Polyunsaturated Fatty Acids Eicosapentaenoic Acid Research Articles

17β-estradiol-induced ACSL4 protein expression promotes an invasive phenotype in estrogen receptor positive mammary carcinoma cells.

Long chain acyl-CoA synthase-4 (ACSL4) expression has been associated with an aggressive phenotype in breast carcinoma cells, whereas its role in ERα-positive breast cancer has not been studied. ACSL4 prefers 20-carbon polyunsaturated fatty acid (PUFA) substrates, and along with other ACSLs has been associated with cellular uptake of exogenous fatty acids. 17β-estradiol induces proliferation and invasive capacities in ERα+ve breast carcinoma that is associated with modifications of cellular lipid metabolism. In this study, treatment of steroid-starved ERα-positive MCF-7 and T47D mammary carcinoma cells with 17β-estradiol resulted in increased cellular uptake of the PUFA arachidonic acid (AA) and eicosapentaenoic acid (EPA), important building blocks for cellular membranes, and increased ACSL4 protein levels. There was no change in the expression of the ACSL1, ACSL3 and ACSL6 protein isotypes. Increased ACSL4 protein expression was not accompanied by changes in ACSL4 mRNA expression, but was associated with a significant increase in the protein half-life compared to untreated cells. ERα silencing reversed the impact of 17β-estradiol on ACSL4 protein levels and half-life. Silencing of ACSL4 eliminated the 17β-estradiol-induced increase in AA and EPA uptake, as well as the 17β-estradiol-induced cell migration, proliferation and invasion capacities. ASCL4 silencing also prevented the 17β-estradiol induced increases in p-Akt and p-GSK3β, and decrease in E-cadherin expression, important events in epithelial to mesenchymal transition. Taken together, these results demonstrate that ACSL4 is a target of 17β-estradiol-stimulated ERα and is required for the cellular uptake of exogenous PUFA and the manifestation of a more malignant phenotype in ERα+ve breast carcinoma cells.

Red blood cell polyunsaturated fatty acids and mortality in the Women's Health Initiative Memory Study

The prognostic value of circulating polyunsaturated fatty acid (PUFA) levels is unclear. To determine the associations between red blood cell (RBC) PUFA levels and risk fordeath. This prospective cohort study included 6501 women aged 65 to 80years who participated in the Women's Health Initiative Memory Study (enrolment began 1996). RBC PUFA levels were measured at baseline and expressed as a percent of total RBC PUFAs. PUFAs of primary interest were the n-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and their sum (the Omega-3 Index). PUFAs of secondary interest included the 2 major n-6 PUFAs, linoleic acid and arachidonic acid, and the PUFA factor score (a calculated variable including 6 PUFAs that accounts for their intercorrelations). The primary outcome was total mortality through August2014. After a median of 14.9years of follow-up, 1851 women (28.5%) had died. RBC levels of EPA and DHA were higher in the survivors (P<.002 for each). In the fully adjusted models, the hazard ratios (99% confidence intervals) for mortality associated with a 1 standard deviation PUFA increase for total mortality were 0.92 (0.85, 0.98) for the Omega-3 Index, 0.89 (0.82, 0.96) for EPA, 0.93 (0.87, 1.0) for DHA, and 0.76 (0.64, 0.90) for the PUFA factor score. There were no significant associations of alpha-linolenic acid, arachidonic acid or linoleic acid with total mortality. Higher RBC levels of marine n-3 PUFAs were associated with reduced risk for all-cause mortality. These findings support the beneficial relationship between the Omega-3 Index and health outcomes.

Effect of ω-3 polyunsaturated fatty acids on arthritic pain: Asystematic review.

Pain is a significant problem in rheumatoid arthritis (RA) and is associated with prostaglandins derived from the ω-6 polyunsaturated fatty acid (PUFA) arachidonic acid. The ω-3 PUFAs eicosapentaenoic acid and docosahexaenoic acid have been shown to reduce inflammation, with some studies showing clinical improvements in RA. The aim of this systematic review was to investigate the effect of ω-3 PUFAs on arthritic pain. A systematic literature review of ω-3 PUFAs and pain associated with RA was performed up to December 2015. Randomized controlled trials (RCTs) investigating the effect of ω-3 PUFAs (>2g/d) on patient or physician assessment of pain, or assessment by both patient and physician, were included. The Cochrane Collaboration's tool for assessing risk for bias was employed. Data for outcomes of interest were extracted and collated for interpretation. Eighteen RCTs published between 1985 and 2013 involving 1143 patients were included. Dosage of ω-3 PUFAs used was 2.1 to 9.1g/d, with study durations of 12 to 52wk. Ten studies supported the hypothesis that there is a reduction in patient or physician assessment of pain associated with RA after intake of ω-3 PUFAs. Eight studies found no statistically significant effect of ω-3 PUFAs on arthritic pain. ω-3 PUFAs may have a therapeutic role in decreasing pain associated with RA, with doses of 3 to 6g/d appearing to have a greater effect. Due to the limitations identified in the RCTs included in this review, more research is needed to investigate ω-3 PUFAs in larger populations and over extended periods of time.

