Beneficial Effects Of Eicosapentaenoic Acid Research Articles

Athletes Can Benefit from Increased Intake of EPA and DHA—Evaluating the Evidence

Fatty fish, which include mackerel, herring, salmon and sardines, and certain species of algae (e.g., Schizochytrium sp., Crytthecodiniumcohnii and Phaeodactylumtricornutum) are the only naturally rich sources of the omega-3 polyunsaturated fatty acids (n-3 PUFAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). EPA and DHA are the most biologically active members of the n-3 PUFA family. Limited dietary sources and fluctuating content of EPA and DHA in fish raise concerns about the status of EPA and DHA among athletes, as confirmed in a number of studies. The beneficial effects of EPA and DHA include controlling inflammation, supporting nervous system function, maintaining muscle mass after injury and improving training adaptation. Due to their inadequate intake and beneficial health-promoting effects, athletes might wish to consider using supplements that provide EPA and DHA. Here, we provide an overview of the effects of EPA and DHA that are relevant to athletes and discuss the pros and cons of supplements as a source of EPA and DHA for athletes.

DHA/EPA (Omega-3) and LA/GLA (Omega-6) as Bioactive Molecules in Neurodegenerative Diseases

Neurodegenerative diseases are characterized by neuroinflammation, neuronal depletion and oxidative stress. They coincide with subtle chronic or flaring inflammation, sometimes escalating with infiltrations of the immune system cells in the inflamed parts causing mild to severe or even lethal damage. Thus, neurodegenerative diseases show all features of autoimmune diseases. Prevalence of neurodegenerative diseases has dramatically increased in recent decades and unfortunately, the therapeutic efficacy and safety profile of available drugs is moderate. The beneficial effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) polyunsaturated fatty acids (omega-3 PUFAs) are nowadays highlighted by a plethora of studies. They play a role in suppression of inflammation, gene expression, cellular membrane fluidity/permeability, immune functionality and intracellular/exocellular signaling. The role of omega-6 polyunsaturated fatty acids, such as linoleic acid (LA), gamma linolenic acid (GLA), and arachidonic acid (AA), on neuroprotection is controversial, as some of these agents, specifically AA, are proinflammatory, whilst current data suggest that they may have neuroprotective properties as well. This review provides an overview of the existing recent clinical studies with respect to the role of omega-3 and omega-6 PUFAs as therapeutic agents in chronic, inflammatory, autoimmune neurodegenerative diseases as well as the dosages and the period used for testing.

Rationale for different formulations of omega-3 fatty acids leading to differences in residual cardiovascular risk reduction

Rationale for different formulations of omega-3 fatty acids leading to differences in residual cardiovascular risk reduction

Beneficial effects of eicosapentaenoic acid on the metabolic profile of obese female mice entails upregulation of HEPEs and increased abundance of enteric Akkermansia muciniphila

Eicosapentaenoic acid (EPA) ethyl esters are of interest given their clinical approval for lowering circulating triglycerides and cardiometabolic disease risk. EPA ethyl esters prevent metabolic complications driven by a high fat diet in male mice; however, their impact on female mice is less studied. Herein, we first investigated how EPA influences the metabolic profile of female C57BL/6J mice consuming a high fat diet. EPA lowered murine fat mass accumulation, potentially through increased biosynthesis of 8-hydroxyeicosapentaenoic acid (HEPE), as revealed by mass spectrometry and cell culture studies. EPA also reversed the effects of a high fat diet on circulating levels of insulin, glucose, and select inflammatory/metabolic markers. Next, we studied if the improved metabolic profile of obese mice consuming EPA was associated with a reduction in the abundance of key gut Gram-negative bacteria that contribute toward impaired glucose metabolism. Using fecal 16S-ribosomal RNA gene sequencing, we found EPA restructured the gut microbiota in a time-dependent manner but did not lower the levels of key Gram-negative bacteria. Interestingly, EPA robustly increased the abundance of the Gram-negative Akkermansia muciniphila, which controls glucose homeostasis. Finally, predictive functional profiling of microbial communities revealed EPA-mediated reversal of high fat diet-associated changes in a wide range of genes related to pathways such as Th-17 cell differentiation and PI3K-Akt signaling. Collectively, these results show that EPA ethyl esters prevent some of the deleterious effects of a high fat diet in female mice, which may be mediated mechanistically through 8-HEPE and the upregulation of intestinal Akkermansia muciniphila.

