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Mediators of Inflammation 2021Omega-3 polyunsaturated fatty acids (omega-3 PUFAs), which are essential fatty acids that humans should obtain from diet, have potential benefits for human health. In... (Review)
Review
Omega-3 polyunsaturated fatty acids (omega-3 PUFAs), which are essential fatty acids that humans should obtain from diet, have potential benefits for human health. In addition to altering the structure and function of cell membranes, omega-3 PUFAs (docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), alpha-linolenic acid (ALA), and docosapentaenoic acid (DPA)) exert different effects on intestinal immune tolerance and gut microbiota maintenance. Firstly, we review the effect of omega-3 PUFAs on gut microbiota. And the effects of omega-3 PUFAs on intestinal immunity and inflammation were described. Furthermore, the important roles of omega-3 PUFAs in maintaining the balance between gut immunity and the gut microbiota were discussed. Additional factors, such as obesity and diseases (NAFLD, gastrointestinal malignancies or cancer, bacterial and viral infections), which are associated with variability in omega-3 PUFA metabolism, can influence omega-3 PUFAs-microbiome-immune system interactions in the intestinal tract and also play roles in regulating gut immunity. This review identifies several pathways by which the microbiota modulates the gut immune system through omega-3 PUFAs. Omega-3 supplementation can be targeted to specific pathways to prevent and alleviate intestinal diseases, which may help researchers identify innovative diagnostic methods.
Topics: Animals; Eicosapentaenoic Acid; Fatty Acids, Omega-3; Fatty Acids, Unsaturated; Gastrointestinal Microbiome; Humans; Intestines
PubMed: 33488295
DOI: 10.1155/2021/8879227 -
Autophagy Jul 2021Recently, we identified a novel mechanism of lipotoxicity in the kidney proximal tubular cells (PTECs); lipid overload stimulates macroautophagy/autophagy for the...
Recently, we identified a novel mechanism of lipotoxicity in the kidney proximal tubular cells (PTECs); lipid overload stimulates macroautophagy/autophagy for the renovation of plasma and organelle membranes to maintain the integrity of the PTECs. However, this autophagic activation places a burden on the lysosomal system, leading to a downstream suppression of autophagy, which manifests as phospholipid accumulation and inadequate acidification in lysosomes. Here, we investigated whether pharmacological correction by eicosapentaenoic acid (EPA) supplementation could restore autophagic flux and alleviate renal lipotoxicity. EPA supplementation to high-fat diet (HFD)-fed mice reduced several hallmarks of lipotoxicity in the PTECs, such as phospholipid accumulation in the lysosome, mitochondrial dysfunction, inflammation, and fibrosis. In addition to improving the metabolic syndrome, EPA alleviated renal lipotoxicity via several mechanisms. EPA supplementation to HFD-fed mice or the isolated PTECs cultured in palmitic acid (PA) restored lysosomal function with significant improvements in the autophagic flux. The PA-induced redistribution of phospholipids from cellular membranes into lysosomes and the HFD-induced accumulation of SQSTM1/p62 (sequestosome 1), an autophagy substrate, during the temporal and genetic ablation of autophagy were significantly reduced by EPA, indicating that EPA attenuated the HFD-mediated increases in autophagy demand. Moreover, a fatty acid pulse-chase assay revealed that EPA promoted lipid droplet (LD) formation and transfer from LDs to the mitochondria for beta-oxidation. Noteworthy, the efficacy of EPA on lipotoxicity is autophagy-dependent and cell-intrinsic. In conclusion, EPA counteracts lipotoxicity in the proximal tubule by alleviating autophagic numbness, making it potentially suitable as a novel treatment for obesity-related kidney diseases. 