Omega-3 fatty acids (OM3FAs) are unsaturated fatty acids with at least one double bond located between the third and fourth omega end carbon. Currently, the three most clinically relevant omega-3 polyunsaturated fatty acids (PUFAs) are α-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). Oils containing these fatty acids originate in plant sources and can be found in fish, fish products, seeds, nuts, green leafy vegetables, and beans.
Currently, the FDA has only approved the use of four prescription omega-3 fatty acids products: icosapent ethyl, omega-3-acid ethyl esters, omega-3-carboxylic acids, and omega-3-acid ethyl esters A. Omega-3-acid ethyl esters,omega-3-carboxylic acids, and omega-3-acid ethyl esters A contain both EPA and DHA, whereas icosapent ethyl contains ethyl esters of EPA only. The aforementioned products are approved for adults (≥18 years of age) with very high triglycerides (≥ 500 mg/dl) as an adjunct to diet to decrease triglyceride levels and reduce cardiovascular events. These prescription OM3FA products have also been recommended in adjunctive therapy in combination with statins to provide an enhanced reduction of the total cholesterol/high-density lipoprotein cholesterol in comparison to statin alone. However, some studies have urged physicians to proceed with caution when prescribing a statin/DHA OM3FA combination due to the possibility of increased low-density lipoprotein (LDL) cholesterol. DHA containing OM3FA can be switched to EPA only icosapent ethyl that is not associated with increased LDL.
It is important to note that while these prescription OM3FA products are the only FDA approved products for the treatment of hypertriglyceridemia, ongoing research is currently investigating the significance of OM3FAs and their promising role in the treatment of conditions and ailments listed below:
Omega-3 intake and/or supplementation have been shown to be beneficial in treating the above conditions; however, much controversy still exists in many of the above uses. More research with well-conducted clinical trials will need to be completed before definitive conclusions can be made.
The mechanism of action of OM3FAs to lower triglycerides (FDA approved use) is still not fully known but is thought to lower triglycerides by suppressing lipogenic gene expression, increasing beta-oxidation of fatty acids, increasing the expression of lipo-protein-lipase (LPL), and influencing total body lipid accretion.
OM3FAs suppress lipogenic gene expression by decreasing the expression of sterol regulatory element-binding protein 1c, inhibiting phosphatidic acid phosphatase, and acyl-CoA:1,2-diacylglycerol acyltransferase (NGAT). Sterol regulatory element-binding proteins (SREBP’s) are membrane-bound enzymes that, when cleaved, travel to the nucleus to transcribe enzymes involved in cholesterol, LDL, and fatty acid synthesis. When a diet is high in omega-3 fatty acids, the SREBPs (particularly 1c) are not activated because of negative feedback inhibition and lowers SREBP synthesis and the cholesterol synthesizing enzymes that it regulates, FPP synthase (farnesyl diphosphate synthase) and HMG-CoA reductase (3-hydroxy-3-methylglutaryl-CoA reductase).
Beta oxidation is the biological pathway used in the body to breakdown fat and converts it into energy. OM3FAs decrease the level of triacylglycerides in the body by increasing the rate of beta-oxidation, by acting specifically on carnitine acetyltransferase 1 (CAT 1) and acetyl-CoA carboxylase. Carnitine acetyltransferase acts to modify fatty acid substrates to enter the inner mitochondrial membrane via the carnitine-acylcarnitine translocation properly. Later, it is converted to acyl-CoA, a precursor substrate to acetyl-CoA used to create ATP in various metabolic pathways. Additionally, EPA also indirectly increases beta-oxidation by slowing feedback inhibition. EPA inhibits acetyl-CoA carboxylase, which is the enzyme that catalyzes the synthesis of malonyl CoA, a strong inhibitor of CAT1. By decreasing the amount of malonyl CoA produced, CAT1 will have increased activity and use more triacylglycerides for beta-oxidation. OM3FAs have also been shown to decrease the sensitivity of CAT1 to malonyl CoA.
Lipoprotein lipase (LPL) is an extracellular enzyme found on the endothelium of vascular tissue that functions to remove triacylglycerol components of chylomicrons, low-density lipoproteins (LDL), and very-low-density lipoproteins (VLDL) in the blood. A diet high in OM3FAs has shown to increase the expression of LPL and subsequent lipoprotein lipase protein on the endothelial lining, as well as a decrease in the size of chylomicrons. By increasing the amount of lipoprotein lipase and decreasing LDL, VLDL, and chylomicron size, triglycerides can be lower in hypertriglyceridemia patients.