Temperature-Dependent Effects of Eicosapentaenoic Acid on Browning of Subcutaneous Adipose Tissue From UCP1 Knockout Mice

ObjectivesActivation and recruitment of thermogenic cells in white adipose tissue (WAT browning), in response to cold exposure, can combat obesity and associated metabolic disorders. We have previously reported that the beneficial effects of eicosapentaenoic acid (EPA), a long-chain omega 3 polyunsaturated fatty acids, in obesity and insulin resistance are independent of UCP1. In this study, we investigate the protective effects of EPA and the role of UCP1 in the browning of subcutaneous adipose tissue (SAT) at ambient and thermoneutral environments using UCP1 knockout (KO) mice. We hypothesized that EPA promotes SAT browning to prevent diet-induced obesity at both temperatures, independently of UCP1. MethodsMale and UCP1 KO and wild type (WT) B6 littermates were housed at room temperature (22°C) or thermoneutrality (28–30°C) and fed a high fat (HF) diet (45% kcal fat) supplemented with or without EPA (36g/kg) for 14 weeks. Body weight and glucose tolerance test (GTT) were measured, and browning-related markers were assessed in SAT. Data were statistically analyzed via three-way ANOVA using GraphPad to determine the individual and interactive effects of temperature, genotype, and diet. ResultsCompared to the WT, the body weight (BW) of KO mice increased at thermoneutrality (P < 0.01) but decreased at ambient temperature (P < 0.0001). Additionally, EPA attenuated weight and fat mass gain at thermoneutrality and improved glucose tolerance at both temperatures in both genotypes. mRNA levels for brown fat markers (Dio2 and Cidea), lipid metabolism (Elovl3, PGC1α, FASN, Cpt1b, and Gpd1), and batokines (Bmp8b and FGF21) were significantly up-regulated in KO mice, compared to WT, at ambient temperature (P < 0.01). Moreover, compared to HF-fed mice, EPA increased above markers in the KO mice at ambient temperature. Compared to HF, EPA-fed mice had significantly higher serum adiponectin levels (P < 0.01) in both genotypes and temperatures. ConclusionsUCP1 KO male mice were protected from diet-induced obesity and glucose intolerance and had increased SAT browning at ambient temperature. These results indicate that alternative thermoregulatory pathways mediate protective metabolic effects of EPA, in the absence of UCP1. These findings may be translated to human subjects with obesity, who exhibit low amounts of brown fat and UCP1. Funding SourcesNIH R15AT008879-01A1.

Randomized Phase II Study of Gemcitabine Monotherapy vs. Gemcitabine with an EPA-Enriched Oral Supplement in Advanced Pancreatic Cancer

Background Pancreatic cancer is often associated with cachexia. It had been reported that eicosapentaenoic acid (EPA) improve cachexia. This study aimed to evaluate the efficacy and safety of gemcitabine with an EPA-enriched oral supplement in patients with advanced pancreatic cancer. Methods This open-label phase II study consisted of patients (pts) who were randomly categorized into the EPA group (1,000 mg/m2 gemcitabine was administered on day 1, 8, and 15, every 4 weeks while an EPA-enriched oral supplement (prosure®, EPA 1.056 mg per pack) was taken daily at the maximum of two packs or the gemcitabine monotherapy group with an allocation ratio of 2:1. The primary endpoint was the evaluation of the 1-year survival estimating 10% addition. Results Randomized 68 pts were examined (EPA: 45, gemcitabine: 23). The 1-year survival probability of the EPA group was 35% while the gemcitabine group was 19%. The median survival times were 8.2 and 9.7 mo, respectively. The hazard ratio for EPA group was 0.79 [95% CI 0.46–1.37]; (P = 0.40). The toxicities were mild and insignificant in both groups. More beneficial effects of EPA in survival were observed in men, pancreatic body-tail and low C-reactive protein patients. Conclusion An EPA-enriched oral supplement may be effective in advanced pancreatic cancer.

