Efficacy of DHA and EPA on Serum Triglyceride Levels of Healthy Participants: Systematic Review

Cardiovascular disease (CVD) is the leading cause of death worldwide and acts as a major barrier to sustainable human development. To address this major global health concern, in 2011, the United Nations officially recognized several noncommunicable diseases, including CVD, and set up an ambitious plan to dramatically reduce the impact of these diseases in all areas ¹.

Hypertriglyceridemia is a type of dyslipidemia characterized by an elevated serum triglycerides (TG] level and has been reported by several prospective studies and randomized controlled trials (RCTs) to be a risk factor for CVD. An increased level of circulating TG is an independent risk factor for the onset of CVD. Hokanson and Austin reported that a fasting serum TG level of 88 mg/dL or more increases the risk of CVD development by 14% and 37% in men and women, respectively². Therefore, lowering or maintaining a low level of fasting serum TG level reduces the risk of CVD.

Fatty acids are comprised of lipids, which are present in almost all parts of the human body. Fatty acids are divided broadly into two categories, saturated and unsaturated fatty acids. Unsaturated fatty acids are further classified into two categories: monounsaturated and poly unsaturated fatty acids (PUFAs). The PUFAs are further divided into two categories: the omega-3 series (metabolic cascade starts with α-linoleic acid (ALA)) and omega-6 series (metabolic cascade starts with linoleic acid (LA)). Docosahexaenoic acid (DHA) and Eicosapentaenoic acid (EPA) are categorized as omega-3 fatty acids ³.

Certain fatty acids, such as ALA and LA, cannot be synthesized in humans, and thus must be obtained in the diet. ALA, a type of omega-3 fatty acid, is converted into DHA and EPA in the body. DHA and EPA also exist naturally in some foods. LA, which is a type of omega-6 fatty acid, is converted to arachidonic acid (AA). DHA and EPA are derived from ALA by a similar biochemical pathway as AA. Omega-3 fatty acids generally lower fasting serum TG levels and very low-density lipoprotein (VLDL) levels ​​in serum among hyperlipidemic patients. In regard to low-density lipoprotein (LDL) level, omega-3 fatty acids increase it or had no influence among the subjects.

EPA is a carbon number 20, omega-3 PUFA with five double bonds, also abbreviated as 20:5 omega-3. Since it has five cis-type double bonds, the molecule is not a linear structure; hence, its melting point is low and it is easily oxidized. It is almost odorless just after purification, but it undergoes auto-oxidation quickly in air and begins to smell. Peroxide is also unstable, and the volatile component is comprised mainly of the carbonyl compound of the secondary product due to the polymerization and decomposition that causes a fishy odor. It is widely distributed as a major constituent of the fatty acids in marine organisms, such as fish, mollusks, crustaceans, seaweed, and microorganisms. In particular, various sardines, mackerels, saury, and so forth which are blue-backed fish.

DHA is also a PUFA and has 22 carbon atoms and six double bonds, and is abbreviated as 22:6 omega-3. It is the final metabolite of omega-3 PUFA, with the first double bond on the third carbon counted from the methyl group end and starting from ALA (18:3 omega-3). Since it has six cis double bonds, it has a large curved molecular structure; hence, the melting point of a DHA-containing lipid is low, such as is the case for EPA. Moreover, it is extremely easy to oxidize, and readily generates a fishy odor that is mainly composed of a carbonyl compound. DHA is present in various marine animals and microorganisms, including fish, crustaceans, mollusks, microorganisms, etc. Fish with high DHA content include sardines, sauries, skipjack tunas, amberjacks, tunas, and mackerel, and in particular, DHA is present in squid liver oil and fat near the eyeballs of tuna.

In recent years, it has become clear that DHA and EPA have various physiological activities. DHA is the major PUFA present in the brain and is important for brain development and function. The synapses contain abundant DHA, suggesting that DHA is involved in neuron signaling. DHA also is required for the production of a group of compounds called resolvin, which are involved in the body’s reaction to inflammation in the brain. Resolvin synthesized specifically from DHA and EPA helps to relieve inflammation caused by ischemic stroke (reduction of blood flow). EPA also suppresses the production of inflammatory compounds, such as cytokines and alleviates inflammatory reactions.