OM3FAs are also believed to reduce high triglycerides by influencing total body lipid accretion. Several studies have found that prolonged use of OM3FAs for greater than six weeks can increase the body's metabolic rate and decrease total body fat. More specifically, study participants showed an increase in lean muscle mass, decreased fat mass, an increase in resting metabolic rate, an increase in energy expenditure during exercise, and an increase in fat oxidation both during rest and exercise. On a cellular level, this is caused by OM3FAs ability to act as a ligand for peroxisome proliferator-activated receptors (PPARs), whose transcription factor activity can change gene expression involved in energy homeostasis. PPARs regulate both fatty acid metabolism (beta-oxidation) and glucose metabolism and can change the basal metabolism of the cell. The increase in fat oxidation and energy needs by changes in body composition is thought to be another mechanism by which OM3FAs helps lower the triglyceride levels in the blood.
Additional mechanisms of actions are thought to exist for OM3FAs that explain the beneficial effects on the brain, brain development, cancer, diabetes, rheumatoid arthritis, irritable bowel disease, and the cardiovascular system outside of triglyceride regulation. Most of these effects are attributed to OM3FAs anti-inflammatory actions. Omega-3 Fatty Acids have been shown to modulate several inflammatory pathways such as:
Although many cancers are helped by OM3FAs anti-inflammatory effect and non-small-cell lung cancer tumor growth has shown to decrease by inhibiting acetyl-CoA carboxylase (decreasing fatty acid production), other antineoplastic mechanisms of OM3FAs have been shown to be beneficial for other cancers, such as breast cancer, colorectal cancer, leukemia, gastric cancer, pancreatic cancer, esophageal cancer, prostate cancer, head and neck cancer, as well as lung cancer. OM3FAs activate AMPK/SIRT, which is involved in cell maintenance and repair, producing an antineoplastic effect that is useful in cancer treatment.
OM3FAs have a stabilizing and protecting effect for certain tissues that have high-fat content, like neural and retinal tissue. Alzheimer's disease, dementia, and cognitive function are improved by OM3FAs ability to maintain cell membrane integrity of neural tissues because DHA is an essential component of the brain's phospholipid membranes. Additionally, macular degeneration can be helped with the supplement of DHA for structural support and EPA based eicosanoids for neovascular and cell survival because DHA and EPA are also an integral component of retinal cell membranes.
OM3FAs have some cardioprotective effects that help protect against heart failure in congestive heart failure (CHF) patients. OM3FAs, specifically DHA, decreases mitochondrial oxygen consumption without reducing power generation for the ventricles by altering the mitochondrial membrane phospholipid composition, protecting the heart from tiring. Whereas EPA inhibits the apoptotic activity stimulated by saturated fatty acid cardiac lipotoxicity, protecting the heart from injury. OM3FAs can protect from arrhythmia by inhibiting inward sodium current in a dose-dependent manner, suppressing intracellular calcium (Ca2+) waves, and helping strengthen autonomic tone. OM3FAs can also vasodilate and decrease blood pressure or afterload to help the heart pump easier because they stimulate the release of nitrous oxide (NO) from vascular endothelial tissue. OM3FAs also protect the heart through its antithrombotic and antiatherosclerotic abilities. OM3FAs have been shown to suppress platelet-derived thromboxane A2 (TXA2) synthesis, which constricts blood vessels and aids in platelet aggregation, and reduces the production of matrix metalloproteinases released by macrophages when there is endothelial injury.
It should be noted that numerous studies continue to determine the exact mechanisms by which OM3FAs have a pharmacological effect. Many studies with conflicting data continue to challenge our current understanding of how OM3FAs can work to help other conditions beyond hypertriglyceridemia.
All OM3FA supplements should be taken whole without being crushed, chewed, or dissolved in the mouth. If a dose is missed, the patient should take it as soon as they remember and should not take a double dose if it is time for their next capsule. Various dietary supplements in different chemical forms are currently available over the counter but have not been FDA approved; hence they are not required to show safety and efficacy prior to marketing the product.
Humans do not possess the enzymes required to synthesize OM3FAs; therefore, they are considered essential fatty acids because they must be obtained from the diet. OM3FAs are mainly consumed in our diets as fish and plant sources, but can also be consumed via prescription OM3FA products. Alpha-linoleic acid (ALA) is a common OM3FA found in seeds and nuts and can be converted to both DHA and EPA inside the body. However, research has found the conversion of DHA from ALA is particularly low, suggesting the importance of direct dietary intake of DHA. OM3FAs may be present in several forms, such as triacylglycerols, free fatty acids (FFA), phospholipids, and ethyl esters. Icosapent ethyl, omega-3-acid ethyl esters, and omega-3-acid ethyl esters A are all in the ethyl ester form, whereas; omega-3-carboxylic acids are in the free fatty acid form.