Reduced acute neuroinflammation and improved functional recovery after traumatic brain injury by α-linolenic acid supplementation in mice.

BackgroundAdequate consumption of polyunsaturated fatty acids (PUFA) is vital for normal development and functioning of the central nervous system. The long-chain n-3 PUFAs docosahexaenoic acid (DHA) and eicosapentaenoic acid are anti-inflammatory and neuroprotective in the models of central nervous system injury including traumatic brain injury (TBI). In the present study, we tested whether a higher brain DHA status in a mouse model on an adequate dietary α-linolenic acid (ALA) leads to reduced neuroinflammation and improved spontaneous recovery after TBI in comparison to a moderately lowered brain DHA status that can occur in humans.MethodsMice reared on diets with differing ALA content were injured by a single cortical contusion impact. Change in the expression of inflammatory cytokines was measured, and cellular changes occurring after injury were analyzed by immunostaining for macrophage/microglia and astrocytes. Behavioral studies included rotarod and beam walk tests and contextual fear conditioning.ResultsMarginal supply (0.04 %) of ALA as the sole dietary source of n-3 PUFA from early gestation produced reduction of brain DHA by 35 % in adult offspring mice in comparison to the mice on adequate ALA diet (3.1 %). The DHA-depleted group showed significantly increased TBI-induced expression of pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 in the brain as well as slower functional recovery from motor deficits compared to the adequate ALA group. Despite the reduction of pro-inflammatory cytokine expression, adequate ALA diet did not significantly alter either microglia/macrophage density around the contusion site or the relative M1/M2 phenotype. However, the glial fibrillary acidic protein immunoreactivity was reduced in the injured cerebral cortex of the mice on adequate ALA diet, indicating that astrocyte activation may have contributed to the observed differences in cellular and behavioral responses to TBI.ConclusionsIncreasing the brain DHA level even from a moderately DHA-depleted state can reduce neuroinflammation and improve functional recovery after TBI, suggesting possible improvement of functional outcome by increasing dietary n-3 PUFA in human TBI.

Serum Omega-3 and Omega-6 Fatty Acids Are Not Associated with Personality Traits in Healthy Japanese Young People

Background: Recent studies have reported that polyunsaturated fatty acids (PUFAs) are associated with mood and behaviors including depression and suicide risk. The aim of this study was to examine the relationship between PUFAs and personality traits in healthy subjects. Methods: A total of 279 subjects completed the Temperament and Character Inventory and Beck Depression Inventory. Serum levels of the PUFAs eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), the ω-6 fatty acid arachidonic acid (AA), and dihomo-γ-linolenic acid were measured. Results: Pearson's correlation analysis showed a positive correlation between DHA and cooperativeness scores. In the multiple regression analysis, harm avoidance scores were positively associated with AA, and a negative association was found between the EPA/AA ratio and reward dependence scores. However, these associations were nonsignificant after a Bonferroni correction. Conclusion: The results of the present study suggest that the blood levels of PUFAs are not likely to be associated with personality traits.

Different Effects of Eicosapentaenoic and Docosahexaenoic Acids on Atherogenic High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease in Mice.

Non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of metabolic syndrome, can progress to steatohepatitis (NASH) and advanced liver damage, such as that from liver cirrhosis and cancer. Recent studies have shown the benefits of consuming n-3 polyunsaturated fatty acids (PUFAs) for the treatment of NAFLD. In the present study, we investigated and compared the effects of the major n-3 PUFAs—eicosapentaenoic acid (EPA, C20:5) and docosahexaenoic acid (DHA, C22:6)—in preventing atherogenic high-fat (AHF) diet-induced NAFLD. Mice were fed the AHF diet supplemented with or without EPA or DHA for four weeks. Both EPA and DHA reduced the pathological features of AHF diet-induced NASH pathologies such as hepatic lobular inflammation and elevated serum transaminase activity. Intriguingly, EPA had a greater hepatic triacylglycerol (TG)-reducing effect than DHA. In contrast, DHA had a greater suppressive effect than EPA on AHF diet-induced hepatic inflammation and ROS generation, but no difference in fibrosis. Both EPA and DHA could be effective for treatment of NAFLD and NASH. Meanwhile, the two major n-3 polyunsaturated fatty acids might differ in a relative contribution to pathological intermediate steps towards liver fibrosis.