Omega-6 fatty acids account for more than 10 times the omega-3 fatty acids in most American meals. At present, there is well-known scientific agreement that omega-3 fatty acids intake should be increased and omega-6 fatty acid intake should be decreased to promote health; however, it is unknown whether the desired ratio of omega-6 and omega-3 fatty acids exists in meals, and how much omega-6 fatty acid ingestion is necessary to inhibit omega-3 production when large amounts of omega-6 are ingested.

Researchers at the Tufts Educational Policy Committee reviewed the database of the Third National Health and Nutrition Examination Survey (NHANES III; 1988–1994) and investigated the intake of omega-3 fatty acids in the United States. ALA intake was significantly lower in males than in females, and greater in adults than in children. It became clear that there were fewer subjects with CVD than without a history of CVD. Only 25% of the population ingested DHA and EPA in a given day. The average daily intake was 14 g for LA, 1.33 g for ALA, 0.04 g for EPA, and 0.07 g for DHA.

ALA is present in green leafy yellow vegetables, nuts, vegetable oils (such as canola and soybean oils), and especially linseed or linseed oil. Good sources of DHA and EPA include seafoods (fish, crustaceans, mollusks, seaweeds and their oils and fish eggs). LA is present in several foods consumed by Americans, such as meat and vegetable oils (safflowers, sunflowers, corns, soybeans, and so forth), as well as processed foods using these oils. Daily consumption of ALA recommended by the Institute of Medicine was set at 1.1–1.6 g and LA at 11–17 g for adults, but the daily adequate intake of DHA and EPA were not set ⁴.

Omega-3 PUFAs have a well-established fasting serum TG lowering effect that may result in normal lipidemia in hyperlipidemic patients ^{5, 6, 7, 8, 9, 10, 11, 12, 13}. In general, omega-3 PUFAs, such as DHA and EPA, can be ingested easily, and because they are highly safe, they are assumed to be suitable for controlling fasting serum TG in the serum of those who do not require drug treatment. To the best of our knowledge, however, almost all systematic reviews on the effects of omega-3 PUFAs on lowering fasting serum TG are directed at patients fulfilling the diagnostic criteria of dyslipidemia. Therefore, our aim was to review and confirm the preventive effect of omega-3 PUFAs against hypertriglyceridemia or positive effects for nondrug treatment in patients with a mild disease. A systematic review was conducted to determine whether there was a fasting serum TG-lowering effect in subjects without disease and those with a slightly higher TG level who consumed DHA and/or EPA orally compared to those with placebo or no intake of DHA and/or EPA.

We found 812 reports from the database retrieval, collections, and other cited references. A total of 53 duplicated studies were excluded. We selected 193 of 759 reports that were at the primary (title and summary) screening stage. Finally, 37 reports meeting the eligibility criteria were extracted at second (full text) screening stage. Figure 1 summarizes the selection process steps. Characteristics of the 37 documents selected are listed in Table 1 together with bibliographic information. Fasting serum TG levels ​​of control and intervention groups of the 37 reports are listed in Table 2^{5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41}. For the total risk of bias, both studies were assessed as having an “overall low risk of bias” (data not show).

Figure 1.Flow diagram of study selection process.

Among the 37 reports used to qualitatively the results, 25 revealed a decrease in fasting serum TG level ​​due to oral ingestion of DHA and/or EPA. Sixteen studies on subjects without disease and 21 on subjects with slightly higher fasting serum TG levels were separated and subjected to stratified analysis. Ten of the 16 (normal TG participant) and 15 of the 21 studies (slightly higher TG participant), respectively, intake of an at least 133 mg/day of DHA and/or EPA intervention revealed a statistically significant decrease in the fasting serum TG level between the intervention group and placebo group. Clinical trials were conducted around the world, and subjects varied in terms of age, sex and race. Moreover, there were several methods for ingesting DHA and/or EPA in foods. Due to the clinical heterogeneity, the results were not quantitatively integrated, but qualitatively integrated and evaluated. Regardless of the diversity of these subjects and the type of intake, there were lower fasting serum TG levels. In this study, DHA and/or EPA intake ranged from 133–10,440 mg and fasting serum TG levels lowered during a 2-week to 12-month DHA and/or EPA oral intake period. Furthermore, there was no evidence of harmful effects due to the intake of DHA and/or EPA.