Digestion of OM3FAs begins in the stomach with gastric lipases that break down triacylglycerols into diacylglycerol and fatty acids. Once broken down, they form fat globules that are subsequently broken down by pancreatic lipases and bile salts in the small intestines. The ethyl esters (icosapent ethyl, omega-3-acid ethyl esters, and omega-3-acid ethyl esters A) are principally broken down by pancreatic carboxylic acid ester lipase in the small intestine to form FFA-EPA and FFA-DHA. Monoacylglycerols and the free fatty acids then passively diffuse into enterocytes as micelles. Fatty acids can also be transported into enterocytes by various fatty acid transport proteins present in the enterocyte membrane. Once within the enterocyte, the fatty acids are then re-esterified into triacylglycerols in the endoplasmic reticulum that then bind to apolipoproteins to form chylomicrons. Chylomicrons are subsequently exocytosed into the lymphatic system and ultimately enter circulation at the thoracic duct to reach target tissues.
While most metabolism of DHA and EPA takes place via beta-oxidation in the liver (as discussed above), cytochrome P450 (CYP)-mediated metabolism is a minor pathway in the breakdown of DHA and EPA.
In the digestion process, the ethyl esters are principally broken down by pancreatic carboxylic acid ester lipase, an enzyme with activity enhanced by high-fat content meals. Moreover, the fat content of a meal can affect the absorption of ethyl esters. Subsequently, absorption of the ethyl esters and icosapent ethyl (EPA formulation only) is decreased when fasting, so it is recommended they are consumed with food. Regarding the absorption of EPA versus DHA, it is thought that EPA is not absorbed as well as DHA and is metabolized faster; thus, there is a higher ratio of DHA to EPA within the serum plasma.
Since OM3FAs may be present in several forms, such as triacylglycerols, free fatty acids, phospholipids, and ethyl esters, the form in which the OM3FA acid is in will affect bioavailability. The suggested bioavailability based on form (lipid structure) from highest to lowest is as follows: phospholipids, re-esterified triacylglycerols, triacylglycerols, free fatty acids, ethyl esters. However, the order is based on lipid structure only and does not reflect other factors that affect the bioavailability OM3FAs, such as the fat content of a meal.
In addition to the form of the OM3FA, the chemical positioning may also affect bioavailability. Some research suggests OM3FA is greater in fish oil due to the OM3FA typically being in the sn-2 position versus marine mammal oils with the OM3FAs in the sn-1 and sn-3 positions. Conversely, other sources state that OM3FAs bioavailability is increased in the sn-1 and sn-3 position due to increased accessibility for lipase hydrolysis, so controversy remains regarding how the position affects the bioavailability of the OM3FAs. Bioavailability also varies depending on the dietary source. For example, krill oil is known to have high bioavailability compared to other marine sources.
Bioavailability of EPA only and both EPA/DHA formulation did not differ based on age or ethnicity; however, the combination formulation bioavailability differed based on gender. Women seem to have higher EPA serum levels than males in the mixed EPA/DHA formulations. However, research done on the availability of EPA and DHA of over-the-counter supplements has indicated that age can indeed play a factor in their levels within the plasma. It has also been found that serum EPA increases in a dose-dependent manner when administered with ethyl esters, but serum DHA does not.
Not all of the half-lives of the prescription OM3FA products have been established. The maximum amount of plasma EPA and DHA can be determined within five to nine hours post-administration. However, persistent EPA and DHA serum levels will not be apparent until 2 weeks of daily supplementation. With repeated administration, the half-life of EPA is 37 hours and 48 hours for DHA.
The FDA approved fatty acid prescriptions (icosapent ethyl, omega-3-acid ethyl esters,omega-3-carboxylic acids, and omega-3-acid ethyl esters A) are generally safe with benign side effects such as fishy taste, eructation, dyspepsia, diarrhea, gas, nausea, and arthralgia. Adverse reactions seen in clinical trials for each of the FDA approved OM3FA products are as follows:
Icosapent ethyl: arthralgia and oropharyngeal pain.
Omega-3-acid ethyl esters: eructation, dyspepsia, taste perversion, constipation, GI disorder, vomiting, increased ALT/AST, pruritus, rash.
Omega-3-carboxylic acids: Diarrhea, nausea, abdominal pain or discomfort, eructation, abdominal distension, constipation, vomiting, fatigue, nasopharyngitis, arthralgia, dysgeusia.
Omega-3-acid ethyl esters A: Eructation, dyspepsia, taste perversion, constipation, GI disorder, vomiting, increased ALT/AST, pruritus, rash.
Caution and periodic monitoring are recommended in patients taking antiplatelet and anticoagulant medication due to the ability of omega-3 fatty acids to reduce platelet activity. Additionally, omega-3 fatty acids are not considered allergenic, but the FDA labels state to use with caution in patients allergic to seafood. The OM3FAs products are contraindicated for those who have hypersensitivity to the individual formulation.
