International Journal of Nutrition
ISSN: 2379-7835
Current Issue
Volume No: 3 Issue No: 2
share this page

Review Article | Open Access
  • Available online freely | Peer Reviewed
  • Efficacy of DHA and EPA on Serum Triglyceride Levels of Healthy Participants: Systematic Review

    Yohei Kawasaki 1       Yoshihiro Iwahori 2     Yosuke Chiba 3     Hiroyuki Mitsumoto 3     Tomoe Kawasaki 2     Sumiko Fujita 2     Yoshinori Takahashi 3    

    1Biostatistics Section, Clinical Research Center, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba, 260-8677, Japan

    2LLC Okutoeru, 4-18-21-314, Minamiaoyama, Minato-ku, Tokyo, 107-0062, Japan

    3Maruha Nichiro Corporation, 16-2, Wadai, Tsukuba-City, Ibaraki, 300-4295, Japan

    Abstract

    Background

    Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are categorized as omega-3 poly unsaturated fatty acids (PUFAs) that are present in fish oil, etc. DHA and EPA omega-3 PUFAs have a well-established fasting serum triglycerides (TG) lowering effect that may result in normal lipidemia in hyperlipidemic patients. 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.

    Objectives

    To review and confirm the preventive effect of omega-3 PUFAs against hypertriglyceridemia or the effect on 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 triglyceride level who consumed DHA and/or EPA orally compared to those with placebo or no intake of DHA and/or EPA.

    Search Methods

    We evaluated articles from searches of PubMed (1946-February 2016), Ichushi-Web (1977-February 2016), and J Dream III (JST Plus, 1981-February 2016; JMED Plus, 1981-February 2016). The keywords were set as follows: “DHA” or “docosahexaenoic acid” or “EPA” or “eicosapentaenoic acid” and “TG” or “triglyceride” or “triglycerol” or “triacylglycerol” or “neutral lipid.”. In addition to the literature group obtained by the database search, we included participants not suffering from any disease (i.e., excluding mild hypertriglyceridemia).

    Eligibility Criteria

    Before the test selection process, the following inclusion criteria were defined. Participants were healthy men and women including those with mild hypertriglyceridemia (fasting serum TG level, 150-199 mg/dL [1.69-2.25 mmol/L)). Intervention was defined as orally ingested DHA and/or EPA. Comparison was made to placebo intake or no intake of DHA and/or EPA. Results were measured for the fasting serum TG level. The test design was RCT, and quasi-RCT.

    Data Abstraction

    Various characteristics were extracted from original reports using a standardized data extraction form, including the author of the study, research year, research design, subject characteristics (sex, age, sample size), period, dose of DHA and/or EPA (mg/day), and comparison group.

    Main Results

    We identified 37 documents for review. Among the 37 reports used to integrate literature results, 25 revealed a decrease in fasting serum TG level ​​due to the 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 stratified analysis was conducted. Ten of the 16 (normal TG participant) and 15 of the 21 studies (slightly higher TG participant) respectively, indicated that at least 133 mg/day of DHA and/or EPA intervention provided a statistically significant decrease in the fasting serum TG level between an intervention group versus a placebo group.

    Received 07 Nov 2018; Accepted 09 Jan 2019; Published 15 Jan 2019;

    Academic Editor:Gaetan Drouin, Laboratory of Biochemistry and Human Nutrition, France.

    Checked for plagiarism: Yes

    Review by: Single-blind

    Copyright©  2019 Yohei Kawasaki, et al.

    License
    Creative Commons License    This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

    Competing interests

    This work was funded by Maruha Nichiro Corporation. YC, HM and YT are employees of Maruha Nichiro Corporation. None of the other authors declare no conflict of interest.

    Citation:

    Yohei Kawasaki, Yoshihiro Iwahori, Yosuke Chiba, Hiroyuki Mitsumoto, Tomoe Kawasaki et al. (2019) Efficacy of DHA and EPA on Serum Triglyceride Levels of Healthy Participants: Systematic Review. International Journal of Nutrition - 3(2):22-40.
    Download as RIS, BibTeX, Text (Include abstract )
    DOI10.14302/issn.2379-7835.ijn-18-2469

    Introduction

    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.