Plasma and erythrocyte uptake of omega-3 fatty acids from an intravenous fish oil based lipid emulsion in patients with advanced oesophagogastric cancer

It has been demonstrated that short term intravenous (IV) administration of omega-3 polyunsaturated fatty acids (PUFAs) is more effective than oral supplementation at promoting incorporation of the bioactive omega-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) into plasma, blood cells and tissues. The effect of repeated short term IV infusion of omega-3 PUFAs was investigated in patients with advanced oesophagogastric cancer during palliative chemotherapy. Patients with advanced oesophagogastric cancer (n=21) were recruited into a phase II pilot clinical trial. All patients were scheduled for an intravenous infusion of Omegaven® (fish oil supplement containing EPA and DHA) at a rate of 2ml/kg body weight for 4h once a week for up to six months. Blood samples were collected to assess omega-3 PUFA uptake into plasma non-esterified fatty acids (NEFAs) and phosphatidylcholine (PC) and into red blood cell (RBC) membranes. Fatty acid profiles were analysed by gas chromatography. Twenty patients received at least one Omegaven® treatment and were included in the analysis. Each infusion of omega-3 PUFAs resulted in increased EPA and DHA in plasma NEFAs, but there was little effect on PUFAs within plasma PC during the infusions. However, with repeated weekly infusion of omega-3 PUFAs, the EPA content of plasma PC and of RBC membranes increased. Repeated weekly omega-3 PUFA infusion is effective in enriching plasma PC and RBC membranes in EPA in patients with advanced oesophagogastric cancer receiving palliative chemotherapy. Clinical Trials.Gov NCT01870791.

Association between serum long-chain omega-3 polyunsaturated fatty acids and cognitive performance in elderly men and women: The Kuopio Ischaemic Heart Disease Risk Factor Study.

Fish intake and the long-chain omega-3 polyunsaturated fatty acids (PUFAs) in fish have been suggested to lower the risk of cognitive decline. We assessed whether serum long-chain omega-3 PUFAs eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA) are associated with performance on neuropsychological tests in an older population and whether exposure to methylmercury, mainly from fish, or apolipoprotein-E4 (Apo-E4) phenotype can modify the associations. A total of 768 participants from the population-based Kuopio Ischaemic Heart Disease Risk Factor Study were included. Cognitive function was measured using five neuropsychological tests: the Trail Making Test, the Verbal Fluency Test, the Selective Reminding Test, the Visual Reproduction Test and the Mini Mental State Exam. Multivariate-adjusted analysis of covariance and linear regression were used to analyze the cross-sectional associations. We found statistically significant associations between serum EPA+DPA+DHA and better performance in the Trail Making Test and the Verbal Fluency Test. The individual associations with EPA and DHA were similar with the findings with EPA+DPA+DHA, although the associations with DHA were stronger. No associations were observed with serum DPA. Pubic hair mercury content was associated only with a worse performance in the Trail Making Test, and mercury had only little impact on the associations between the serum PUFAs and cognitive performance. Apo-E4 phenotype did not modify the associations with PUFAs or mercury. Higher serum long-chain omega-3 PUFA concentrations were associated with better performance on neuropsychological tests of frontal lobe functioning in older men and women. Mercury exposure or Apo-E4 phenotype had little impact on cognitive performance.

Eicosapentaenoic acid and docosahexaenoic acid increase the degradation of amyloid-β by affecting insulin-degrading enzyme.

Omega-3 polyunsaturated fatty acids (PUFAs) have been proposed to be highly beneficial in Alzheimer's disease (AD). AD pathology is closely linked to an overproduction and accumulation of amyloid-β (Aβ) peptides as extracellular senile plaques in the brain. Total Aβ levels are not only dependent on its production by proteolytic processing of the amyloid precursor protein (APP), but also on Aβ-clearance mechanisms, including Aβ-degrading enzymes. Here we show that the omega-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) increase Aβ-degradation by affecting insulin-degrading enzyme (IDE), the major Aβ-degrading enzyme secreted into the extracellular space of neuronal and microglial cells. The identification of the molecular mechanisms revealed that EPA directly increases IDE enzyme activity and elevates gene expression of IDE. DHA also directly stimulates IDE enzyme activity and affects IDE sorting by increasing exosome release of IDE, resulting in enhanced Aβ-degradation in the extracellular milieu. Apart from the known positive effect of DHA in reducing Aβ production, EPA and DHA might ameliorate AD pathology by increasing Aβ turnover.