The aim of this study was to confirm the preventive effect of DHA and/or EPA on hypertriglyceridemia or the effect on nondrug treatment for people with a slightly higher fasting serum TG level. A systematic review examined whether oral DHA and/or EPA compared to placebo or no DHA and/or EPA would lower serum TG levels in participants without disease and for those with a slightly higher fasting serum TG level. Among the 37 RCTs, there were 16 healthy subjects and the remaining 21 subjects had slightly higher fasting serum TG levels. Among the former 16 RCTs, significant differences were found in the five double-blind RCTs with a high evidence level, and four studies suggested a lowering effect, although there were no significant differences. Considering that a ceiling effect exists for healthy subjects, this result might suggest the magnitude of the preventive effect of DHA and/or EPA. Among the 21 RCTs targeting people with somewhat higher fasting serum TG levels, several reported reduced fasting serum TG levels after oral ingestion of DHA and/or EPA, suggesting that oral intake of DHA and/or EPA suppresses the progression to hypertriglyceridemia. Thus, DHA and/or EPA dietary intake could contribute to decreasing the number of persons who require medicine to control their fasting serum TG level.

Although several previous studies have reported the fasting serum TG lowering effect of DHA and/or EPA in subjects with hyperlipidemia, our study strongly suggests that the effect is maintained among the subjects with borderline hyperlipidemia and normal lipidemia. Overall, the studies involving dietary interventions assessed in our review revealed that consuming 133–10,440 mg of DHA and EPA produces fasting serum TG lowering effects in healthy or slightly higher fasting serum TG level individuals.

EPA is already used as an ethical drug, and thus, its effect can be considered to be well established; however, the mechanism of omega-3 fatty acids, such as DHA and EPA, to lower the fasting serum TG level, remains unclear. There are some hypothetical mechanisms, including inhibition of diacylglycerol acyltransferase, increase in plasma lipoprotein lipase activity, decrease in liver lipid production, and increase in liver beta oxidation ⁴³.

Based on the results of the preclinical and clinical trials, omega-3 fatty acids have been proposed as exerting a decreasing action on fasting serum TG via numerous mechanisms. For example, it is believed to reduce lipid production in the liver by suppressing the expression of sterol regulatory element binding protein-1c. This is due to the downregulation of expression of cholesterol, fatty acids, and TG synthase ^{44, 45}. It also is presumed to increase beta-oxidation of fatty acids, and consequently, the TG are suppressed by decreasing the substrate necessary for the synthesis of TG ⁴⁶. Furthermore, omega-3 fatty acids are assumed to inhibit TG synthesis in the liver by inhibiting important enzymes involved in hepatic TG synthesis, such as phosphatidic acid phosphatase and diacylglycerol acyltransferase ⁴⁷. Moreover, it has been reported to increase the removal of fasting serum TG from circulating VLDL and chylomicron particles ^{48, 49}.

DHA and EPA, the major omega-3 fatty acids, have been reported to lower fasting serum TG levels; however, they are known to have different effects on LDL and high density lipoprotein (HDL) ^{50, 51, 52}. In a direct comparative study, in a meta-analysis comparing the effects of DHA and EPA, DHA was associated with a greater decrease in fasting serum TG and a greater increase in LDL than EPA. DHA also increased HDL compared to placebo, but EPA did not ⁵¹. Further studies are needed to clarify the mechanisms and significance of these differences ^{50, 51, 52}.