    Method

    Identification of Relevant Research

    PubMed (1946–February 2016), Ichushi-Web (1977–February 2016), and J Dream III (JSTPlus, 1981–February 2016; JMEDPlus, 1981–February 2016) were independently searched by two reviewers (Y. C, and Y. T). The keywords were set as follows: “DHA” or “docosahexaenoic acid” or “EPA” or “eicosapentaenoic acid” and “TG” or “triglyceride” or “triglycerol” or “triacylglycerol” or “neutral lipid.”. In addition to the literature group obtained by the database search, we included participants without any disease (i.e., excluding mild hypertriglyceridemia). Our systematic literature search utilized Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.

    Eligibility Criteria

    The following inclusion criteria were defined prior to the test selection process:

    Participants were healthy adult men and women including those with mild hypertriglyceridemia (fasting serum TG level, 150–199 mg/dL (1.69–2.25 mmol/L)). 2 Intervention was defined as orally ingested DHA and/or EPA. 3 A comparison was made for placebo intake or no intake of DHA and/or EPA. 4 Results were measured according to the fasting serum TG level. 5 The test design was RCT, and quasi-RCT. Based on these requirements, two reviewers (Y. T and H. M) independently selected studies and extracted data regarding the study characteristics and outcomes from the selected studies.

    Data Abstraction

    Various characteristics were extracted from original reports using a standardized data extraction form, including author of the study, research year, research design, subject characteristics (sex, age, sample size), period, dose of DHA and/or EPA (mg/day), and comparison group.

    Risk of Bias Assessment

    Using the Cochrane Collaboration tool to evaluate the risk of bias42; low, ambiguous, or highly biased risks for five categories (random sequence generation, assignment hiding, blinded participants and personnel, incomplete outcome data, and selective outcome report) were evaluated in each study. Quality assessments for each included study were also conducted using the Cochrane Collaboration’s tool for assessing risk of bias. Disagreements at any step were resolved through discussion.

    Result

    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 25, 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.
    Figure 1.