Changes in Triglyceride‐Rich Lipoprotein Composition in Response to a High‐Fat Meal Promote Endothelial Inflammation in Hypertriglyceridemic Subjects

Cardiovascular disease (CVD) remains the leading cause of death and disability globally, despite the realization that much of this burden is preventable. Poor diet, and associated obesity and hypertriglyceridemia (HTG), are among the principal modifiable risk factors that collectively account for &gt; 50% of deaths due to CVD. These factors contribute to metabolic dysregulation, chronic low‐grade inflammation, and an array of stress responses, leading to endothelial dysfunction and accelerating atherosclerosis. Inflammatory responses mediated by endothelium are exacerbated by a high‐fat diet and the postprandial state, and culminate in the preferential recruitment of leukocytes to sites of nascent plaque formation via the upregulation of cell adhesion molecules (CAMs) such as VCAM‐1. The mechanisms linking unhealthy diets to the inflammation driving atherogenesis remain elusive. The prevalence of HTG as a component of the metabolic syndrome motivated us to study the atherogenicity of triglyceride‐rich lipoproteins (TGRL) isolated from human subjects after a high‐fat meal. We hypothesized that the composition of postprandial TGRL changes in proportion to the level of HTG to directly influence signaling responses in endothelium that underlie the earliest events of atherosclerosis. To study the maladaptive responses to dietary lipoproteins ex vivo, we developed a microfluidic lab‐on‐a‐chip assay, to quantify the expression of VCAM‐1 and capture of monocytes by endothelium. Our studies revealed that TGRL, isolated from human serum 3.5 hrs after a high‐fat meal challenge, primes either a pro‐ or anti‐atherogenic state in endothelium, defined as a net up‐ or down‐regulation of VCAM‐1 expression on cultured human aortic endothelial cells (HAEC) relative to inflammatory stimulation with TNFα. Pro‐inflammatory responses were associated with larger, more triglyceride‐rich particles, and correlated with subject abdominal obesity and HTG. The changes elicited by TGRL were functionally significant as they strongly correlated with flow‐dependent monocyte recruitment. To demonstrate a putative role for changes in the fatty acid (FA)‐rich triglyceride pool as a mediator of these responses, we examined TGRL from 13 subjects (ranging from pro‐ to anti‐inflammatory) for the total and non‐esterified FA (NEFA) constituents. A principle component analysis revealed discrete groupings of subjects by inflammatory phenotype. The relative abundance of NEFA provided the greatest discrimination between the samples, and implicated FA composition as a mediator of the relative inflammatory capacity of TGRL. Pro‐atherogenic changes in VCAM‐1 correlated with enrichment in the ratio of omega‐6 to omega‐3 polyunsaturated FA (PUFA). In our lab‐chip assay, the PUFA docosahexaenoic acid, eicosapentaenoic acid, and arachadonic acid significantly reduced VCAM‐1 expression by HAEC. Ongoing analysis of the bioactive metabolites of these fatty acids (oxylipins) is advancing our understanding of links between nutrition, lipid metabolism, and the earliest changes in endothelium that initiate atherosclerosis.Support or Funding InformationSupported by National Institute of Health grant HL082689 (SIS and AGP).

Supplementation with dietary EPA/DHA influences red blood cell fatty acid desaturase estimates and reflects tissue changes in fatty acids in systemic organs