Research on most omega-3 fatty acids is directed toward DHA and EPA; however, recently omega-3 docosapentaenoic acid (DPA) also has been drawing attention. The level of DPA in serum has is individually associated with a reduction in the risk of myocardial infarction and coronary heart disease ^{53, 54}. When the DPA level in the serum decreases, the risk of peripheral arterial disease such as vascular plaque formation increases ^{55, 56}. DPA has a stronger inhibitory action on platelet aggregation than DHA and EPA ⁵⁷. Like DHA and EPA, DPA has been reported to decrease the expression of inflammatory genes ⁵⁸. As the fasting serum TG-lowering mechanism of action of long-chain omega-3 fatty acids differs from that of other lipid-lowering drugs, such as statins, they can potentially provide complementary benefits on the lipid profile when administered in combination ³⁵. This is supported by a study examining the synergistic effect of the lowering action of fasting serum TG by omega-3 fatty acids in addition to statin therapy ^{59, 60, 61, 62}.

This research had certain limitations. There was a possibility that sampling bias existed in the studies used and there was language bias due to the database search using only English and Japanese keywords; however, all reports adopted in this study were peer-reviewed RCTs, the quality of each research was thought to be high, the bias risk was roughly not a problem, and the quality of scientific evidence could be sufficiently judged. In this systematic review, meta-analysis could not be performed due to several reasons, mainly clinical heterogeneity; however, the evidence level of an individual RCT is considered to be sufficiently high, that is, it can be said that DHA and/or EPA intake can reduce and maintain a suitable level of fasting serum TG.

In modern society, the importance of functional foods is increasing in terms of medical economics; however, it will be necessary to accumulate evidence from interventional studies targeting healthy people and perform meta-analysis.

1. 1.Assembly U G. (2011) Political declaration of the high-level meeting of the general assembly on the prevention and control of non-communicable diseases. , New York: United Nations
   Search at Google Scholar

1. 2.Hokanson J E, Austin M A. (1996) Plasma triglyceride level is a risk factor for cardiovascular disease independent of high-density lipoprotein cholesterol level: a meta-analysis of population-based prospective studies. , J Cardiovasc Risk 3, 213-219.
   PubMed·Search at Google Scholar

1. 3.Nichiro Maruha.Corporation. What is DHA?. (Japanese). URL https://www.maruha-nichiro.co.jp/dha/dha20000.html
   Search at Google Scholar

1. 4.National Centerfor Complementary and Integrative Health . Omega-3 Supplements: In Depth. https://nccih.nih.gov/health/omega3/introduction.htm
   Search at Google Scholar

1. 5.Mann N J, O’Connell S L, Baldwin K M, Singh I, Meyer B J. (2010) Effects of seal oil and tuna-fish oil on platelet parameters and plasma lipid levels in healthy subjects. Lipids. 45, 669-681.
   PubMed·View article·Search at Google Scholar

1. 6.Watanabe N, Watanabe Y, Kumagai M, Fujimoto K. (2009) Administration of dietary fish oil capsules in healthy middle-aged Japanese men with a high level of fish consumption. , Int J Food Sci Nutr 60, 136-142.
   PubMed·View article·Search at Google Scholar

1. 7.Caslake M J, Miles E A, Kofler B M. (2008) Effect of sex and genotype on cardiovascular biomarker response to fish oils:. , the FINGEN Study. Am J Clin Nutr 88, 618-629.
   PubMed·View article·Search at Google Scholar

1. 8.Buckley J D, Burgess S, Murphy K J, Howe P R. (2009) DHA-rich fish oil lowers heart rate during submaximal exercise in elite Australian Rules footballers. , J Sci Med Sport 12, 503-507.
   PubMed·View article·Search at Google Scholar

1. 9.Gunnarsdottir I, Tomasson H, Kiely M. (2008) Inclusion of fish or fish oil in weight-loss diets for young adults: effects on blood lipids. , Int J Obes 32, 1105-1112.
   PubMed·View article·Search at Google Scholar

1. 10.Plat J, Jellema A, Ramakers J, Mensink R P. (2007) Weight loss, but not fish oil consumption, improves fasting and postprandial serum lipids, markers of endothelial function, and inflammatory signatures in moderately obese men. , J Nutr 137, 2635-2640.
   Search at Google Scholar