Eicosapentaenoic Acid Reduces Hepatic Steatosis Independently of UCP1

Hepatic steatosis is characterized by excessive accumulation of triglyceride (TG). Mitochondrial membrane uncoupling proteins (UCPs) are potential targets for obesity treatment, given their ability to dissipate energy as heat. Previous studies in our lab have indicated that the omega‐3 polyunsaturated fatty acid, eicosapentaenoic acid (EPA), reduced obesity, inflammation and hepatic steatosis, and upregulated brown adipose tissue UCP1 protein in high fat (HF) fed mice housed at ambient temperature (22–23°C). However, EPA‐mediated improvements were attenuated and were independent of UCP1 when mice were housed in a thermoneutral environment (28–30°C). Thus, the objective of this work is to determine mechanisms of EPA‐mediated improvements in liver steatosis in UCP1 Knockout (KO) mice. Wild type (WT) and UCP1‐KO B6 mice were fed a HF diet with 36 g/kg AlaskOmega, 800mg/g fish oil of EPA (WT‐EPA, KO‐EPA) or without EPA (WT‐HF, KO‐HF) for 14 weeks. Mice were metabolically phenotyped during the feeding period, and histology and molecular analyses were performed in the liver after euthanasia. The KO‐HF group were highest in body weight, while KO‐HF, WT‐HF and WT‐EPA were comparable. Surprisingly, EPA attenuated weight gain in the KO‐EPA group compared to KO‐HF. Further, liver TG levels were significantly reduced in the KO‐EPA group compared to the KO‐HF. Consistent with this finding, EPA upregulated fatty acid beta‐oxidation markers only in the KO‐EPA group, indicated by significant increases in peroxisome proliferator activated receptor‐alpha (Ppara) and carnitine palmitoyltransferase (Cpt) 1a compared to KO‐HF. In conclusion, EPA rescued the detrimental effects of UCP1 deficiency in the livers of HF fed mice in a thermoneutral environment. Further studies are ongoing to dissect mechanistic basis for UCP1‐independent beneficial effects of EPA in liver steatosis. Our promising findings warrant further EPA supplementation studies in humans with obesity, given the limited activity of brown adipose tissue and downregulation of UCP1 in this population.Support or Funding InformationFunded by NIH/NCCIH grant #R15AT008879‐01A1 (N.M.M.)

Researches on the Pharmacological Effects of Eicosapentaenoic Acid

Fish oils are the most common source of omega-3 polyunsaturated fatty acids (n-3 PUFAs), mainly eicosapentaenoic acid(EPA). It has been pointed out protective effects and beneficial effects of EPA on body weight reduction, heart health, blood lipid profile, cardiovascular diseases and other diseases. Based on its biological activities, EPA may be developed to a complementary and alternative medicine through further research. In this paper, the pharmacological effects of EPA were summarized by reviewing the recent related literatures.

Abstract 3668: Chemopreventive effect of omega-3 fatty acid, EPA, in non-small cell lung cancer through formation of PGE3 and inhibition of PI3kinase/mTOR pathways.