EPA and DHA can act as alternative substrates for CYP450 metabolism and are partially metabolized by the CYP450 metabolic pathway, however significant inhibition of CYP450 enzymes by DHA or EPA has not been observed, and no drug-drug interactions have been established with medications that use the CYP450 metabolic pathway. EPA exclusive supplements have shown to have no drug-drug interactions with other medications that may use the P450 metabolic pathway, such as omeprazole, warfarin, atorvastatin, and rosiglitazone. DHA has shown to have no interactions with other statin drugs.
It is recommended that the healthcare provider monitor the direct low-density lipoprotein (LDL) cholesterol for patients taking the DHA containing products omega-3-acid ethyl esters, omega-3-acid ethyl esters A, and omega-3-carboxylic acids due to DHA’s association with an increase in LDL cholesterol.
In patients with dyslipidemia, icosapent ethyl can be used instead since it has no association with increased LDL cholesterol. For patients with hepatic impairment, monitoring of the AST and ALT should also be done. In patients with paroxysmal or persistent atrial fibrillation, the prescription products containing omega-3-acid ethyl esters and omega-3-acid ethyl esters A have a possible association with increased recurrences of symptomatic atrial fibrillation or flutter.
EPA and DHA are considered generally safe. The FDA recommends that daily intake does not exceed 3g/day of EPA and DHA combined, with no more than 2g/day deriving from supplements.
Caution should be taken when taking high doses as it may reduce immune function because of changes in the inflammatory response and may cause bleeding problems. EPA and DHA have not been found to be carcinogenic or mutagenic in human models, but icosapent ethyl (EPA only formulation) have shown benign neoplasm growth in murine models.
The FDA approved fatty acid prescriptions (icosapent ethyl, omega-3-acid ethyl esters,omega-3-carboxylic acids, and omega-3-acid ethyl esters A) are all pregnancy category C drugs, and it is unknown if the drug can cause fetal harm or can affect reproductive capacity. Conversely, some studies concluded that pregnant mothers should incorporate DHA into their diet via high DHA content food or supplements to increase latency and birth-weight.
Additionally, it is not recommended that nursing mothers take DHA or EPA supplements because it can be highly concentrated (possibly 6 to 14 times serum levels), requiring only 200 to 300 mg DHA intake per day in a nursing mother.
Methyl mercury, a toxic organometallic cation, is found in fish. Individuals who use fish as their primary source of OM3FAs or pregnant and nursing women should limit their intake to two to four servings of fish a week and/or replace fish that are high in methyl mercury, such as swordfish, albacore tuna, dolphinfish, kingfish, and shark and replace with fish that have a lower amount of methylmercury, such as salmon, herring, sardines, and trout. Fortunately, DHA and EPA supplements do not contain methylmercury.
Proper patient education on dosage and use of the prescription EPA only icosapent ethyl and DHA/EPA formulations are necessary to ensure that the patient achieves the therapeutic benefits. The responsibility of the interprofessional healthcare team, including physicians, nurse practitioners, pharmacists, etc. is to ensure the patient is aware of the possible adverse effects, especially for individuals on polypharmacy with multiple comorbidities, like those with hepatic and pancreatic impairment, those taking anticoagulants, and individuals with a possible fish sensitivity. Proper physician education on considerations when prescribing, monitoring, and stopping treatment is also necessary.
Current FDA guidelines approve DHA and EPA for use in patients with very high triglycerides in conjunction with proper diet and exercise. The patient should be encouraged to eat a balanced diet (or one that is low in cholesterol) and regular exercise. Routine monitoring should occur when prescribing icosapent ethyl (EPA only) and DHA/EPA formulation to patients with hypertriglyceridemia to check the level of triglycerides as well as AST and ALT for hepatic function. Care is also necessary when prescribing EPA and DHA to pregnant and nursing patients because of unknown toxicity to the fetus and infant. Additionally, pharmacists and physicians should inform the patient that better absorption of EPA and DHA occurs when co-administered with food.