1. 11.Kobayashi K, Hamazaki K, Fujioka S, Terao K, Yamamoto J et al. (2007) The effect of omega-3 PUFA/gamma-cyclodextrin complex on serum lipids in healthy volunteers--a randomized, placebo-controlled, double-blind trial. , Asia Pac J Clin Nutr 16, 429-434.
   PubMed·Search at Google Scholar

1. 12.Bovet P, Faeh D, Madeleine G, Viswanathan B, Paccaud F. (2007) Decrease in blood triglycerides associated with the consumption of eggs of hens fed with food supplemented with fish oil. Nutr Metab Cardiovasc Dis. 17, 280-287.
   PubMed·View article·Search at Google Scholar

1. 13.Wu W H, Lu S C, Wang T F, Jou H J, Wang T A. (2006) Effects of docosahexaenoic acid supplementation on blood lipids, estrogen metabolism, and in vivo oxidative stress in postmenopausal vegetarian women. , Eur J Clin Nutr 60, 386-392.
   PubMed·View article·Search at Google Scholar

1. 14.Burns-Whitmore B, Haddad E, Sabaté J, Rajaram S. (2014) Effects of supplementing omega-3 fatty acid enriched eggs and walnuts on cardiovascular disease risk markers in healthy free-living lacto-ovo-vegetarians: a randomized, crossover, free-living intervention study. , Nutr J 13-29.
   PubMed·View article·Search at Google Scholar

1. 15.O’sullivan A, Armstrong P, Schuster G U, Pedersen T L, Allayee H et al. (2013) Habitual Diets Rich in Dark-Green Vegetables Are Associated with an Increased Response to ω-3 Fatty Acid Supplementation in Americans of African Ancestry–. , J Nutr 144, 123-131.
   Search at Google Scholar

1. 16.Signori C, DuBrock C, Richie J P. (2012) Administration of omega-3 fatty acids and Raloxifene to women at high risk of breast cancer: interim feasibility and biomarkers analysis from a clinical trial. , Eur J Clin Nutr 66, 878-884.
   PubMed·View article·Search at Google Scholar

1. 17.García-Alonso F J, Jorge-Vidal V, Ros G, Periago M J. (2012) Effect of consumption of tomato juice enriched with omega-3 polyunsaturated fatty acids on the lipid profile, antioxidant biomarker status, and cardiovascular disease risk in healthy women. , Eur J Clin Nutr 51, 415-424.
   Search at Google Scholar

1. 18.Bragt M C, Mensink R P. (2012) Comparison of the effects of omega-3 long chain polyunsaturated fatty acids and fenofibrate on markers of inflammation and vascular function, and on the serum lipoprotein profile in overweight and obese subjects Nutr Metab Cardiovasc Dis. 22, 966-973.
   PubMed·View article·Search at Google Scholar

1. 19.Ulven S M, Kirkhus B. (2011) Lamglait A et al. Metabolic effects of krill oil are essentially similar to those of fish oil but at lower dose of DHA and EPA, in healthy volunteers. Lipids. 46, 37-46.
   PubMed·View article·Search at Google Scholar

1. 20.Buckley R, Shewring B, Turner R, Yaqoob P, Minihane A M. (2004) Circulating triacylglycerol and apoE levels in response to EPA and docosahexaenoic acid supplementation in adult human subjects. , Br J Nutr 92, 477-483.
   PubMed·Search at Google Scholar

1. 21.Theobald H E, Chowienczyk P J, Whittall R, Humphries S E, Sanders T A. (2004) LDL cholesterol–raising effect of low-dose docosahexaenoic acid in middle-aged men and women. , Am J Clin Nutr 79, 558-563.
   Search at Google Scholar

1. 22.Grimsgaard S, Bonaa K H, Hansen J B, Nordøy A. (1997) Highly purified eicosapentaenoic acid and docosahexaenoic acid in humans have similar triacylglycerol-lowering effects but divergent effects on serum fatty acids. , Am J Clin Nutr 66, 649-659.
   PubMed·View article·Search at Google Scholar