    Table 1. Characteristics of the selected 37 documents.
    No. Author  Reference PICO Participants Dose Study term
    54 Burns-Whitmore B, et al.14 Nutr J, 13: 29 (2014) P:healthy adult male and female [Placebo group] DHA 429 mg, 8 weeks
             I:DHA / EPA [Intervention group] EPA 34 mg
      C:placebo  N=20, 38±3 years old    
      O:TG level, Cardiovascular risk      
    74 O'Sullivan A, et al. 15 J Nutr, 144(2): 123–131 (2013) P:healthy adult male and female [Placebo group] DHA 1,000 mg, 6 weeks
          I:DHA/EPA N=42, 34.1±12.0 years old EPA 2,000 mg  
          C:placebo [Intervention group]    
          O:TG level, lipid metabolism ・HR group    
            N=28, 37.2±12.0 years old    
            ・LR group    
            N=13, 38.0±9.6 years old    
    138 Signori C, et al. 16 Eur J Clin Nutr, 66(8): 878–884 (2012) P:healthy adult female [Placebo group] DHA 1,500 mg, 12 months
          I:DHA/EPA, etc. N=8, 35-75 years old EPA 1,860 mg  
          C:no intervention [Intervention group]    
          O:Breast cancer risk, lipid-profile including TG level N=11, 35-75 years old    
    165 García-Alonso FJ, et al. 17 Eur J Nutr, 51(4): 415–424 (2012) P:healthy adult female [Placebo group] DHA 125 mg, 2 weeks
          I:DHA / EPA N=7, 35-55 years old EPA 125 mg  
          C:placebo [Intervention group]    
          O:TG level, lipid metabolism N=11, 35-55 years old    
    172 Bragt MCE, et al. 18 Nutr Metab Cardiovasc Dis, 22(11): 966–973 (2012) P:adult male and female [Placebo group] DHA 1,200 mg, 6 weeks
          I:DHA/EPA [Intervention group] EPA 1,700 mg  
          C:placebo  N=20, 52±12 years old    
          O:TG level, lipid metabolism      
    181 Ulven SM, et al. 19  Lipids, 46(1): 37–46 (2011) P:healthy adult male and female [Placebo group] ・FO group 7 weeks
          I:DHA/EPA N=42, 40.5±12.1 years old DHA 414 mg,  
          C:no intervention [Intervention group] EPA 450 mg  
          O:TG level, lipid metabolism ・FO group ・KO group  
            N=43, 38.7±11.1 years old DHA 195 mg,  
            ・KO group EPA 348 mg  
            N=44, 40.3±14.8 years old    
    188 Mann NJ, et al. 5  Lipids, 45(8): 669–681 (2010) P:healthy adult male and female [Placebo group] ・FO group 14 days
          I:DHA/EPA N=7, 29±5 years old DHA 810 mg,  
          C:placebo [Intervention group] EPA 210 mg  
          O:TG level, lipid metabolism ・FO group ・SO group  
            N=10, 30±8 years old DHA 450 mg,  
            ・SO group EPA 340 mg  
            N=10, 31±6 years old    
    225 Watanabe N, et al. 6 Int J Food Sci Nutr, 60(S5): 136–142 (2009) P:healthy adult male [Placebo group] DHA 540 mg, 4 weeks
          I:DHA / EPA [Intervention group] EPA 1,260 mg  
          C:placebo  N=17, 50.1±9.2 years old    
          O:TG level, lipid metabolism      
    236 Caslake MJ, et al. 7 Am J Clin Nutr, 88(3): 618–629 (2008) P:healthy adult male and female [Placebo group] ・LD group 8 weeks
          I:DHA/EPA [Intervention group] DHA 407 mg,  
          C:placebo N=312, 45.0±0.7 years old EPA 293 mg  
          O:TG level, lipid metabolism   ・HD group  
              DHA 1,047 mg,  
              EPA 753 mg  
    245 Buckley JD, et al. 8  J Sci Med Sport, 12(4): 503–507 (2009) P:adult male [Placebo group] DHA 1,560 mg, 5 weeks
          I:DHA/EPA N=13, 23.2±1.1 years old  
          C:placebo [Intervention group]  EPA 360 mg  
          O:TG level, lipid metabolism N=12, 21.7±1.0 years old    
    248 Gunnarsdottir I, et al. 9  Int J Obes (Lond), 32(7): 1105–1112 (2008) P:healthy adult male and female [Placebo group] ・CD group 8 weeks
          I:DHA / EPA N=76, 32.1±5.3 years old DHA 207 mg,  
          C:placebo [Intervention group] EPA 54 mg  
          O:TG level, lipid metabolism ・CD group ・SD group  
            N=79, 31.3±5.7 years old DHA 1,370 mg,  
            ・SD group EPA 774 mg  
            N=80, 31.3±5.3 years old ・FO group  
            ・FO group DHA 430 mg,  
            N=79, 31.0±5.3 years old EPA 633 mg  
    257 Plat J, et al. 10  J Nutr, 137(12): 2635–2640 (2007) P:healthy adult male [Placebo group] DHA 500 mg, 6 weeks
          I:DHA/EPA [Intervention group] EPA 600 mg  
          C:placebo  N=11, 59±9 years old    