The healthcare team should remain knowledgeable of other potential indications for DHA and EPA use as it is also available over the counter, and patients may take it even if it is not recommended. Physicians and pharmacists could help patients taking over the counter EPA and DHA supplements by informing them of foods that they could incorporate into their diet if they wanted to stop using the supplements. Furthermore, physicians should inquire about patients' diets to ensure proper DHA and EPA levels are being achieved, and fish high in methyl mercury are avoided.
|||Shahidi F,Ambigaipalan P, Omega-3 Polyunsaturated Fatty Acids and Their Health Benefits. Annual review of food science and technology. 2018 Mar 25; [PubMed PMID: 29350557]|
|||Behl T,Kotwani A, Omega-3 fatty acids in prevention of diabetic retinopathy. The Journal of pharmacy and pharmacology. 2017 Aug; [PubMed PMID: 28481011]|
|||Fialkow J, Omega-3 Fatty Acid Formulations in Cardiovascular Disease: Dietary Supplements are Not Substitutes for Prescription Products. American journal of cardiovascular drugs : drugs, devices, and other interventions. 2016 Aug; [PubMed PMID: 27138439]|
|||Skulas-Ray AC,Wilson PWF,Harris WS,Brinton EA,Kris-Etherton PM,Richter CK,Jacobson TA,Engler MB,Miller M,Robinson JG,Blum CB,Rodriguez-Leyva D,de Ferranti SD,Welty FK, Omega-3 Fatty Acids for the Management of Hypertriglyceridemia: A Science Advisory From the American Heart Association. Circulation. 2019 Sep 17; [PubMed PMID: 31422671]|
|||Li R,Jia Z,Zhu H, Dietary Supplementation with Anti-Inflammatory Omega-3 Fatty Acids for Cardiovascular Protection: Help or Hoax? Reactive oxygen species (Apex, N.C.). 2019 Mar; [PubMed PMID: 30854465]|
|||Ito MK, A Comparative Overview of Prescription Omega-3 Fatty Acid Products. P [PubMed PMID: 26681905]|
|||Choi HD,Chae SM, Comparison of efficacy and safety of combination therapy with statins and omega-3 fatty acids versus statin monotherapy in patients with dyslipidemia: A systematic review and meta-analysis. Medicine. 2018 Dec; [PubMed PMID: 30558030]|
|||Kim CH,Han KA,Yu J,Lee SH,Jeon HK,Kim SH,Kim SY,Han KH,Won K,Kim DB,Lee KJ,Min K,Byun DW,Lim SW,Ahn CW,Kim S,Hong YJ,Sung J,Hur SH,Hong SJ,Lim HS,Park IB,Kim IJ,Lee H,Kim HS, Efficacy and Safety of Adding Omega-3 Fatty Acids in Statin-treated Patients with Residual Hypertriglyceridemia: ROMANTIC (Rosuvastatin-OMAcor iN residual hyperTrIglyCeridemia), a Randomized, Double-blind, and Placebo-controlled Trial. Clinical therapeutics. 2018 Jan; [PubMed PMID: 29223557]|
|||Barter P,Ginsberg HN, Effectiveness of combined statin plus omega-3 fatty acid therapy for mixed dyslipidemia. The American journal of cardiology. 2008 Oct 15; [PubMed PMID: 18929706]|
|||Gutstein AS,Copple T, Cardiovascular disease and omega-3s: Prescription products and fish oil dietary supplements are not the same. Journal of the American Association of Nurse Practitioners. 2017 Dec; [PubMed PMID: 29280361]|
|||Weintraub HS, Overview of prescription omega-3 fatty acid products for hypertriglyceridemia. Postgraduate medicine. 2014 Nov; [PubMed PMID: 25387209]|
|||Calder PC,Deckelbaum RJ, Editorial: Omega-3 fatty acids and cardiovascular outcomes: an update. Current opinion in clinical nutrition and metabolic care. 2019 Mar; [PubMed PMID: 30585800]|
|||Endo J,Arita M, Cardioprotective mechanism of omega-3 polyunsaturated fatty acids. Journal of cardiology. 2016 Jan; [PubMed PMID: 26359712]|
|||Simopoulos AP, The importance of the ratio of omega-6/omega-3 essential fatty acids. Biomedicine [PubMed PMID: 12442909]|
|||Nabavi SF,Bilotto S,Russo GL,Orhan IE,Habtemariam S,Daglia M,Devi KP,Loizzo MR,Tundis R,Nabavi SM, Omega-3 polyunsaturated fatty acids and cancer: lessons learned from clinical trials. Cancer metastasis reviews. 2015 Sep; [PubMed PMID: 26227583]|
|||Jing K,Wu T,Lim K, Omega-3 polyunsaturated fatty acids and cancer. Anti-cancer agents in medicinal chemistry. 2013 Oct; [PubMed PMID: 23919748]|