Delta‐5‐desaturase (D5D) and delta‐6‐desaturase (D6D) are critical in polyunsaturated fatty acid (PUFA) metabolism. D5D and D6D catalyze the conversion of linoleic acid (LA) into arachidonic acid (AA) and that of alpha‐linolenic acid (ALA) into eicosapentaenoic acid (EPA). Altered PUFA desaturation (i.e., increased D6D and decreased D5D) can exacerbate inflammatory responses. Supplementation with the long chain PUFAs (LCPUFAs) EPA and DHA can influence PUFA metabolism and decrease pro‐inflammatory responses. Furthermore, changes in D5D and D6D activity are associated with obesity, type‐2 diabetes, and dysregulated metabolism. The objective of this study was to determine how increasing dietary EPA and DHA alters the D5D and D6D enzyme activity estimates (EAEs) in the RBC (red blood cell) and systemic tissues. In this study, mice were fed control plus three diets with increasing percent of energy (%en) derived from EPA+DHA. Dietary levels reflected recommended intakes of fish/fish oil by the American Heart Association. These doses translated to 0.1%en, 0.675%en, and 1.8%en from dietary EPA+DHA. Phospholipid (PL) fatty acids (FAs) were isolated from heart, skeletal muscle, spleen, lung, adipose tissue, and RBCs. PL FAs were converted to FA methyl esters and analyzed using gas chromatography. D5D and D6D EAEs were calculated using the ratio of arachidonic/dihomo‐gamma linolenic acid (DGLA) and DGLA/linoleic acid, respectively. We observed a positive correlation between RBC D5D EAEs and tissue D5D EAEs across all tissues. RBC D6D EAEs were positively correlated with muscle and negatively correlated with adipose D6D EAEs. D5D and D6D EAEs varied with EPA+DHA supplementation. When comparing the control vs the 1.8%en EPA+DHA diets, a significant decrease in D5D EAE was observed in heart (−42.51%), lung (−54.99%), spleen (−51.46%), and adipose (−78.06%). No significant difference was observed in muscle D5D EAE. Muscle D6D EAE significantly decreased (−39.95%). In adipose tissue, D6D was significantly increased compared to control (+97.80%). No significant dietary effect on D6D EAE was observed in heart, lung, or spleen with supplementation. RBC desaturase EAEs are reflective of tissue desaturase EAEs. Interestingly, RBC desaturase EAEs remained reflective of tissue desaturase EAEs despite changes in mean D5D and D6D EAEs after EPA+DHA supplementation. The high correlation between RBC desaturase EAEs and tissue desaturase EAEs with increasing dietary EPA and DHA, indicates RBC D5D and D6D EAEs are accurate non‐invasive methods to assess tissue PUFA metabolism. Future studies should investigate the usefulness of RBC desaturases in assessing tissues desaturases in disease models such as obesity, type‐2 diabetes, and metabolic syndrome and how EPA+DHA may alter fatty acid metabolism to favor an anti‐inflammatory profile.Support or Funding InformationResearch Support: NIH R03CA142000

Omega-3 polyunsaturated fatty acid supplementation and white matter changes in major depression

White matter abnormalities are implicated in major depressive disorder (MDD). As omega-3 polyunsaturated fatty acids (PUFAs) are low in MDD and affect myelination, we hypothesized that PUFA supplementation may alleviate depression through improving white matter integrity. Acutely depressed MDD patients (n = 16) and healthy volunteers (HV, n = 12) had 25-direction diffusion tensor imaging before and after 6 weeks of fish oil supplementation. Plasma phospholipid omega-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and omega-6 PUFA arachidonic acid (AA) levels were determined before and after supplementation using high-throughput extraction and gas chromatography and expressed as a percentage of total phospholipids (PUFA%). Fractional anisotropy (FA) was computed using a least-squares-fit diffusion tensor with non-linear optimization. Regression analyses were performed with changes in PUFA levels or Hamilton Depression Rating Scale scores as predictors, voxel-wise difference maps of FA as outcome, covariates age and sex, with family-wise correction for multiple comparisons. Increases in plasma phospholipid DHA% (but not EPA% or AA%) after fish oil predicted increases in FA in MDD but not HV, in a cluster including genu and body of the corpus callosum, and anterior corona radiata and cingulum (cluster-level p < 0.001, peak t-score = 8.10, p = 0.002). There was a trend for greater change in FA in MDD responders over nonresponders (t = −1.874, df = 13.56, p = 0.08). Decreased depression severity predicted increased FA in left corticospinal tract and superior longitudinal fasciculus (cluster-level p < 0.001, peak t-score = 5.04, p = 0.0001). Increased FA correlated with increased DHA% and decreased depression severity after fish oil supplementation suggests therapeutic effects of omega-3 PUFAs may be related to improvements in white matter integrity.

Treatment of LS174T colorectal cancer stem-like cells with n-3 PUFAs induces growth suppression through inhibition of survivin expression and induction of caspase-3 activation.