Abstract The beneficial effects of eicosapentaenoic acid (EPA) are due, in part, to selective alteration of arachidonic acid metabolism that involves cyclooxygenase enzymes. We previously reported that the anti-proliferative effect of EPA in human non-small cell lung cancer (NSCLC) A549 cells was associated with formation of PGE3, a COX-2 metabolite of the fish oil derived EPA (J. Lipid Res. 45: 1030-1039, 2004). Here we report that EPA differentially regulated the in vitro anti-proliferative effect in non-small cell lung cancer A549 and H596 cells and the in vivo chemopreventive effect in K-ras transgenic murine lung carcinoma. When both A549 and H596 cells were treated with EPA (1 to 100 μM) for 72 hrs, EPA inhibited proliferation of A549 cells (IC50 &amp;lt; 6.25 μM) more effectively than H596 cells (IC50 &amp;gt; 50 μM), although both expressed similar level of COX-2. Analysis by MALDI MS showed that the level of EPA incorporated into phospholipids in H596 cells was 4-fold higher than A549 cells. Unexpectedly, H596 cells produced much less PGE3 than A549 cells. This is likely due to the relatively lower expression and activity of cytosolic phospholipase A2 (cPLA2) in H596 cells than in A549 cells. Use of siRNA to knock down cPLA2 in A549 cells markedly reduced the anti-proliferative activity of EPA compare to the control siRNA transfected cells. Intriguingly, PGE3 exhibited a dose dependent inhibition of proliferation, invasion and migration in A549 cells, possibly through down regulation of phosphorylation of Akt and S6 proteins. To assess the chemopreventive effect of EPA in lung cancer development, FVB/Kras (LA2) mouse were fed either a soybean oil diet (control) or one containing 1% or 2% EPA for 20 weeks. There was a 54% reduction in the number of tumor nodules in the 2% EPA diet group compared to control (P &amp;lt; 0.05). In addition, average tumor volume was dramatically reduced by 67% in the 2% EPA diet fed animals compared with the control group (P &amp;lt; 0.05). These results were confirmed by micro-CT and histopathology examinations. Interestingly, the endogenous levels of PGE2 in mouse lung tumor tissues were significantly reduced from control level of 489.1 ± 125.5 ng/mg to 171.9 ± 57.3 ng/mg protein in EPA (2%) treated mice, whereas PGE3 levels were significantly increased to 76.2 ± 33.3 ng/mg protein in EPA (2%) diet group compared to control group (5.1 ± 2.0 ng/mg protein). Furthermore, EPA (2%) markedly inhibited expression of both pAkt and pS6 in lung tumor tissues compared to the control. Taken together, the data suggest that EPA has the ability to inhibit the proliferation of NSCLC cells and prevent the development of mouse lung carcinoma. The anti-proliferative effect of EPA might be mediated through increased production of PGE3, which is regulated by cPLA2 and COX-2 enzymes, and inhibition of mTOR and PI3kinase pathways. This study is supported by NCI Grant 1R01CA144053-01. Citation Format: Yong Pan, David Pirman, Ekem Efuet, Patrea Rhea, Carrie Cartwright, Murali Ravoori, Vikas Kundra, Susan Fischer, Peiying Yang. Chemopreventive effect of omega-3 fatty acid, EPA, in non-small cell lung cancer through formation of PGE3 and inhibition of PI3kinase/mTOR pathways. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3668. doi:10.1158/1538-7445.AM2013-3668

The Assessment of Risk for Gastrointestinal Injury with Anticoagulant and Antiplatelet Drugs: The Possible Beneficial Effect of Eicosapentaenoic Acid for the Risk of Gastrointestinal Injury

Antithrombotic drugs have been increasingly used for treating ischemic cardiovascular diseases among the elderly in Japan. However, antithrombotic drugs are known to be risk factors for gastrointestinal injury. Therefore, we conducted a pharmacoepidemiologic study on patients receiving antithrombotic drugs to identify the risk factors for gastrointestinal injury. This retrospective case-control study included patients who were prescribed antithrombotic drugs at the Ehime University Hospital between April and September 2010. Of the 3271 patients who received antithrombotic drug therapy, 172 (5.3%) developed gastrointestinal injuries, including gastric ulcers, duodenal ulcers, and hemorrhagic gastrointestinal injuries. Further, the incidence of gastrointestinal injury was higher in patients with hypertension than in those without (p<0.0001). Multivariate adjusted odds ratios and 95% confidence intervals were calculated using stepwise logistic regression. The adjusted odds ratios for gastrointestinal injury were 1.56 (95% confidence interval 1.07-2.36) for hypertension, 1.70 (1.17-2.50) for low-dose aspirin, 2.77 (1.70-4.49) for clopidogrel, 1.95 (1.23-3.08) for warfarin, and 4.13 (2.88-5.95) for nonsteroidal anti-inflammatory drugs. On the other hand, the non-adjusted odds ratio for drug-associated gastrointestinal injury was 0.43 (0.20-0.84) for eicosapentaenoic acid (EPA). In addition, we found that patients aged 70 years or older were at increased risk of drug-associated gastrointestinal injury. These findings suggest that while many antithrombotic drugs are risk factors for gastrointestinal injury, EPA may be a safe option for suppressing or preventing gastrointestinal injury.