|||Costantini L,Molinari R,Farinon B,Merendino N, Impact of Omega-3 Fatty Acids on the Gut Microbiota. International journal of molecular sciences. 2017 Dec 7; [PubMed PMID: 29215589]|
|||Sakamoto A,Saotome M,Iguchi K,Maekawa Y, Marine-Derived Omega-3 Polyunsaturated Fatty Acids and Heart Failure: Current Understanding for Basic to Clinical Relevance. International journal of molecular sciences. 2019 Aug 18; [PubMed PMID: 31426560]|
|||NaPier Z,Kanim LEA,Arabi Y,Salehi K,Sears B,Perry M,Kim S,Sheyn D,Bae HW,Glaeser JD, Omega-3 Fatty Acid Supplementation Reduces Intervertebral Disc Degeneration. Medical science monitor : international medical journal of experimental and clinical research. 2019 Dec 14; [PubMed PMID: 31836696]|
|||Chang JP,Su KP,Mondelli V,Pariante CM, Omega-3 Polyunsaturated Fatty Acids in Youths with Attention Deficit Hyperactivity Disorder: a Systematic Review and Meta-Analysis of Clinical Trials and Biological Studies. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2018 Feb; [PubMed PMID: 28741625]|
|||Bozzatello P,Brignolo E,De Grandi E,Bellino S, Supplementation with Omega-3 Fatty Acids in Psychiatric Disorders: A Review of Literature Data. Journal of clinical medicine. 2016 Jul 27; [PubMed PMID: 27472373]|
|||Hsu MC,Tung CY,Chen HE, Omega-3 polyunsaturated fatty acid supplementation in prevention and treatment of maternal depression: Putative mechanism and recommendation. Journal of affective disorders. 2018 Oct 1; [PubMed PMID: 29860183]|
|||Mohammady M,Janani L,Jahanfar S,Mousavi MS, Effect of omega-3 supplements on vasomotor symptoms in menopausal women: A systematic review and meta-analysis. European journal of obstetrics, gynecology, and reproductive biology. 2018 Sep; [PubMed PMID: 30056356]|
|||Brigham EP,Woo H,McCormack M,Rice J,Koehler K,Vulcain T,Wu T,Koch A,Sharma S,Kolahdooz F,Bose S,Hanson C,Romero K,Diette G,Hansel NN, Omega-3 and Omega-6 Intake Modifies Asthma Severity and Response to Indoor Air Pollution in Children. American journal of respiratory and critical care medicine. 2019 Jun 15; [PubMed PMID: 30922077]|
|||Kumar A,Mastana SS,Lindley MR, n-3 Fatty acids and asthma. Nutrition research reviews. 2016 Jun; [PubMed PMID: 26809946]|
|||Chee B,Park B,Fitzsimmons T,Coates AM,Bartold PM, Omega-3 fatty acids as an adjunct for periodontal therapy-a review. Clinical oral investigations. 2016 Jun; [PubMed PMID: 26885664]|
|||Bahagat KA,Elhady M,Aziz AA,Youness ER,Zakzok E, [Omega-6/omega-3 ratio and cognition in children with epilepsy]. Anales de pediatria (Barcelona, Spain : 2003). 2019 Aug; [PubMed PMID: 30660389]|
|||Tejada S,Martorell M,Capó X,Tur JA,Pons A,Sureda A, Omega-3 Fatty Acids in the Management of Epilepsy. Current topics in medicinal chemistry. 2016; [PubMed PMID: 26845549]|
|||Rosenberg K, Omega-3 Fatty Acid Intake Lowers Risk of Diabetic Retinopathy. The American journal of nursing. 2017 Jan; [PubMed PMID: 28030412]|
|||de la Rosa Oliva F,Meneses García A,Ruiz Calzada H,Astudillo de la Vega H,Bargalló Rocha E,Lara-Medina F,Alvarado Miranda A,Matus-Santos J,Flores-Díaz D,Oñate-Acuña LF,Gutiérrez-Salmeán G,Ruiz García E,Ibarra A, Effects of omega-3 fatty acids supplementation on neoadjuvant chemotherapy-induced toxicity in patients with locally advanced breast cancer: a randomized, controlled, double-blinded clinical trial. Nutricion hospitalaria. 2019 Aug 26; [PubMed PMID: 31192682]|
|||Bahmanyar S,Higgins GA,Goldgaber D,Lewis DA,Morrison JH,Wilson MC,Shankar SK,Gajdusek DC, Localization of amyloid beta protein messenger RNA in brains from patients with Alzheimer's disease. Science (New York, N.Y.). 1987 Jul 3; [PubMed PMID: 3299701]|
|||Behboudi-Gandevani S,Hariri FZ,Moghaddam-Banaem L, The effect of omega 3 fatty acid supplementation on premenstrual syndrome and health-related quality of life: a randomized clinical trial. Journal of psychosomatic obstetrics and gynaecology. 2018 Dec; [PubMed PMID: 28707491]|