Colorectal cancer stem cells (CCSCs) are thought to contribute to tumor initiation, progression, metastasis, chemo-resistance and therapy failure. Therefore, assessment of the effectiveness of agents with anti-proliferative activities against CCSCs is warranted. Several studies have shown that different tumorigenic steps, ranging from initiation to metastasis, can be affected by n-3 polyunsaturated fatty acids (PUFAs). Here, we evaluated the effects of the PUFA components docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), alone or in combination, on LS174T cells that serve as a model for colorectal cancer initiating cells with stem cell-like properties. LS174T cells were treated with 50, 100 and 150 μM DHA and EPA, or equal mixtures of DHA/EPA (i.e., 25/25, 50/50 and 75/75 μM), after which cell number, viability, growth inhibition, survivin expression, caspase-3 activation and apoptotic rate were evaluated. We found that treatment of LS174T cells with increasing PUFA concentrations significantly increased growth inhibition in a dose- and time-dependent manner. After a 72 h treatment with 150 μM DHA and EPA, or their combination (75/75 μM), growth rates were inhibited by 80.3 ± 5.5%, 79.3 ± 5% and 71.1 ± 1%, respectively, compared to untreated cells. We also found that treatment for 48 h with 100 μM DHA and EPA, or their combination (50/50 μM), resulted in 2.9-, 3- and 2.6-fold increases in caspase-3 activation, as well as 54, 62.4 and 100% decreases in survivin mRNA expression levels, respectively, compared to untreated cells. Low survivin mRNA levels combined with high caspase-3 activity levels were found to correlate with a higher growth inhibition in PUFA-treated cells. DHA appears to be a more potent growth inhibitor than EPA and the DHA/EPA combination. An increase in the number of apoptotic cells (early + late), ranging from 12.9 to 44.7%, was observed with increasing DHA doses. From our data we conclude that PUFAs induce growth inhibition via targeting survivin expression in LS174T cells, which serve as a model for CCSCs.

N-3 polyunsaturated fatty acids and adiponectin in patients with end-stage renal disease.

In subjects without kidney disease, adiponectin appears to have anti-inflammatory, anti-diabetic, and anti-atherogenic effects. n-3 polyunsaturated fatty acids (PUFA) from seafood have several beneficial effects in patients with endstage renal disease (ESRD) and the aim of the present study was to assess the effect of n-3 PUFA supplementation on plasma adiponectin levels in ESRD patients. In a double blinded intervention trial, 162 ESRD patients (mean age 67 years  ± 13, 56 women and 106 men) undergoing chronic hemodialysis were randomized to 1.7 g n-3 PUFA daily or placebo for 3 months. Adiponectin, plasma lipids and lipoproteins were measured at baseline and after the intervention period. At baseline, adiponectin was positively correlated to HDL-cholesterol (r = 0.55, p < 0.001) and inversely correlated to plasma triglycerides, body mass index (BMI) and high sensitive C-reactive protein (Hs-CRP) (r = -0.32, p < 0.01, r = -0.43, p < 0.01, and r = -0.21, p < 0.01, respectively). Furthermore, adiponectin was inversely correlated to the plasma levels of the two major n-3 PUFA docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) (r = -0.19, p < 0.001, and r = -0.30, p < 0.001, respectively). Baseline plasma adiponectin levels were high in both groups but after 3 months of supplementation no significant change was observed in the groups. Thus, n-3 PUFA supplementation did not change adiponectin levels. We found an elevated plasma adiponectin level, which was inversely associated with plasma levels of DHA and EPA at baseline. Supplementation with n-3 PUFAs for 3 months did not change adiponectin levels. The negative result in this study may be related to a relatively low dose and future studies with higher dose and longer duration are needed to explore this mechanism.

Dietary intake of fish, polyunsaturated fatty acids, and survival after breast cancer: A population-based follow-up study on Long Island, New York.

In laboratory experiments, ω-3 polyunsaturated fatty acids (PUFAs) have been found to reduce inflammatory eicosanoids resulting from ω-6 PUFA metabolism via competitive inhibition, and the ω-3-induced cytotoxic environment increases apoptosis and reduces cell growth in breast cancer cells. To the authors' knowledge, epidemiologic investigations regarding whether dietary ω-3 PUFA intake benefits survival after breast cancer are limited and inconsistent. The authors used resources from a population-based follow-up study conducted on Long Island, New York, among 1463 women newly diagnosed with first primary breast cancer who were interviewed an average of approximately 3 months after diagnosis to assess risk and prognostic factors, including dietary intake (using a food frequency questionnaire). Vital status was determined through 2011, yielding a median follow-up of 14.7 years and 485 deaths. Adjusted hazard ratios (HRs) and 95% confidence intervals (95% CIs) were estimated using Cox proportional hazards regression. All-cause mortality was reduced among women with breast cancer reporting the highest quartile of intake (compared with never) for tuna (HR, 0.71; 95% CI, 0.55-0.92), other baked/broiled fish (HR, 0.75; 95% CI, 0.58-0.97), and the dietary long-chain ω-3 PUFAs docosahexaenoic acid (HR, 0.71; 95% CI, 0.55-0.92) and eicosapentaenoic acid (HR, 0.75; 95% CI, 0.58-0.97). All-cause mortality was reduced by 16% to 34% among women with breast cancer who reported a high intake of fish and long-chain ω-3 PUFAs. Long-chain ω-3 PUFA intake from fish and other dietary sources may provide a potential strategy to improve survival after breast cancer.