4-HNE: 4-hydroxy-2-nonenal; ACTB: actin beta; ADGRE1/F4/80: adhesion G protein-coupled receptor E1; ATG: autophagy-related; ATP: adenosine triphosphate; BODIPY: boron-dipyrromethene; BSA: bovine serum albumin; cKO: conditional knockout; CML: N-carboxymethyllysine; COL1A1: collagen type I alpha 1 chain; COX: cytochrome c oxidase; CTRL: control; DGAT: diacylglycerol O-acyltransferase; EPA: eicosapentaenoic acid; FA: fatty acid; FFA: free fatty acid; GFP: green fluorescent protein; HFD: high-fat diet; iKO: inducible knockout; IRI: ischemia-reperfusion injury; LAMP1: lysosomal-associated membrane protein 1; LD: lipid droplet; LRP2: low density lipoprotein receptor-related protein 2; MAP1LC3: microtubule-associated protein 1 light chain 3; MTORC1: mechanistic target of rapamycin kinase complex 1; OA: oleic acid; PAS: periodic-acid Schiff; PPAR: peroxisome proliferator activated receptor; PPARGC1/PGC1: peroxisome proliferator activated receptor, gamma, coactivator 1; PTEC: proximal tubular epithelial cell; ROS: reactive oxygen species; RPS6: ribosomal protein S6; SDH: succinate dehydrogenase complex; SFC/MS/MS: supercritical fluid chromatography triple quadrupole mass spectrometry; SQSTM1/p62: sequestosome 1; TFEB: transcription factor EB; TG: triglyceride; TUNEL: terminal deoxynucleotidyl transferase dUTP nick end labeling.
Topics: Acute Kidney Injury; Animals; Autophagy; Diet, High-Fat; Eicosapentaenoic Acid; Kidney; Kidney Tubules, Proximal; Lysosomes; Mice; Mice, Transgenic; Phospholipids
PubMed: 32546086
DOI: 10.1080/15548627.2020.1782034 -
Annual Review of Pharmacology and... Jan 2023The long-chain omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are found in seafood, supplements, and concentrated pharmaceutical... (Review)
Review
The long-chain omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are found in seafood, supplements, and concentrated pharmaceutical preparations. Prospective cohort studies demonstrate an association between higher intakes of EPA+DHA or higher levels of EPA and DHA in the body and lower risk of developing cardiovascular disease (CVD), especially coronary heart disease and myocardial infarction, and of cardiovascular mortality in the general population. The cardioprotective effect of EPA and DHA is due to the beneficial modulation of a number of risk factors for CVD. Some large trials support the use of EPA+DHA (or EPA alone) in high-risk patients, although the evidence is inconsistent. This review presents key studies of EPA and DHA in the primary and secondary prevention of CVD, briefly describes potential mechanisms of action, and discusses recently published RCTs and meta-analyses. Potential adverse aspects of long-chain omega-3 fatty acids in relation to CVD are discussed.
Topics: Humans; Prospective Studies; Fatty Acids, Omega-3; Cardiovascular System; Docosahexaenoic Acids; Eicosapentaenoic Acid; Cardiovascular Diseases
PubMed: 36662586
DOI: 10.1146/annurev-pharmtox-051921-090208 -
Genomics, Proteomics & Bioinformatics Oct 2021Oleic acid (OA), a monounsaturated fatty acid (MUFA), has previously been shown to reverse saturated fatty acid palmitic acid (PA)-induced hepatic insulin resistance...
Oleic acid (OA), a monounsaturated fatty acid (MUFA), has previously been shown to reverse saturated fatty acid palmitic acid (PA)-induced hepatic insulin resistance (IR). However, its underlying molecular mechanism is unclear. In addition, previous studies have shown that eicosapentaenoic acid (EPA), a ω-3 polyunsaturated fatty acid (PUFA), reverses PA-induced muscle IR, but whether EPA plays the same role in hepatic IR and its possible mechanism involved need to be further clarified. Here, we confirmed that EPA reversed PA-induced IR in HepG2 cells and compared the proteomic changes in HepG2 cells after treatment with different free fatty acids (FFAs). A total of 234 proteins were determined to be differentially expressed after PA+OA treatment. Their functions were mainly related to responses to stress and endogenous stimuli, lipid metabolic process, and protein binding. For PA+EPA treatment, the PA-induced expression changes of 1326 proteins could be reversed by EPA, 415 of which were mitochondrial proteins, with most of the functional proteins involved in oxidative phosphorylation (OXPHOS) and tricarboxylic acid (TCA) cycle. Mechanistic studies revealed that the protein encoded by JUN and reactive oxygen species (ROS) play a role in OA- and EPA-reversed PA-induced IR, respectively. EPA and OA alleviated PA-induced abnormal adenosine triphosphate (ATP) production, ROS generation, and calcium (Ca) content. Importantly, HO-activated production of ROS increased the protein expression of JUN, further resulting in IR in HepG2 cells. Taken together, we demonstrate that ROS/JUN is a common response pathway employed by HepG2 cells toward FFA-regulated IR.