          O:TG level, lipid metabolism      
    262 Kobayashi K, et al. 11  Asia Pac J Clin Nutr, 16(3): 429–434 (2007) P:healthy adult male and female [Placebo group] DHA 280 mg, 8 weeks
          I:DHA/EPA N=18, 48.4±7.7 years old EPA 660 mg  
          C:placebo [Intervention group]    
          O:TG level N=20, 48.5±7.8 years old    
    282 Bovet P, et al. 12 Nutr Metab Cardiovasc Dis, 17(4): 280–287 (2007) P:healthy adult male and female [Placebo group] DHA 124 mg, 3 weeks
        I:DHA/ EPA [Intervention group] EPA 9 mg
          C:placebo  N=25, 34.8±7.9 years old    
          O:TG level, lipid metabolism      
    305 Wu WH, et al. 13 Eur J Clin Nutr, 60(3): 386–392 (2006) P:adult female [Placebo group] DHA 2,140 mg 6 weeks
       I:DHA  N=11, 52.3±5.1 years old  
          C:placebo [Intervention group]    
          O:TG level, lipid metabolism N=1452.6±4.4 years old    
    325 Buckley R, et al. 20 Br J Nutr, 92(3): 477–483 (2004) P:healthy adult male and female [Placebo group] ・EH group 4 weeks
        I:DHA/EPA N=15, 48±4 years old DHA 729 mg,
          C:placebo [Intervention group] EPA 4,752 mg  
          O:TG level, lipid metabolism ・EH group ・DH group  
            N=15, 46±3 years old
            ・DH group  DHA 4,914 mg,  
            N=12, 45±4 years old  EPA 846 mg  
    334 Theobald HE, et al. 21 Am J Clin Nutr, 79(4): 558–563 (2004) P:healthy adult male and female [Placebo group] DHA 680 mg 3 months
        I:DHA/EPA N=38, 40-65 years old
          C:placebo  [Intervention group]    
          O:TG level, lipid metabolism      
    419 Grimsgaard S, et al. 22  Am J Clin Nutr, 66(3): 649–659 (1997) P:healthy adult male and female [Placebo group] ・EH group 7 weeks
        I:DHA/EPA N=77, 45±6years old DHA 48 mg,
          C:placebo [Intervention group] EPA 3,764 mg  
          O:TG level, lipid metabolism ・EH group ・DH group  
            N=75, 44±5years old DHA 3,556 mg,  
            ・DH group EPA 72 mg  
            N=72, 43±5years old    
    420 Lovegrove JA, et al. 23  Br J Nutr, 78(2): 223–236 (1997) P:healthy adult male [Placebo group] DHA 500 mg, 22days
        I:DHA/EPA [Intervention group] EPA 860 mg
          C:placebo  N=9, 50±7.2 years old    
          O:TG level, lipid metabolism      
    421 Harris WS, et al. 24  Am J Clin Nutr, 66(2): 254–260 (1997) P:healthy adult male and female etc. [Placebo group] DHA 1,145 mg, 3 weeks
        I:DHA/EPA [Intervention group] EPA 2,055 mg
          C:placebo N=20, 31±9years old    
          O:TG level, lipid metabolism      
    433 Conquer JA, et al. 25  J Nutr, 126(12): 3032–3039 (1996) P:healthy adult male and female [Placebo group] DHA 1,620 mg 6 weeks
          I:DHA    
          C:placebo [Intervention group]    
          O:TG level, lipid metabolism N=12, 29.6±1.7 years old    
    434 Ågren JJ, et al. 26  Eur J Clin Nutr, 50(11): 765–771 (1996) P:healthy adult male [Placebo group] ・FD group 14 weeks
        I:DHA / EPA   DHA 670 mg,
          C:no intervention [Intervention group] EPA 380 mg  
          O:TG level, lipid metabolism ・FD group ・FO group  
            N=13, 23±2 years old DHA 952 mg,  
            ・FO group EPA 1,328 mg  
            N=14, 23±2 years old ・DH group  
            ・DH group DHA 1,680 mg  
            N=14, 24±4 years old    
    435 Hamazaki T, et al. 11  J Nutr, 126(11): 2784–2789 (1996) P:healthy adult male and female [Placebo group] DHA 1,775 mg, 13 weeks
         I:DHA / EPA [Intervention group] EPA 241 mg
          C:placebo N=18,21-30 years old    
          O:TG level, lipid metabolism    
    468 Hansen JB, et al. 22  Eur J Clin Nutr, 47(7): 497–507 (1993) P:healthy adult male [Placebo group] TG group 7 weeks
         I:DHA/EPA N=10, 21-47 years old DHA 1,400 mg,
          C:placebo [Intervention group] EPA 2,200 mg  
          O:TG level, lipid metabolism ・TG group ・EE group  
            N=11, 21-47 years old DHA 1,200 mg,  
            ・EE group EPA 2,200 mg  
            N=10, 21-47 years old    
    490 Luley C, et al. 29  Arzneimittelforschung, 42(1): 77–80 (1992) P:healthy adult male and female [Placebo group] DHA 1,440 mg, 4 weeks
         I:DHA/EPA [Intervention group] EPA 2,040 mg
          C:no intervention Study DI    