N-3 Fatty Acid-Derived Lipid Mediators in the Brain: New Weapons Against Oxidative Stress and Inflammation

Neuroprotectins, resolvins, and maresins are subfamilies of endogenous oxygenated metabolites derived from n-3 or ω-3 fatty acids (eicosapentaenoic and docosahexaenoic acids). These metabolites are associated with signal transduction processes involved in downregulation of oxidative stress, neuroinflammation and apoptosis. Eicosapentaenoic acid-derived E-series resolvins (RvE₁ and RvE₂) and docosahexaenoic acid-derived D-series resolvins (RvD₁ and RvD₂) and neuroprotectins have potent anti-inflammatory and proresolution, and antioxidant properties. They not only retard excessive inflammatory process, but also promote resolution by enhancing clearance of apoptotic cells and debris from inflamed brain tissue and vasculature leading to tissue homeostasis. These actions may underlie the beneficial effects of eicosapentaenoic acid and docosahexaenoic acid in normal human health, neurotraumatic and neurodegenerative diseases. Aspirin initiates resolution not only by exerting antithrombotic actions, but also triggering biosynthesis of specific and stereoselective epimers of resolvins, protectins, and maresins. In addition during the onset of resolution, these lipid mediators also display potent protective roles in neural systems, liver, lungs, and eyes. Potent anti-inflammatory actions of resolvins, and protectins in models of chronic human diseases indicate that down-regulation in resolution pathways may contribute to the decrease in the intensity of many chronic neurodegenerative and visceral diseases.

Evaluación de la eficacia de un suplemento oral en polvo enriquecido con ácido eicosapentaenoico en un grupo de pacientes con cáncer

Background and objectives: The beneficial effect of eicosapentaenoic acid in cancer patients is widely described especially in relation to its role in tumour cachexia. The aim of the study was to evaluate the efficacy of administration of a new oral powder supplement enriched with eicosapentaenoic acid compared to a standard liquid supplement in cancer patients. Patients and methods: A total of 61cancer patients, aged more than 18 years, were randomized to receive during a month a bonus of 600 kcal/ day to their regular diet with an oral powder supplement enriched with eicosapentaenoic acid (1.5 g) (RSI) or with a standard liquid supplement (RE). The following data were collected at baseline and after one month: the Patient-Generated Subjective Global Assessment (pg-SGA), anthropometric measurements (skin folds, circumferences and bioimpedance), dietary parameters (3-day food record), biochemical and inflammatory parameters (basic biochemistry, cytokines, prealbumin and Reactive C Protein). Quality of life was evaluated using the SF-36 questionnaire. At the end, scales were used to asses sensory perception, tolerance and satiety induced by the products and motivation to eat. Results: 40 patients completed the study. After intervention, anthropometric parameters do not change and prealbumin values increased significantly in both groups (RSI 16.11 ± 5.66 mg/dl vs. 19.81 ± 6.75 mg/dl p < 0.05 and RE 6.13 ± 16.55 mg/dl vs. 19.03 ± 5.47 mg / dl p < 0.05). RSI group significantly decreased interferon gamma (INF- γ) values (0.99 ± 0.95 vs. 0.65 ± 0.92 pg/ml, p < 0.05). In contrast, RE group increased INF-γ after intervention (1.62 ± 1 27 vs. 2.2 ± 3.19 pg/ml, p < 0.05). There were no significant differences in hunger, appetite, satiety and intake capacity in both groups. The SF-36 scores improved in both groups. Conclusions: Supplementation based on an oral powder formula enriched with 1.5g EPA during one month in cancer patients improved certain inflammatory parameters. This product may be a novel and valuable option to be added to the nutritional intervention strategies used for cancer patients.