Topics: Eicosapentaenoic Acid; Hep G2 Cells; Humans; Hydrogen Peroxide; Insulin Resistance; Oleic Acid; Palmitic Acid; Proteomics; Reactive Oxygen Species
PubMed: 33631425
DOI: 10.1016/j.gpb.2019.06.005 -
Nutrients Mar 2021Brain structure and function depend on a constant and sufficient supply with eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) by blood. Blood levels of EPA and... (Review)
Review
Brain structure and function depend on a constant and sufficient supply with eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) by blood. Blood levels of EPA and DHA reflect dietary intake and other variables and are preferably assessed as percentage in erythrocytes with a well-documented and standardized analytical method (HS-Omega-3 Index). Every human being has an Omega-3 Index between 2 and 20%, with an optimum of 8-11%. Compared to an optimal Omega-3 Index, a lower Omega-3 Index was associated with increased risk for total mortality and ischemic stroke, reduced brain volume, impaired cognition, accelerated progression to dementia, psychiatric diseases, compromises of complex brain functions, and other brain issues in epidemiologic studies. Most intervention trials, and their meta-analyses considered EPA and DHA as drugs with good bioavailability, a design tending to produce meaningful results in populations characterized by low baseline blood levels (e.g., in major depression), but otherwise responsible for many neutral results and substantial confusion. When trial results were evaluated using blood levels of EPA and DHA measured, effects were larger than comparing EPA and DHA to placebo groups, and paralleled epidemiologic findings. This indicates future trial design, and suggests a targeted use EPA and DHA, based on the Omega-3 Index.
Topics: Brain; Docosahexaenoic Acids; Eicosapentaenoic Acid; Humans
PubMed: 33806218
DOI: 10.3390/nu13041074 -
European Heart Journal Oct 2020Despite the effects of statins in reducing cardiovascular events and slowing progression of coronary atherosclerosis, significant cardiovascular (CV) risk remains.... (Randomized Controlled Trial)
Randomized Controlled Trial
AIMS
Despite the effects of statins in reducing cardiovascular events and slowing progression of coronary atherosclerosis, significant cardiovascular (CV) risk remains. Icosapent ethyl (IPE), a highly purified eicosapentaenoic acid ethyl ester, added to a statin was shown to reduce initial CV events by 25% and total CV events by 32% in the REDUCE-IT trial, with the mechanisms of benefit not yet fully explained. The EVAPORATE trial sought to determine whether IPE 4 g/day, as an adjunct to diet and statin therapy, would result in a greater change from baseline in plaque volume, measured by serial multidetector computed tomography (MDCT), than placebo in statin-treated patients.
METHODS AND RESULTS
A total of 80 patients were enrolled in this randomized, double-blind, placebo-controlled trial. Patients had to have coronary atherosclerosis as documented by MDCT (one or more angiographic stenoses with ≥20% narrowing), be on statin therapy, and have persistently elevated triglyceride (TG) levels. Patients underwent an interim scan at 9 months and a final scan at 18 months with coronary computed tomographic angiography. The pre-specified primary endpoint was change in low-attenuation plaque (LAP) volume at 18 months between IPE and placebo groups. Baseline demographics, vitals, and laboratory results were not significantly different between the IPE and placebo groups; the median TG level was 259.1 ± 78.1 mg/dL. There was a significant reduction in the primary endpoint as IPE reduced LAP plaque volume by 17%, while in the placebo group LAP plaque volume more than doubled (+109%) (P = 0.0061). There were significant differences in rates of progression between IPE and placebo at study end involving other plaque volumes including fibrous, and fibrofatty (FF) plaque volumes which regressed in the IPE group and progressed in the placebo group (P < 0.01 for all). When further adjusted for age, sex, diabetes status, hypertension, and baseline TG, plaque volume changes between groups remained significantly different, P < 0.01. Only dense calcium did not show a significant difference between groups in multivariable modelling (P = 0.053).