          O:lipid-profile including TG level N=16, 21-55 years old    
          P:healthy adult male and female [Placebo group] DHA 4,320 mg, EPA 6,120 mg  4 weeks
         I:DHA/EPA [Intervention group]  
          C:no intervention Study DIII    
          O:lipid-profile including TG level N=15, 21-55 years old    
    505 Childs MT, et al. 30  Am J Clin Nutr, 52(4): 632–639 (1990) P:healthy adult male [Placebo group][Intervention group] ・PO group 3 weeks
         I:DHA/EPA  N=8, 29±2 years old  DHA 681 mg,
          C:placebo   EPA 2,560 mg  
          O:lipid-profile including TG level   ・TU group  
              DHA 4,514 mg,  
              EPA 1,568 mg  
              ・SA group  
              DHA 1,380 mg,  
              EPA 1,104 mg  
    510 Blonk MC, et al. 31  Am J Clin Nutr, 52(1): 120–127 (1990) P:healthy adult male [Placebo group] ・LD group 12 weeks
         I:DHA / EPA [Intervention group] DHA 600 mg,
          C:no intervention ・LD group EPA 900 mg  
          O:lipid-profile including TG level N=11, 33.7±6.2 years old ・MD group  
            ・MD group DHA 1,200 mg,  
            N=10, 33.7±6.2 years old EPA 1,800 mg  
            ・HD group ・HD group  
            N=14, 33.7±6.2 years old DHA 2,400 mg,  
            EPA 3,600 mg  
    529 Zucker ML, et al. 32  Atherosclerosis, 73(1): 13–22 (1988) P:healthy adult male and female, et al [Placebo group] DHA 2,160 mg, 6 weeks
        I:DHA/EPA [Intervention group] EPA 3,240 mg
          C:placebo N=9, 36-60 years old    
          O:lipid-profile including TG level      
    567 Fujimoto, et al. 33 Journal of Japanese society of Clinical Nutritioomega-33(3): 120–135 (2011) P:adult male and female [Placebo group] DHA 260 mg, 12 weeks
        I:DHA/EPA N=52, 47.9±9.2 years old EPA 600 mg
          C:placebo [Intervention group]    
          O:TG level N=49, 46.1±10.1 years old    
    583 Tamai,et al. 34 Pharmacology and Therap, 36(4): 333–345 (2008) P:adult male and female [Placebo group] DHA 910 mg, 12 weeks
        I:DHA / EPA N=36, 49.8±9.0 years old EPA 200 mg
          C:placebo [Intervention group]    
          O:TG level N=39, 48.9±8.9 years old    
    707 Dyerberg J, et al. 35 Eur J Clin Nutr, 58(7): 1062–1070 (2004) P:healthy adult male [Placebo group] DHA 949 mg, 8 weeks
        I:DHA/EPA, et al N=27, 37.6±10.6 years old EPA 1,492 mg
          C:placebo [Intervention group]    
          O:risk for Cardiovascular related including TG level N=24, 39.2±10.5 years old    
    709 Prisco D, et al. 36 Thromb Res, 76(3): 237–244 (1994) P:healthy adult male [Placebo group] DHA 1,400 mg, 4months
        I:DHA/EPA N=10, 32±4y ears old  EPA 2,040 mg
          C:placebo  [Intervention group]
          O:lipid-profile including TG level  N=10, 32±4 years old  
    712 Rizza S, et al. 37 Atherosclerosis, 206(2): 569–574 (2009) P:healthy adult male and female [Placebo group] 12 weeks
        I:DHA/EPA  N=24, 29.9±6.2 years old DHA/EPA 1,700 mg
          C:placebo  [Intervention group]  
          O:lipid-profile including TG level   N=26, 29.9±6.2 years old
    715 Logan SL, et al. 38 Plos One, 10(12): e0144828 (2015) P:healthy adult female [Placebo group] DHA 1,000 mg, 12 weeks
         N=12, 66±1years old EPA 2,000 mg
          I:DHA/EPA  [Intervention group]  
          C:placebo  N=12, 66±1 years old  
          O:lipid-profile including TG level    
    755 Matsumoto39 Pharmacology and Therapy, 44(2): 235–246 (2016) P:healthy adult male and female [Placebo group] DHA 544 mg, 12 weeks
        I:DHA/EPA  N=26, 59.1±5.3 years old EPA 59.2 mg
          C:placebo [Intervention group]    
          O:TG level N=28, 57.4±5.8 years old    
    757 Rajkumar H, et al. 40 Mediators Inflamm, Article ID 348959 (2014) P:healthy adult male and female [Placebo group] DHA 120 mg, 6 weeks
        I:DHA/EPA, et al. N=15, 40-60 years old  EPA 180 mg
          C:placebo    
          O:lipid-profile including TG level.    
    758 Marckmann P, et al. 41 Arterioscler Thromb Vasc Biol, 17(12): 3384–3391 (1997) P:healthy adult male [Placebo group] DHA 508 mg, 4 weeks
        I:DHA/EPA  N=24, 41±9 years old EPA 355 mg
          C:placebo [Intervention group]    
          O:lipid-related including TG level. N=23, 41±9 years old    