1. 23.Lovegrove J A, Brooks C N, Murphy M C, Gould B J, Williams C M. (1997) Use of manufactured foods enriched with fish oils as a means of increasing long-chain n− 3 polyunsaturated fatty acid intake. , Br J Nutr 78, 223-236.
   Search at Google Scholar

1. 24.Harris W S, Lu G, Rambjør G S, Wålen A I, Ontko J A et al. (1997) Influence of omega-3 fatty acid supplementation on the endogenous activities of plasma lipases. , Am J Clin Nutr 66, 254-260.
   PubMed·View article·Search at Google Scholar

1. 25.Conquer J A, Holub B J. (1996) Supplementation with an algae source of docosahexaenoic acid increases (omega-3) fatty acid status and alters selected risk factors for heart disease in vegetarian subjects. , J Nutr 126-3032.
   PubMed·View article·Search at Google Scholar

1. 26.Agren J J, Hänninen O, Julkunen A. (1996) Fish diet, fish oil and docosahexaenoic acid rich oil lower fasting and postprandial plasma lipid levels. , Eur J Clin Nutr 765-771.
   PubMed·Search at Google Scholar

1. 27.Hamazaki T, Sawazaki S, Asaoka E. (1996) Docosahexaenoic acid-rich fish oil does not affect serum lipid concentrations of normolipidemic young adults. , J Nutr 126, 2784-2789.
   Search at Google Scholar

1. 28.Hansen J B, Olsen J O, Wilsgård L, Lyngmo V, Svensson B. (1996) Comparative effects of prolonged intake of highly purified fish oils as ethyl ester or triglyceride on lipids, haemostasis and platelet function in normolipaemic men. , Eur J Clin Nutr 47, 497-507.
   PubMed·Search at Google Scholar

1. 29.Luley C, Lelieur I, Hanisch M. (1992) Fish oil treatment and apolipoprotein (a). Arzneimittel-Forschung. 42, 77-80.
   Search at Google Scholar

1. 30.Childs M T, King I B, Knopp R H. (1990) Divergent lipoprotein responses to fish oils with various ratios of eicosapentaenoic acid and docosahexaenoic acid. , Am J Clin Nutr 52, 632-639.
   PubMed·View article·Search at Google Scholar

1. 31.Blonk M C, Bilo H J, Nauta J J, Popp-Snijders C, Mulder C et al. (1990) Dose-response effects of fish-oil supplementation in healthy volunteers. , Am J Clin Nutr 52, 120-127.
   PubMed·View article·Search at Google Scholar

1. 32.Zucker M L, Bilyeu D S, Helmkamp G M, Harris W S, Dujovne C A. (1988) Effects of dietary fish oil on platelet function and plasma lipids in hyperlipoproteinemic and normal subjects. Atherosclerosis. 73, 13-22.
   PubMed·Search at Google Scholar

1. 33.Fujimoto Y, Tsuji T, Ozasa H, Itakura H.The Efficacy and Safety of 12 Week Daily Ingestion of a Beverage Containing DHA and EPA on the Moderately High Fasting Blood Triglyceride in a Randomized Controlled Trial. , J Jpn Soc Clin Nutr 33(3), 120-135.
   Search at Google Scholar

1. 34.Tamai T. (2014) Utilization of Processed Foods Rich in Docosahexaenoic Acid: Clinical Trials Using Foods for Specific Health Purposes. 23, 45-52.
   Search at Google Scholar

1. 35.Dyerberg J, Eskesen D C, Andersen P W. (2004) Effects of trans-and omega-3 unsaturated fatty acids on cardiovascular risk markers in healthy males. An 8 weeks dietary intervention study. , Eur J Clin Nutr 58, 1062-1070.
   PubMed·View article·Search at Google Scholar

1. 36.Prisco D, Paniccia R, Filippini M. (1994) No changes in PAI-1 levels after four-month omega-3 PUFA ethyl ester supplementation in healthy subjects. Thromb Res. 76, 237-244.
   PubMed·Search at Google Scholar