CONCLUSIONS
Icosapent ethyl demonstrated significant regression of LAP volume on MDCT compared with placebo over 18 months. EVAPORATE provides important mechanistic data on plaque characteristics that may have relevance to the REDUCE-IT results and clinical use of IPE.
Topics: Aged; Coronary Artery Disease; Eicosapentaenoic Acid; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Middle Aged; Triglycerides
PubMed: 32860032
DOI: 10.1093/eurheartj/ehaa652 -
Pharmacology & Therapeutics Sep 2022Atherosclerotic cardiovascular disease (ASCVD) and its atherothrombotic complications impose a substantial disease burden in Europe, representing a cost of €210... (Review)
Review
Atherosclerotic cardiovascular disease (ASCVD) and its atherothrombotic complications impose a substantial disease burden in Europe, representing a cost of €210 billion per year for the European Union. Hypertriglyceridemia, a major risk factor for premature ASCVD, is present in more than 20% of the European population, and is a key feature of atherogenic dyslipidemia. Recent findings from the Progression of Early Subclinical Atherosclerosis (PESA) cohort in Spain showed that even in apparently healthy, middle-aged individuals without a history of cardiovascular (CV) risk, elevated triglyceride levels are associated with subclinical atherosclerosis and arterial inflammation. Emerging evidence from epidemiologic and genetic studies supports an independent causative role of triglycerides, triglyceride-rich lipoproteins, and their remnants in this pathology. Icosapent ethyl (IPE) is a highly purified, stable ethyl ester of eicosapentaenoic acid (EPA) that was initially approved by the United States Food and Drug Administration to treat severe hypertriglyceridemia, and subsequently received an expanded indication to reduce the risk of CV events in adult statin-treated patients. Approval was based on the pivotal, randomized, placebo-controlled, double-blind Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT), which showed that high-dose IPE (4 g/day) significantly reduced the risk of primary and secondary composite endpoints comprising major CV events and CV death relative to placebo. In 2021, the European Medicines Agency (EMA) approved IPE to reduce the risk of CV events in adult statin-treated patients at high CV risk with elevated triglyceride levels (≥1.7 mmol/L [≥150 mg/dL]) and established CV disease, or diabetes and at least one other CV risk factor. Clinical studies in Europe, which included patients with acute myocardial infarction, coronary artery disease, and those undergoing cardiac rehabilitation, established that 12.5% to 23.3% of these high-risk populations may benefit from treatment with IPE. Such clinical benefit may in part result from the moderate triglyceride-lowering properties of IPE/EPA; equally however, concentrations of atherogenic remnant particle-cholesterol are markedly reduced. Furthermore, IPE/EPA exerts pleiotropic actions beyond its lipid-lowering properties, which include modulation of endothelial function, attenuation of intra-plaque inflammation and oxidative stress, and reduction in macrophage accumulation. Plasma phospholipids, into which EPA is primarily incorporated and transported, appear to serve as precursors for a series of anti-inflammatory metabolites involving the resolvins RvE1 to RvE3, a pathway which may confer cardioprotective benefits. In addition, plaque imaging data from the Effect of Icosapent Ethyl on Progression of Coronary Atherosclerosis in Patients With Elevated Triglycerides on Statin Therapy (EVAPORATE) and the Combination Therapy of Eicosapentaenoic Acid and Pitavastatin for Coronary Plaque Regression Evaluated by Integrated Backscatter Intravascular Ultrasonography (CHERRY) trials show that plaque stabilization may be favorably affected. These factors may act synergistically to stabilize atherosclerotic plaques and reduce CV risk. In addition to robust efficacy data, multiple cost-utility studies across several countries indicate that IPE/EPA is a cost-effective treatment option that is favorably situated relative to some common willingness-to-pay thresholds. This review will evaluate the relevance of hypertriglyceridemia to residual ASCVD burden in statin-treated dyslipidemic patients, the potential of IPE/EPA to reduce the risk of ASCVD and cardiovascular mortality in high-risk patient populations, and the mechanisms which may underlie these effects. Finally, the clinical implications of the EMA label for IPE will be critically appraised in light of the updated 2019 European Society of Cardiology/European Atherosclerosis Society guidelines on the management of dyslipidemia and the recent European Atherosclerosis Society consensus statement on triglyceride-rich lipoproteins and their remnants, together with considerations of its cost-effectiveness across several countries.