    Table 2. Triglyceride level of control and intervention groups of 37 study documents.
    No. Intervention group (pre) Intervention group(post) Intervention group(mean difference) Intervention group vs. placebo group (mean difference) Vs. baseline(p value) Between groups(p value)
    54 1.13 (1.07_1.18) 0.97 (0.87_1.08) NA NA NA NS
    74 HR group 81.7±58 58.1±35 NA NA NA <0.05
    LR group 84.6±32 73.1±26 NA NA NA NS
    138 119±15.1 101±14.0 NA NA <0.05 NS
    165 65.91±8.51 65.45±7.93 NA NA NS NS
    172 1.63±0.59 NA NA −0.34 NA 0.048
    181 FO group 0.95±0.541 0.94±0.542 −0.01±0.462 NA NS NS
    KO group 1.10±0.638 1.01±0.649 −0.09±0.417 NA NS NS
    188 FO group 1.25±0.65 0.99±0.45 −0.26 NA NS NS
    SO group 1.58±0.52 1.18±0.37 −0.40 NA <0.05 NS
    225 98.3±52.4 106.7±70.9 NA NA NS NS
    236 LD group 1.25±0.04 1.17±0.03 NA NA NA <0.017
    HD group 1.28±0.04 1.13±0.03 NA NA NA <0.017
    245 1.14±0.13 NA −0.32±0.09 NA NA <0.001
    248 CD group 1.31±0.73 NA −0.28±0.51 NA NA 0.038
    SD group 1.18±0.52 NA −0.26±0.44 NA NA 0.001
    FO group 1.15±0.73 NA −0.20±0.61 NA NA 0.035
    257 1.53±0.60 1.11±0.47 NA NA NA NS
    262 4 weeks 1.05±0.63 0.91±0.34 NA NA NA NS
    8 weeks 0.88±0.34 NA NA NA <0.05
    282 GA group 0.68±0.23 0.54±0.15 NA NA 0.013 NA
    GB group 0.68±0.42 0.61±0.25 NA NA NS NA
    (total) 0.68 0.57 (−15.6%) (−18.3%) <0.01 <0.01
    305 1.40±0.62 1.16±0.46 −0.25±0.59 NA NA NS
    325 EH group 1.18±0.19 0.92±0.15 NA NA 0.003 NS
    DH group 1.16±0.19 0.72±0.07 NA NA 0.006 0.032
    334 1.03±0.094 1.01±0.089 NA −0.18 (−0.37_0.05) NS NS
    419 EH group 1.23±0.57 NA −0.15±0.40 NA <0.01 0.0001
    DH group 1.24±0.58 NA −0.22±0.31 NA <0.001 0.0001
    420 1.54±0.54 1.49±0.37 NA NA NS NS
    421 1.44±0.34 1.05±0.29 NA NA NA <0.001
    433 3 weeks 0.96±0.11 0.75±0.09 NA NA <0.05 NS
    6 weeks 0.80±0.11 NA NA <0.05 NS
    434 FDgroup 4 weeks 1.36±0.47 1.27±0.45 NA NA NS NS
    9 weeks 0.99±0.31 NA NA <0.05 <0.05
    14 weeks 1.16±0.40 NA NA <0.05 <0.05
    FOgroup 4 weeks 1.21±0.35 1.11±0.24 NA NA NS NS
    9 weeks 0.95±0.18 NA NA <0.05 NS
    14 weeks 0.89±0.13 NA NA <0.05 <0.05
    DHgroup 4 weeks 1.17±0.38 1.03±0.27 NA NA NS NS
    9 weeks 1.00±0.33 NA NA <0.05 NS
    14 weeks 0.97±0.21 NA NA <0.05 <0.05
    435 0.82±0.55 0.81±0.58 −0.01±0.34 NA NS NS
    468 TG group 0.83±0.13 NA −0.19±0.09 NA NA NS
    EE group 0.82±0.14 NA −0.05±0.10 NA NA NS
    490 DⅠ NA NA NA −15 (−52_3) NA 0.0008
    DⅢ NA NA NA −34 (−55_−4) NA 0.0008
    505 PO group NA NA NA (−34%±6%) NA <0.01
    TU group NA NA NA (−44%±7%) NA <0.05
    SA group NA NA NA (−45%±10%) NA NS
    510 LD group 1.01±0.14 0.87±0.12 NA NA NA <0.05
    MD group 0.93±0.07 0.70±0.07 NA NA NA <0.05
    HD group 1.00±0.09 0.78±0.06 NA NA NA <0.05
    529 0.87±0.07 0.87±0.07 0.67±0.05 NA NA NS NS
    567 NA NA NA −24.1 NA NA <0.05
    583 4 weeks 172±6 140±9 NA NA <0.05 NS
    8 weeks 120±8 NA NA <0.05 <0.05
    10 weeks 126±10 NA NA <0.05 NS
    12 weeks 129±7 NA NA <0.05 <0.05
    707 1.34±0.11 0.99±0.07 NA NA NA <0.05
    709 2 months 1.2±0.3 0.9±0.1 NA NA NS NA
    4 months 0.9±0.2 NA NA NS NA
    712 116.8±72.6 86.2±43.6 −30.6±40.0 NA <0.01 <0.01
    715 1.30±0.14 1.01±0.14 NA NA <0.05 NS
    755 4 weeks 140.5±11.0 133.7±12.6 −6.8±8.8 NA NA NS
    8 weeks 132.0±8.8 −8.5±9.6 NA NA 0.028
    12 weeks 132.8±10.0 −7.8±6.8 NA NA 0.040
    757 105.90±6.53 102.62±6.44 NA NA <0.05 NS
    758 1.06±0.09 0.93±0.09 NA NA <0.01 NS