Maternal diet of Daphnia magna affects offspring growth responses to supplementation with particular polyunsaturated fatty acids

Previous studies examining the effects of food quality on zooplankton often controlled for maternal effects of resource provisioning using standardized maternal diets. However, varying nutritional history of mothers may change resource provisioning to their progeny, especially regarding polyunsaturated fatty acids (PUFAs), which may change the interpretation of previously observed fitness responses of offspring. To assess PUFA-mediated maternal provisioning effects on offspring, we raised females of the cladoceran Daphnia magna on diets differing considerably in PUFA composition and raised their offspring on a PUFA-lacking diet supplemented with the ω3 PUFAs α-linolenic acid (ALA) and/or eicosapentaenoic acid (EPA). The mass-specific growth responses of offspring to their own diets were affected by the maternal diet regime, probably due to varying maternal PUFA provisioning. A low maternal provisioning of EPA or ALA was sufficient to prevent growth limitation of offspring by these PUFAs until reaching maturity. A comparison with results of published ALA and EPA supplementation experiments suggests that the previously observed limitation effects depended on the usage of a single algae genus as maternal diet. Therefore, we suggest that maternal diets should be deliberately varied in future studies assessing ecological relevant food quality effects on zooplankton, especially regarding PUFAs.

Endogenous Production of Long-Chain Polyunsaturated Fatty Acids and Metabolic Disease Risk.

Long chain polyunsaturated fatty acids (PUFAs) are important structural components of cellular membranes and are converted into eicosanoids which serve various biological roles. The most common dietary n-6 and n-3 PUFAs are linoleic acid and α-linoleic acid, respectively. These 18-carbon chain fatty acids undergo a series of desaturation and elongation steps to become the 20-carbon fatty acids arachidonic acid and eicosapentaenoic acid, respectively. Evidence from genome wide association studies has consistently demonstrated that plasma and tissue levels of the n-6 long-chain PUFA arachidonic acid and to a lesser extent the n-3 long-chain PUFA eicosapentaenoic acid, are strongly influenced by variation in fatty acid desaturase-1,-2, and elongation of very long chain fatty acid genes. Studies of functional variants in these genes, as well as studies in which desaturase activity has been indirectly estimated by fatty acid product-to -precursor ratios, have suggested that endogenous capacity to synthesize long-chain PUFAs may be associated with metabolic diseases such as diabetes mellitus. Interventional studies are starting to tease out the complicated relationship between dietary intakes of specific fatty acids, variation in desaturase and elongase genes and tissue levels of long chain PUFAs. Thus future studies of dietary PUFA interventions designed to reduce inflammatory and metabolic diseases will need to carefully consider how an individual's genetically-determined endogenous long-chain PUFA synthesis capacity might modify therapeutic response.

Low plasma eicosapentaenoic acid levels are associated with elevated trait aggression and impulsivity in major depressive disorder with a history of comorbid substance use disorder