Efficacy evaluation of an oral powder supplement enriched with eicosapentaenoic acid in cancer patients

The beneficial effect of eicosapentaenoic acid in cancer patients is widely described especially in relation to its role in tumour cachexia. The aim of the study was to evaluate the efficacy of administration of a new oral powder supplement enriched with eicosapentaenoic acid compared to a standard liquid supplement in cancer patients. A total of 61 cancer patients, aged more than 18 years, were randomized to receive during a month a bonus of 600 kcal/ day to their regular diet with an oral powder supplement enriched with eicosapentaenoic acid (1.5 g) (RSI) or with a standard liquid supplement (RE). The following data were collected at baseline and after one month: the Patient-Generated Subjective Global Assessment (pg-SGA), anthropometric measurements (skin folds, circumferences and bioimpedance), dietary parameters (3-day food record), biochemical and inflammatory parameters (basic biochemistry, cytokines, prealbumin and Reactive C Protein). Quality of life was evaluated using the SF-36 questionnaire. At the end, scales were used to asses sensory perception, tolerance and satiety induced by the products and motivation to eat. 40 patients completed the study. After intervention, anthropometric parameters do not change and prealbumin values increased significantly in both groups (RSI 16.11 ± 5.66 mg/dl vs. 19.81 ± 6.75 mg/dl p < 0.05 and RE 6.13 ± 16.55 mg/dl vs. 19.03 ± 5.47 mg / dl p < 0.05). RSI group significantly decreased interferon gamma (INF-γ) values (0.99 ± 0.95 vs. 0.65 ± 0.92 pg/ml, p < 0.05). In contrast, RE group increased INF-γ after intervention (1.62 ± 1 27 vs. 2.2 ± 3.19 pg/ml, p < 0.05). There were no significant differences in hunger, appetite, satiety and intake capacity in both groups. The SF-36 scores improved in both groups. Supplementation based on an oral powder formula enriched with 1.5 g EPA during one month in cancer patients improved certain inflammatory parameters. This product may be a novel and valuable option to be added to the nutritional intervention strategies used for cancer patients.

Eicosapentaenoic acid reduces ischemic ventricular fibrillation via altering monophasic action potential in pigs

Although high intake of n-3 fatty acids is associated with reduced mortality of patients with ischemic heart disease, especially reduction in sudden cardiac death (SCD), the detailed mechanisms remain to be elucidated. Thus, the present study was designed to examine whether long-term treatment with eicosapentaenoic acid (EPA), a major component of n-3 fatty acids, reduces ischemia-induced ventricular fibrillation (VF) in pigs in vivo, and if so, what molecular mechanisms are involved. Male pigs were treated with either a control chow (control group) or a control chow plus EPA (600 mg/kg/day, PO, EPA group) for 3 weeks and were subjected to myocardial ischemia for 90 min (n = 8 each) with measurement of the monophasic action potential (MAP), as a marker of ventricular electrophysiological activities. The EPA treatment significantly attenuated the occurrence of VF (control 5.1 ± 1.7 vs. EPA 1.5 ± 0.8 times/animal, P < 0.05) and markedly reduced the mortality (control 50% vs. EPA 0%, P < 0.05), with the attenuation of MAP duration shortening during ischemia (control − 28.1 ± 3.0% vs. EPA − 18.2 ± 1.4%, P < 0.05). These beneficial effects of EPA were abolished by pre-treatment with cromakalim, a K ATP channel opener (0.3 μg/kg/min, IC). Furthermore, EPA significantly inhibited the mRNA and protein expression of Kir6.2, a major component of sarcolemmal K ATP channels, in both the ischemic region and non-ischemic regions. These results indicate that long-term treatment with EPA reduces ischemia-induced VF and SCD in pigs in vivo, for which attenuation of MAP duration shortening may be involved.