|||Spooner MH,Jump DB, Omega-3 fatty acids and nonalcoholic fatty liver disease in adults and children: where do we stand? Current opinion in clinical nutrition and metabolic care. 2019 Mar; [PubMed PMID: 30601174]|
|||Backes J,Anzalone D,Hilleman D,Catini J, The clinical relevance of omega-3 fatty acids in the management of hypertriglyceridemia. Lipids in health and disease. 2016 Jul 22; [PubMed PMID: 27444154]|
|||Noreen EE,Sass MJ,Crowe ML,Pabon VA,Brandauer J,Averill LK, Effects of supplemental fish oil on resting metabolic rate, body composition, and salivary cortisol in healthy adults. Journal of the International Society of Sports Nutrition. 2010 Oct 8; [PubMed PMID: 20932294]|
|||Bays HE,Tighe AP,Sadovsky R,Davidson MH, Prescription omega-3 fatty acids and their lipid effects: physiologic mechanisms of action and clinical implications. Expert review of cardiovascular therapy. 2008 Mar; [PubMed PMID: 18327998]|
|||Le Jossic-Corcos C,Gonthier C,Zaghini I,Logette E,Shechter I,Bournot P, Hepatic farnesyl diphosphate synthase expression is suppressed by polyunsaturated fatty acids. The Biochemical journal. 2005 Feb 1; [PubMed PMID: 15473864]|
|||Horton JD,Bashmakov Y,Shimomura I,Shimano H, Regulation of sterol regulatory element binding proteins in livers of fasted and refed mice. Proceedings of the National Academy of Sciences of the United States of America. 1998 May 26; [PubMed PMID: 9600904]|
|||Pirahanchi Y,Anoruo MD,Sharma S, Biochemistry, Lipoprotein Lipase 2020 Jan; [PubMed PMID: 30725725]|
|||He PP,Jiang T,OuYang XP,Liang YQ,Zou JQ,Wang Y,Shen QQ,Liao L,Zheng XL, Lipoprotein lipase: Biosynthesis, regulatory factors, and its role in atherosclerosis and other diseases. Clinica chimica acta; international journal of clinical chemistry. 2018 May; [PubMed PMID: 29453968]|
|||Mead JR,Irvine SA,Ramji DP, Lipoprotein lipase: structure, function, regulation, and role in disease. Journal of molecular medicine (Berlin, Germany). 2002 Dec; [PubMed PMID: 12483461]|
|||Park Y,Harris WS, Omega-3 fatty acid supplementation accelerates chylomicron triglyceride clearance. Journal of lipid research. 2003 Mar; [PubMed PMID: 12562865]|
|||Logan SL,Spriet LL, Omega-3 Fatty Acid Supplementation for 12 Weeks Increases Resting and Exercise Metabolic Rate in Healthy Community-Dwelling Older Females. PloS one. 2015; [PubMed PMID: 26679702]|
|||Couet C,Delarue J,Ritz P,Antoine JM,Lamisse F, Effect of dietary fish oil on body fat mass and basal fat oxidation in healthy adults. International journal of obesity and related metabolic disorders : journal of the International Association for the Study of Obesity. 1997 Aug; [PubMed PMID: 15481762]|
|||Kopecky J,Rossmeisl M,Flachs P,Kuda O,Brauner P,Jilkova Z,Stankova B,Tvrzicka E,Bryhn M, n-3 PUFA: bioavailability and modulation of adipose tissue function. The Proceedings of the Nutrition Society. 2009 Nov; [PubMed PMID: 19698199]|
|||Seo T,Blaner WS,Deckelbaum RJ, Omega-3 fatty acids: molecular approaches to optimal biological outcomes. Current opinion in lipidology. 2005 Feb; [PubMed PMID: 15650558]|
|||Kota BP,Huang TH,Roufogalis BD, An overview on biological mechanisms of PPARs. Pharmacological research. 2005 Feb; [PubMed PMID: 15629253]|
|||Calder PC, Omega-3 fatty acids and inflammatory processes: from molecules to man. Biochemical Society transactions. 2017 Oct 15; [PubMed PMID: 28900017]|
|||Calder PC, Omega-3 polyunsaturated fatty acids and inflammatory processes: nutrition or pharmacology? British journal of clinical pharmacology. 2013 Mar; [PubMed PMID: 22765297]|
|||Ishihara T,Yoshida M,Arita M, Omega-3 fatty acid-derived mediators that control inflammation and tissue homeostasis. International immunology. 2019 Aug 23; [PubMed PMID: 30772915]|