Major depressive disorder (MDD) is associated with low levels of omega-3 polyunsaturated fatty acids (PUFAs), holding promise for new perspectives on disease etiology and treatment targets. As aggressive and impulsive behaviors are associated with low omega-3 PUFA levels in some clinical contexts, we investigated plasma PUFA relationships with trait aggression and impulsivity in patients with MDD. Medication-free MDD patients (n = 48) and healthy volunteers (HV, n = 35) were assessed with the Brown-Goodwin Aggression Inventory. A subset (MDD, n = 39; HV, n = 33) completed the Barratt Impulsiveness Scale. Plasma PUFAs eicosapentaenoic acid (EPA, 20:5n-3), docosahexaenoic acid (DHA, 22:6n-3), and arachidonic acid (AA, 20:4n-6) were quantified and ln-transformed to mitigate distributional skew. Ln-transformed PUFA (lnPUFA) levels were predictors in regression models, with aggression or impulsivity scores as outcomes, and cofactors of sex and diagnostic status (MDD with or without a history of substance use disorder [SUD], or HV). Interactions were tested between relevant PUFAs and diagnostic status. Additional analyses explored possible confounds of depression severity, self-reported childhood abuse history, and, in MDD patients, suicide attempt history. Among PUFA, lnEPA but not lnDHA predicted aggression (F1,76 = 12.493, p = 0.001), and impulsivity (F1,65 = 5.598, p = 0.021), with interactions between lnEPA and history of SUD for both aggression (F1,76 = 7.941, p = 0.001) and impulsivity (F1,65 = 3.485, p = 0.037). Results remained significant when adjusted for childhood abuse, depression severity, or history of suicide attempt. In conclusion, low EPA levels were associated with aggression and impulsivity only in patients with MDD and comorbid SUD, even though in most cases SUD was in full sustained remission.

Clinical correlates of red blood cell omega-3 fatty acid content in male veterans with peripheral arterial disease

Despite available medical therapies, patients with peripheral arterial disease (PAD) remain at high risk for cardiovascular events. The n-3 polyunsaturated fatty acids (PUFA), derived from marine sources, have been shown to improve cardiovascular mortality. The Omega-3 Index (O3I), a proportion of the n-3 PUFA eicosapentaenoic acid and docosahexaenoic acid in the red blood cell membrane, correlates with cardiovascular risk. Previous investigations have found that n-3 PUFA supplementation, fish consumption, older age, and smoking history affect the O3I in different patient populations, although similar correlations have never been explored in PAD. We hypothesized that in our PAD cohort, blood content of omega-3 fatty acids would directly and positively correlate with a history of fish oil supplementation and older age and inversely correlate with a smoking history and obesity. This cross-sectional study included 111 patients who had an ankle-brachial index of<0.9 associated with claudication symptoms. We used linear regression to determine the association between clinical factors and the O3I. The mean age of the cohort was 69± 8years; 37% had diabetes mellitus (hemoglobin A1c, 7%± 1%), and 94% reported current smoking or a history of smoking. The mean O3I was 5%± 2%. In multivariate linear regression analysis, the O3I was associated with older age, increasing body mass index, and a history of smoking and fish oil intake. This is the first report of the relation between blood content of omega-3 fatty acids and clinical factors in a PAD population. In patients with PAD, older age, elevated body mass index, and prior fish oil supplementation predicted a higher O3I. A history of smoking correlated with a lower O3I. These results demonstrate that the O3I is a reliable measure of dietary n-3 PUFA intake and that clinical factors related to the O3I in PAD are similar to those observed in other populations.

Cell proliferation and long chain polyunsaturated fatty acid metabolism in a cell line from southern bluefin tuna (Thunnus maccoyii).

Southern bluefin tuna (SBT, Thunnus maccoyii) aquaculture is a highly valuable industry, but research on these fish is hampered by strict catch quotas and the limited success of captive breeding. To address these limitations, we have developed a SBT cell line (SBT-E1) and here we report on fatty acid metabolism in this cell line. The SBT-E1 cells proliferated well in standard Leibovitz's L-15 cell culture medium containing fetal bovine serum (FBS) as the source of fatty acids. Decreasing the FBS concentration decreased the cell proliferation. Addition of the C(18) polyunsaturated fatty acids (PUFA) α-linolenic acid (ALA, 18:3n-3) or linoleic acid (LNA, 18:2n-6) to the cell culture medium had little effect on the proliferation of the cells, whereas addition of the long-chain PUFA (LC-PUFA) arachidonic acid (ARA, 20:4n-6), eicosapentaenoic acid (EPA, 20:5n-3) or docosahexaenoic acid (DHA, 22:6n-3) significantly reduced the proliferation of the cells, especially at higher concentrations and especially for DHA. Addition of vitamin E to the culture medium overcame this effect, suggesting that it was due to oxidative stress. The fatty acid profiles of the total lipid from the cells reflected those of the respective culture media with little evidence for desaturation or elongation of any of the fatty acids. The only exceptions were EPA and ARA, which showed substantial elongation to 22:5n-3 and 22:4n-6, respectively, and DHA, which was significantly enriched in the cells compared with the culture medium. The results are discussed in light of the dietary PUFA requirements of SBT in the wild and in aquaculture.