Anti‐inflammatory and metabolic mechanisms by which omega‐3 fatty acids improve insulin resistance in high fat diet‐induced obese mice

In this study, we investigated the effects of eicosapentaenoic acid (EPA) on prevention (P) and reversal (R) of high‐fat (HF) diet‐induced obesity and metabolic alterations. Male C57BL/6J mice were fed low‐fat (LF), HF or a HF‐EPA‐P diet for 11 weeks. A fourth group was initially fed HF for 6 weeks followed by HF‐EPA‐R diet for 5 weeks. As expected, mice fed HF diet developed obesity and glucose intolerance. In contrast, mice fed HF‐EPA‐P diet maintained normal glucose tolerance despite weight gain when compared to the LF group. While the HF group developed fasting hyperglycemia and hyperinsulinemia, both HF‐EPA groups (P and R)‐R exhibited normal glycemia and insulinemia, demonstrating EPA's ability to prevent and improve insulin resistance associated with high fat feeding. Analysis of adipokines revealed that plasma adiponectin levels were lower in the HF group, but were comparable between LF and HF‐EPA groups, regardless of the high fat content of the diet. Further analysis of adipose tissue adipokine levels and proteomic studies in cultured adipocytes demonstrated that EPA reduces adipose inflammation (MCP‐1 and PAI‐1) and lipogenesis, while increasing fatty acid oxidation and mitochondrial content. These studies demonstrate that beneficial effects of EPA in improving insulin resistance are in part mediated by EPA's lipid oxidizing and anti‐inflammatory effects.Grant Funding Source: UT‐ORC, AHA and USDA‐NRI

Beneficial Effects of Eicosapentaenoic Acid in Coronary Heart Disease With Peripheral Vascular Diseases: But How and Why?

Beneficial Effects of Eicosapentaenoic Acid in Coronary Heart Disease With Peripheral Vascular Diseases: But How and Why?

Beneficial Effects of Eicosapentaenoic Acid in Coronary Heart Disease With Peripheral Vascular Diseases: But How and Why?

Beneficial Effects of Eicosapentaenoic Acid in Coronary Heart Disease With Peripheral Vascular Diseases: But How and Why?

Protective Effects of EPA and Deleterious Effects of DHA on eNOS Activity in Ea hy 926 Cultured with Lysophosphatidylcholine

Oxidized low density lipoprotein (Ox-LDL) is a well-established risk factor in atherosclerosis and lysophosphatidylcholine (LysoPtdCho) is considered to be one of the major atherogenic component of Ox-LDL. The purpose of this work was to investigate the effects of two membrane n-3 long chain polyunsaturated fatty acids (n-3 PUFAs), EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid) compared to n-6 PUFA, ARA (arachidonic acid), on the activation of endothelial NO synthase (eNOS) by histamine in Ea hy 926 endothelial cells incubated during 24 h in the presence or the absence of LysoPtdCho. DHA (50 muM) produced a ROS induction in cells and aggravated the LysoPtdCho-induced oxidative stress. It did not modify the basal eNOS activity but impaired the stimulation of eNOS induced by histamine and was unable to correct the deleterious effect of LysoPtdCho on histamine-stimulated eNOS activity or phosphorylation of Ser 1177. In contrast, EPA (90 muM) did not modify the ROS level produced in the presence or absence of LysoPtdCho or basal eNOS activity and the stimulating effect of histamine on eNOS. However, it diminished the deleterious effect of LysoPtdCho as well as on the histamine-stimulated eNOS activity on the phosphorylation on Ser 1177 of eNOS. The beneficial effect of EPA but not DHA on endothelial eNOS activity in Ea hy 926 could be also partially due to a slight decrease in membrane DHA content in EPA-treated cells. Consequently, the equilibrium between NO generated by eNOS and ROS due to oxidative stress could explain, in part, the beneficial effect of EPA on the development of cardiovascular diseases. By contrast ARA an n-6 PUFA was devoid of any effect on ROS generation or eNOS activity in the basal state or after histamine-induced stimulation. In vivo experiments should be undertaken to confirm these results.