1. 37.Rizza S, Tesauro M, Cardillo C. (2009) Fish oil supplementation improves endothelial function in normoglycemic offspring of patients with type 2 diabetes. , Atherosclerosis 206, 569-574.
   PubMed·View article·Search at Google Scholar

1. 38.Logan S L, Spriet L L. (2015) Omega-3 fatty acid supplementation for 12 weeks increases resting and exercise metabolic rate in healthy community-dwelling older females. PloS One. 10-0144828.
   PubMed·View article·Search at Google Scholar

1. 39.Matsumoto Y. (2016) Effects of Purified Fish Oil-containing Dietary Supplement on Serum Triglycerides, Blood Pressure, and Cognitive Function in Healthy Japanese Middle-agers ―Randomized, Double-blind, Placebo-controlled Parallel-group Trial― Jpn Pharmacol Ther. 44(2), 235-46.
   Search at Google Scholar

1. 40.Rajkumar H, Mahmood N, Kumar M, Varikuti S R, Challa H R et al. (2014) Effect of probiotic (VSL# 3) and omega-3 on lipid profile, insulin sensitivity, inflammatory markers, and gut colonization in overweight adults: a randomized, controlled trial. Mediators Inflamm.
   PubMed·View article·Search at Google Scholar

1. 41.Marckmann P, Bladbjerg E M, Jespersen J. (1997) Dietary fish oil (4 g daily) and cardiovascular risk markers in healthy men. Arterioscler Thromb Vasc Biol. 17, 3384-3391.
   Search at Google Scholar

1. 42.Higgins J P, Altman D G, Gøtzsche P C, Jüni P, Moher D et al. Cochrane Bias Methods Group, Cochrane Statistical Methods GroupThe Cochrane Collaboration’s tool for assessing risk of bias in randomized trials.BMJ,343(oct182),d5928(2011).
   Search at Google Scholar

1. 43.Backes J, Anzalone D, Hilleman D, Catini J. (2016) The clinical relevance of omega-3 fatty acids in the management of hypertriglyceridemia. Lipids Health Dis. 15-118.
   PubMed·View article·Search at Google Scholar

1. 44.C Le Jossic-, Gonthier C, Zaghini I, Logette E, Shechter I et al.Hepatic farnesyl diphosphate synthase expression is suppressed by polyunsaturated fatty acids. , Biochem J 385, 787-794.
   Search at Google Scholar

1. 45.Horton J D, Bashmakov Y, Shimomura I, Shimano H. (1998) Regulation of sterol regulatory element binding proteins in livers of fasted and refed mice. Proc Natl Acad Sci 95, 5987-5992.
   PubMed·Search at Google Scholar

1. 46.Bays H E, Tighe A P, Sadovsky R, Davidson M H. (2008) Prescription omega-3 fatty acids and their lipid effects: physiologic mechanisms of action and clinical implications. Expert Rev Cardiovasc Ther. 6, 391-409.
   PubMed·View article·Search at Google Scholar

1. 47.Harris W S, Bulchandani D. (2006) Why do omega-3 fatty acids lower serum triglycerides? Curr Opin Lipidol. 17, 387-393.
   PubMed·View article·Search at Google Scholar

1. 48.Park Y, Harris W S. (2003) Omega-3 fatty acid supplementation accelerates chylomicron triglyceride clearance. , J Lipid Res 44, 455-463.
   PubMed·View article·Search at Google Scholar

1. 49.Khan S, Minihane A M, Talmud P J, Wright J W, Murphy M C et al. (2002) Dietary long-chain omega-3 PUFAs increase LPL gene expression in adipose tissue of subjects with an atherogenic lipoprotein phenotype. , J Lipid Res 43, 979-985.
   Search at Google Scholar

1. 50.Jacobson T A, Glickstein S B, Rowe J D, Soni P N. (2012) Effects of eicosapentaenoic acid and docosahexaenoic acid on low-density lipoprotein cholesterol and other lipids: a review. J Clin Lipidol. 6, 5-18.
   PubMed·View article·Search at Google Scholar