    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.

    Discussion

    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.

    Authors' Conclusions

    The studies involving dietary interventions assessed in our review and results from healthy participants revealed that consuming 133-10,440 mg of DHA and/or EPA produces fasting serum TG lowering effects in healthy or slightly higher fasting serum TG level individuals.

    Abbreviations

    AA:Arachidonic acid

    ALA: α-linoleic acid

    CVD: Cardiovascular disease

    DHA: Docosahexaenoic acid

    DPA: Docosapentaenoic acid

    EPA: Eicosapentaenoic acid

    HDL: High density lipoprotein

    LA: Linoleic acid

    LDL: Low density lipoprotein

    LTs: Leukotrienes

    PUFAs: Polyunsaturated fatty acids

    RCTs: Randomized controlled trials

    TG: Triglycerides

    VLDL: Very low-density lipoprotein

    References

    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
    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.
    3.Nichiro Maruha.Corporation. What is DHA?. (Japanese). URL https://www.maruha-nichiro.co.jp/dha/dha20000.html
    4.National Centerfor Complementary and Integrative Health . Omega-3 Supplements: In Depth. https://nccih.nih.gov/health/omega3/introduction.htm
    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.
    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.
    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.
    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.
    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.
    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.
    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.
    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.
    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.
    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.
    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.
    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.
    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.
    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.
    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.
    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.
    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.
    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.
    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.
    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.
    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.
    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.
    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.
    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.
    29.Luley C, Lelieur I, Hanisch M. (1992) Fish oil treatment and apolipoprotein (a). Arzneimittel-Forschung. 42, 77-80.
    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.
    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.
    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.
    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.
    34.Tamai T. (2014) Utilization of Processed Foods Rich in Docosahexaenoic Acid: Clinical Trials Using Foods for Specific Health Purposes. 23, 45-52.
    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.
    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.
    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.
    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.
    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.
    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.
    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.
    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).
    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.
    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.
    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.
    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.
    47.Harris W S, Bulchandani D. (2006) Why do omega-3 fatty acids lower serum triglycerides? Curr Opin Lipidol. 17, 387-393.
    48.Park Y, Harris W S. (2003) Omega-3 fatty acid supplementation accelerates chylomicron triglyceride clearance. , J Lipid Res 44, 455-463.
    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.
    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.
    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.
    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.
    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.
    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.
    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.
    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.
    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.
    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.
    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.
    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.
    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.
    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.