, as well as higher concentrations of oxidized lipids derived from these fatty acids, in hind paw and plasma, compared to control fed rats. LA and oxidized LA metabolites were lower in the plasma and hind paw of H3L6 compared to control fed rats. Diet did not affect thermal or mechanical sensitivity, nor did it affect hind paw weight bearing. In conclusion, the H3L6 diet evoked biochemical changes in rats but did not impact pain related behavioral measures in this chronic monoarthritis model.

| S-EPMC9729441 | biostudies-literature

Docosahexaenoic acid, but not eicosapentaenoic acid, improves septic shock-induced arterial dysfunction in rats.

Project description:IntroductionLong chain n-3 fatty acid supplementation may modulate septic shock-induced host response to pathogen-induced sepsis. The composition of lipid emulsions for parenteral nutrition however remains a real challenge in intensive care, depending on their fatty acid content. Because they have not been assessed yet, we aimed at determining the respective effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) during septic shock-induced vascular dysfunction.MethodsIn a peritonitis-induced septic shock model, rats were infused with EPA, DHA, an EPA/DHA mixture or 5% dextrose (D5) during 22 hours. From H18, rats were resuscitated and monitored during 4 hours. At H22, plasma, aorta and mesenteric resistance arteries were collected to perform ex vivo experiments.ResultsWe have shown that septic rats needed an active resuscitation with fluid challenge and norepinephrine treatment, while SHAM rats did not. In septic rats, norepinephrine requirements were significantly decreased in DHA and EPA/DHA groups (10.6±12.0 and 3.7±8.0 μg/kg/min respectively versus 17.4±19.3 μg/kg/min in D5 group, p<0.05) and DHA infusion significantly improved contractile response to phenylephrine through nitric oxide pathway inhibition. DHA moreover significantly reduced vascular oxidative stress and nitric oxide production, phosphorylated IκB expression and vasodilative prostaglandin production. DHA also significantly decreased polyunsaturated fatty acid pro-inflammatory mediators and significantly increased several anti-inflammatory metabolites.ConclusionsDHA infusion in septic rats improved hemodynamic dysfunction through decreased vascular oxidative stress and inflammation, while EPA infusion did not have beneficial effects.

| S-EPMC5738044 | biostudies-literature

Eicosapentaenoic acid but not docosahexaenoic acid restores skeletal muscle mitochondrial oxidative capacity in old mice.

Project description:Mitochondrial dysfunction is often observed in aging skeletal muscle and is implicated in age-related declines in physical function. Early evidence suggests that dietary omega-3 polyunsaturated fatty acids (n-3 PUFAs) improve mitochondrial function. Here, we show that 10 weeks of dietary eicosapentaenoic acid (EPA) supplementation partially attenuated the age-related decline in mitochondrial function in mice, but this effect was not observed with docosahexaenoic acid (DHA). The improvement in mitochondrial function with EPA occurred in the absence of any changes in mitochondrial abundance or biogenesis, which was evaluated from RNA sequencing, large-scale proteomics, and direct measurements of muscle mitochondrial protein synthesis rates. We find that EPA improves muscle protein quality, specifically by decreasing mitochondrial protein carbamylation, a post-translational modification that is driven by inflammation. These results demonstrate that EPA attenuated the age-related loss of mitochondrial function and improved mitochondrial protein quality through a mechanism that is likely linked with anti-inflammatory properties of n-3 PUFAs. Furthermore, we demonstrate that EPA and DHA exert some common biological effects (anticoagulation, anti-inflammatory, reduced FXR/RXR activation), but also exhibit many distinct biological effects, a finding that underscores the importance of evaluating the therapeutic potential of individual n-3 PUFAs.

| S-EPMC4568961 | biostudies-literature

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