Topics: Adult; Atherosclerosis; Cardiovascular Diseases; Coronary Artery Disease; Eicosapentaenoic Acid; Heart Disease Risk Factors; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertriglyceridemia; Lipoproteins; Middle Aged; Plaque, Atherosclerotic; Randomized Controlled Trials as Topic; Risk Factors; Triglycerides
PubMed: 35304222
DOI: 10.1016/j.pharmthera.2022.108172 -
Advances in Nutrition (Bethesda, Md.) Jul 2023The current guidelines recommend that people consume 2 or more servings of fat-rich fish per week to obtain enough omega-3 (ω-3) polyunsaturated fatty acids to prevent... (Meta-Analysis)
Meta-Analysis Review
The current guidelines recommend that people consume 2 or more servings of fat-rich fish per week to obtain enough omega-3 (ω-3) polyunsaturated fatty acids to prevent cardiovascular events. However, the cardiovascular benefits of ω-3 polyunsaturated fatty acids in patients with diabetes are unclear, and related large-scale trials have produced conflicting results. We aimed to perform a meta-analysis of all randomized controlled trials that attempted to assess the effects of ω-3 fatty acid supplementation on cardiovascular outcomes in patients with diabetes. In PubMed, EMBASE, and the Cochrane Library, we searched for data from all randomized controlled trials on ω-3 fatty acids and cardiovascular outcomes in patients with diabetes published before July 2022. Eight eligible studies involving 57,754 participants were ultimately included. Meta-analysis showed that ω-3 fatty acid supplementation reduces cardiovascular disease (CVD) risk in patients with diabetes (rate ration [RR] = 0.93; 95% confidence interval [CI]: 0.90, 0.97; P = 0.0009). Among them, eicosapentaenoic acid (EPA), but not EPA plus docosahexaenoic acid (DHA), significantly reduced the risk of CVD in patients with diabetes (EPA [RR = 0.81; 95% CI: 0.73, 0.90; P=0.0001]). This meta-analysis suggests that ω-3 fatty acid supplementation is an effective strategy to prevent CVD in patients with diabetes, but further well-designed, large-scale randomized controlled trials are necessary to evaluate the safety of ω-3 fatty acid supplementation, and its effect on atrial fibrillation. This study was registered with PROSPERO as CRD42022346302.
Topics: Humans; Dietary Supplements; Randomized Controlled Trials as Topic; Fatty Acids, Omega-3; Eicosapentaenoic Acid; Docosahexaenoic Acids; Diabetes Mellitus; Cardiovascular Diseases
PubMed: 37121469
DOI: 10.1016/j.advnut.2023.04.009 -
Journal of the American Academy of... Oct 2011Several studies have demonstrated differences in omega-3 fatty acid composition in plasma and in erythrocyte membranes in patients with attention-deficit/hyperactivity... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
Several studies have demonstrated differences in omega-3 fatty acid composition in plasma and in erythrocyte membranes in patients with attention-deficit/hyperactivity disorder (ADHD) compared with unaffected controls. Omega-3 fatty acids have anti-inflammatory properties and can alter central nervous system cell membrane fluidity and phospholipid composition. Cell membrane fluidity can alter serotonin and dopamine neurotransmission. The goal of this meta-analysis was to examine the efficacy of omega-3 fatty acid supplementation in children with ADHD.