Abstract 5061: Long-Term Treatment with Eicosapentaenoic Acid Suppresses Ischemia-Induced Ventricular Fibrillation: Potential Involvement of ATP-Sensitive Potassium (KATP) Channel

Although epidemiologic studies demonstrated that eicosapentaenoic acid (EPA) reduces sudden cardiac death in patients with coronary artery disease, the mechanisms remain to be examined. It was reported that during early myocardial ischemia, activated KATP channels could cause fatal ventricular arrhythmia. We thus hypothesized that long-term treatment with EPA suppresses ischemia-induced ventricular fibrillation (VF) by inhibiting myocardial KATP channels. Male pigs were treated with either a control chow or EPA (600 mg/kg/day, PO) for 3 weeks (n=8 each). They were subjected to myocardial ischemia (90 min) by occlusion of the left circumflex coronary artery and monophasic action potential (MAP) that reflects electrical activity of the LV in vivo was measured. In the EPA group, EPA content in red blood cells was increased to 4.5±0.3 mol%, a comparable level in the clinical studies (~5.8 mol%). The EPA treatment significantly reduced the occurrence of VF and the need for DC cardioversion, with a resultant marked improvement in mortality (EPA 0% vs. control 50%, P&lt;0.05). Furthermore, the EPA treatment significantly inhibited ischemia-induced shortening of MAP duration (measured at 90% repolarization) (EPA −19.5±3.0% vs. control −27.6±8.1%, P&lt;0.05). Importantly, the beneficial effect of EPA on MAP was abolished by pre-treatment with diazoxide, a KATP channel opener (5 mg/kg/min for 20 min, IC) (EPA+diazoxide −27.9±6.4%, P&lt;0.05 vs. EPA) ( Figure ). These results indicate that long-term treatment with EPA stabilizes ventricular electrical property during myocardial ischemia partly through suppression of KATP channels in vivo. Representative Recordings of Monophasic Action Potential(MAP) in Pigs

Eicosapentaenoic acid ameliorates diabetic nephropathy of type 2 diabetic KKAy/Ta mice: Involvement of MCP-1 suppression and decreased ERK1/2 and p38 phosphorylation

Previous studies reported that eicosapentaenoic acid (EPA) was effective against any renal diseases including diabetic nephropathy. Monocyte chemoattractant protein-1 (MCP-1) is a regulating macrophage recruitment protein, which is up-regulated in patients with diabetic nephropathy. The objectives of the present study were to evaluate the effects of EPA including renal MCP-1 expression in diabetic KKAy/Ta mice, MCP-1 production and signal transduction in mouse mesangial cells (MMCs). KKAy/Ta mice were injected with EPA ethyl ester (1 g/kg/day) intraperitoneally. Immunohistochemical staining of MCP-1, F4/80, phospho-extracellular signal-regulated kinase 1/2 (p-ERK1/2) and phospho-p38 in the renal sections were performed. EPA or specific inhibitors were incorporated in MMCs, and the levels of supernatant MCP-1 were measured. The effect of EPA on ERK1/2, c-jun NH2-terminal kinase (JNK), p38 or phosphoinositide 3-kinase (PI3K) activity in MMCs was examined using Western blot. EPA decreased the levels of serum triglycerides, leptin, urinary albumin and MCP-1, and improved glucose intolerance, mesangial matrix accumulation and tubulointerstitial fibrosis in KKAy/Ta mice. Immunohistochemical staining of MCP-1 and F4/80 in the glomeruli and tubulointerstitial regions was decreased in the EPA-treated group. EPA and specific inhibitors of ERK1/2, JNK and PI3K decreased levels of MCP-1 in MMCs. EPA suppressed phosphorylation of ERK1/2 and p38 in MMCs, and decreased p-ERK positive cells in glomeruli of KKAy/Ta mice. EPA ameliorates diabetic nephropathy of type 2 diabetic KKAy/Ta mice. We propose that the observed down-regulation of MCP-1 is critically involved in the beneficial effect of EPA, probably in concert with improvement of other clinical parameters.