1. 51.Wei M Y, Jacobson T A. (2011) Effects of eicosapentaenoic acid versus docosahexaenoic acid on serum lipids: a systematic review and meta-analysis. Curr Atheroscler Rep. 13, 474-483.
   PubMed·View article·Search at Google Scholar

1. 52.Davidson M H. (2013) Omega-3 fatty acids: new insights into the pharmacology and biology of docosahexaenoic acid, docosapentaenoic acid, and eicosapentaenoic acid. Curr Opin Lipidol. 24, 467-474.
   PubMed·View article·Search at Google Scholar

1. 53.Simon J A, Hodgkins M L, Browner W S, Neuhaus J M, Bernert Jr JT et al. (1995) Serum fatty acids and the risk of coronary heart disease. , Am J Epidemiol 142, 469-476.
   PubMed·Search at Google Scholar

1. 54.Sun Q, Ma J, Campos H, Rexrode K M, Albert C M et al. (2008) Blood concentrations of individual long-chain omega-3 fatty acids and risk of nonfatal myocardial infarction. , Am J Clin Nutr 88, 216-223.
   PubMed·Search at Google Scholar

1. 55.Amano T, Matsubara T, Uetani T, Kato M. (2011) Impact of omega-3 polyunsaturated fatty acids on coronary plaque instability: an integrated backscatter intravascular ultrasound study. , Atherosclerosis 218, 110-116.
   Search at Google Scholar

1. 56.Leng G C, Horrobin D F, Fowkes F G, Smith F B, Lowe G D et al. (1994) Plasma essential fatty acids, cigarette smoking, and dietary antioxidants in peripheral arterial disease. A population-based case-control study. Arterioscler Thromb Vasc Biol. 14, 471-478.
   Search at Google Scholar

1. 57.Akiba S, Murata T, Kitatani K, SATO T. (2000) Involvement of lipoxygenase pathway in docosapentaenoic acid-induced inhibition of platelet aggregation. , Biol Pharm Bull 23, 1293-1297.
   Search at Google Scholar

1. 58.Kishida E, Tajiri M, Masuzawa Y. (2006) Docosahexaenoic acid enrichment can reduce L929 cell necrosis induced by tumor necrosis factor. Biochim Biophys Acta Molecular and Cell Biology of Lipids. 1761, 454-462.
   Search at Google Scholar

1. 59.Davidson M H, Stein E A, Bays H E. (2007) Efficacy and tolerability of adding prescription omega-3 fatty acids 4 g/d to simvastatin 40 mg/d in hypertriglyceridemic patients: an 8-week, randomized, double-blind, placebo-controlled study. Clin Ther. 29, 1354-1367.
   Search at Google Scholar

1. 60.Maki K C, Orloff D G, Nicholls S J. (2013) A highly bioavailable omega-3 free fatty acid formulation improves the cardiovascular risk profile in high-risk, statin-treated patients with residual hypertriglyceridemia (the ESPRIT trial). Clin Ther. 35, 1400-1411.
   Search at Google Scholar

1. 61.Ballantyne C M, Bays H E, Kastelein J J, Stein E, Isaacsohn J L et al. (2012) Efficacy and safety of eicosapentaenoic acid ethyl ester (AMR101) therapy in statin-treated patients with persistent high triglycerides (from the ANCHOR study). , Am J Cardiol 110, 984-992.
   Search at Google Scholar

1. 62.Chan D C, Watts G F, Barrett P H, Beilin L J, Redgrave T G et al. (2002) Regulatory effects of HMG CoA reductase inhibitor and fish oils on apolipoprotein B-100 kinetics in insulin-resistant obese male subjects with dyslipidemia. Diabetes. 51, 2377-2386.
   Search at Google Scholar

1. 1.Konishi Tatsuya, Takahashi Yoshinori, Shiina Yasuhiko, Oike Hideaki, Oishi Katsutaka, 2021, Time-of-day effects of consumption of fish oil–enriched sausages on serum lipid parameters and fatty acid composition in normolipidemic adults: A randomized, double-blind, placebo-controlled, and parallel-group pilot study, Nutrition, 90(), 111247, 10.1016/j.nut.2021.111247