METHOD
PubMed was searched for randomized placebo-controlled trials examining omega-3 fatty acid supplementation in children with ADHD symptomatology. The primary outcome measurement was standardized mean difference in rating scales of ADHD severity. Secondary analyses were conducted to determine the effects of dosing of different omega-3 fatty acids in supplements.
RESULTS
Ten trials involving 699 children were included in this meta-analysis. Omega-3 fatty acid supplementation demonstrated a small but significant effect in improving ADHD symptoms. Eicosapentaenoic acid dose within supplements was significantly correlated with supplement efficacy. No evidence of publication bias or heterogeneity between trials was found.
CONCLUSION
Omega-3 fatty acid supplementation, particularly with higher doses of eicosapentaenoic acid, was modestly effective in the treatment of ADHD. The relative efficacy of omega-3 fatty acid supplementation was modest compared with currently available pharmacotherapies for ADHD such as psychostimulants, atomoxetine, or α(2) agonists. However, given its relatively benign side-effect profile and evidence of modest efficacy, it may be reasonable to use omega-3 fatty supplementation to augment traditional pharmacologic interventions or for families who decline other psychopharmacologic options.
Topics: Attention Deficit Disorder with Hyperactivity; Child; Eicosapentaenoic Acid; Fatty Acids, Omega-3; Humans
PubMed: 21961774
DOI: 10.1016/j.jaac.2011.06.008 -
Journal of the American College of... May 2022REDUCE-IT was a double-blind trial that randomized 8,179 statin-treated patients with controlled low-density lipoprotein cholesterol and moderately elevated... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
REDUCE-IT was a double-blind trial that randomized 8,179 statin-treated patients with controlled low-density lipoprotein cholesterol and moderately elevated triglycerides to icosapent ethyl (IPE) or placebo. There was a significant reduction in the primary endpoint, including death from cardiovascular (CV) causes. The specific impact of IPE among patients with prior myocardial infarction (MI) was unknown.
OBJECTIVES
Our goal was to examine the benefit of IPE on ischemic events among patients with prior MI in REDUCE-IT.
METHODS
We performed post hoc analyses of patients with prior MI. The primary endpoint was CV death, MI, stroke, coronary revascularization, or hospitalization for unstable angina. The key secondary endpoint was CV death, MI, or stroke.
RESULTS
A total of 3,693 patients had a history of prior MI. The primary endpoint was reduced from 26.1% to 20.2% with IPE vs placebo; HR: 0.74 (95% CI: 0.65-0.85; P = 0.00001). The key secondary endpoint was reduced from 18.0% to 13.3%; HR: 0.71 (95% CI: 0.61-0.84; P = 0.00006). There was also a significant 35% relative risk reduction in total ischemic events (P = 0.0000001), a 34% reduction in MI (P = 0.00009), a 30% reduction in CV death (P = 0.01), and a 20% lower rate of all-cause mortality (P = 0.054), although there was a slight increase in atrial fibrillation. Sudden cardiac death and cardiac arrest were also significantly reduced by 40% and 56%, respectively.
CONCLUSIONS
Patients with a history of prior MI in REDUCE-IT treated with IPE demonstrated large and significant relative and absolute risk reductions in ischemic events, including CV death. (A Study of AMR101 to Evaluate Its Ability to Reduce Cardiovascular Events in High Risk Patients With Hypertriglyceridemia and on Statin. The Primary Objective is to Evaluate the Effect of 4 g/Day AMR101 for Preventing the Occurrence of a First Major Cardiovascular Event. [REDUCE-IT]; NCT01492361).
Topics: Eicosapentaenoic Acid; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertriglyceridemia; Myocardial Infarction; Stroke
PubMed: 35483753
DOI: 10.1016/j.jacc.2022.02.035