|||Svensson RU,Parker SJ,Eichner LJ,Kolar MJ,Wallace M,Brun SN,Lombardo PS,Van Nostrand JL,Hutchins A,Vera L,Gerken L,Greenwood J,Bhat S,Harriman G,Westlin WF,Harwood HJ Jr,Saghatelian A,Kapeller R,Metallo CM,Shaw RJ, Inhibition of acetyl-CoA carboxylase suppresses fatty acid synthesis and tumor growth of non-small-cell lung cancer in preclinical models. Nature medicine. 2016 Oct; [PubMed PMID: 27643638]|
|||Chew EY,Clemons TE,Agrón E,Launer LJ,Grodstein F,Bernstein PS, Effect of Omega-3 Fatty Acids, Lutein/Zeaxanthin, or Other Nutrient Supplementation on Cognitive Function: The AREDS2 Randomized Clinical Trial. JAMA. 2015 Aug 25; [PubMed PMID: 26305649]|
|||Sydenham E,Dangour AD,Lim WS, Omega 3 fatty acid for the prevention of cognitive decline and dementia. The Cochrane database of systematic reviews. 2012 Jun 13; [PubMed PMID: 22696350]|
|||Tully AM,Roche HM,Doyle R,Fallon C,Bruce I,Lawlor B,Coakley D,Gibney MJ, Low serum cholesteryl ester-docosahexaenoic acid levels in Alzheimer's disease: a case-control study. The British journal of nutrition. 2003 Apr; [PubMed PMID: 12654166]|
|||SanGiovanni JP,Chew EY, The role of omega-3 long-chain polyunsaturated fatty acids in health and disease of the retina. Progress in retinal and eye research. 2005 Jan; [PubMed PMID: 15555528]|
|||Nodari S,Metra M,Milesi G,Manerba A,Cesana BM,Gheorghiade M,Dei Cas L, The role of n-3 PUFAs in preventing the arrhythmic risk in patients with idiopathic dilated cardiomyopathy. Cardiovascular drugs and therapy. 2009 Feb; [PubMed PMID: 18982439]|
|||Haglund O,Mehta JL,Saldeen T, Effects of fish oil on some parameters of fibrinolysis and lipoprotein(a) in healthy subjects. The American journal of cardiology. 1994 Jul 15; [PubMed PMID: 8023790]|
|||Cholewski M,Tomczykowa M,Tomczyk M, A Comprehensive Review of Chemistry, Sources and Bioavailability of Omega-3 Fatty Acids. Nutrients. 2018 Nov 4; [PubMed PMID: 30400360]|
|||Anderson BM,Ma DW, Are all n-3 polyunsaturated fatty acids created equal? Lipids in health and disease. 2009 Aug 10; [PubMed PMID: 19664246]|
|||Schuchardt JP,Hahn A, Bioavailability of long-chain omega-3 fatty acids. Prostaglandins, leukotrienes, and essential fatty acids. 2013 Jul; [PubMed PMID: 23676322]|
|||Arnold C,Konkel A,Fischer R,Schunck WH, Cytochrome P450-dependent metabolism of omega-6 and omega-3 long-chain polyunsaturated fatty acids. Pharmacological reports : PR. 2010 May-Jun; [PubMed PMID: 20631419]|
|||Brinton EA,Mason RP, Prescription omega-3 fatty acid products containing highly purified eicosapentaenoic acid (EPA). Lipids in health and disease. 2017 Jan 31; [PubMed PMID: 28137294]|
|||Fabian CJ,Kimler BF,Hursting SD, Omega-3 fatty acids for breast cancer prevention and survivorship. Breast cancer research : BCR. 2015 May 4; [PubMed PMID: 25936773]|
|||Saccone G,Berghella V, Omega-3 long chain polyunsaturated fatty acids to prevent preterm birth: a systematic review and meta-analysis. Obstetrics and gynecology. 2015 Mar; [PubMed PMID: 25730231]|
|||Breastfeeding and the use of human milk. Pediatrics. 2012 Mar; [PubMed PMID: 22371471]|
|||Zamora-Arellano NY,Betancourt-Lozano M,Ilizaliturri-Hernández C,García-Hernández J,Jara-Marini M,Chávez-Sánchez C,Ruelas-Inzunza JR, Mercury Levels and Risk Implications Through Fish Consumption on the Sinaloa Coasts (Gulf of California, Northwest Mexico). Risk analysis : an official publication of the Society for Risk Analysis. 2018 Dec; [PubMed PMID: 30229961]|
|||García-Hernández J,Ortega-Vélez MI,Contreras-Paniagua AD,Aguilera-Márquez D,Leyva-García G,Torre J, Mercury concentrations in seafood and the associated risk in women with high fish consumption from coastal villages of Sonora, Mexico. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association. 2018 Oct; [PubMed PMID: 30026089]|
|||Mozaffarian D,Rimm EB, Fish intake, contaminants, and human health: evaluating the risks and the benefits. JAMA. 2006 Oct 18; [PubMed PMID: 17047219]|