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1.  Protective role of fish oil (Maxepa) on early events of rat mammary carcinogenesis by modulation of DNA-protein crosslinks, cell proliferation and p53 expression 
Background
Fish oil is known to protect from many types of cancers of the colon, liver, breast, prostate and lung [1-3]. The objective of the present study was to evaluate the role of fish oil [Maxepa, supplemented at a dose of 0.5 ml is equivalent to 90 mg eicosapentaenoic acid (EPA) and 60 mg docosahexaenoic acid (DHA)] on cell proliferation, expression of p53 tumor suppressor protein and DNA protein crosslinks (DPCs) in a defined model of chemical rat mammary carcinogenesis. Mammary carcinogenesis was initiated by a single, intravenous (i.v.) tail vein injection of 7,12 dimethylbenz(α)anthracene (DMBA) at a dose of 5 mg DMBA/2 ml corn oil/kg body weight in female Sprague-Dawley rats at 7 weeks of age. Fish oil supplementation was started daily, 2 weeks prior to DMBA injection and continued for 24 (31 weeks of animal age) weeks and 35 (42 weeks of animal age) weeks of post DMBA injection, for histopathological and immunohistochemical and for morphological studies, respectively.
Results
Our results indicate the chemopreventive effect of fish oil (Maxepa) on DMBA-induced rat mammary carcinogenesis. Administration of fish oil further showed a prominent reduction of cell proliferation (24.34%, P = 0.001); DPCs (25%, P < 0.001) and an increased expression of p53 protein (4.636 ± 0.19, P < 0.001) in preneoplastic mammary tissue when compared to carcinogen control counterpart. Histopathological and morphological analyses were carried out as end-point biomarkers.
Conclusion
Our study thus provides evidence for the anticarcinogenic effect of fish oil (Maxepa) in limiting mammary preneoplasia in Sprague-Dawley rats.
doi:10.1186/1475-2867-7-6
PMCID: PMC1872018  PMID: 17470299
2.  Fish oil, but not flaxseed oil, decreases inflammation and prevents pressure overload-induced cardiac dysfunction 
Cardiovascular Research  2008;81(2):319-327.
Aims
Clinical studies suggest that intake of ω-3 polyunsaturated fatty acids (ω-3 PUFA) may lower the incidence of heart failure. Dietary supplementation with ω-3 PUFA exerts metabolic and anti-inflammatory effects that could prevent left ventricle (LV) pathology; however, it is unclear whether these effects occur at clinically relevant doses and whether there are differences between ω-3 PUFA from fish [eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)] and vegetable sources [α-linolenic acid (ALA)].
Methods and results
We assessed the development of LV remodelling and pathology in rats subjected to aortic banding treated with ω-3 PUFA over a dose range that spanned the intake of humans taking ω-3 PUFA supplements. Rats were fed a standard food or diets supplemented with EPA+DHA or ALA at 0.7, 2.3, or 7% of energy intake. Without supplementation, aortic banding increased LV mass and end-systolic and -diastolic volumes. ALA supplementation had little effect on LV remodelling and dysfunction. In contrast, EPA+DHA dose-dependently increased EPA and DHA, decreased arachidonic acid in cardiac membrane phospholipids, and prevented the increase in LV end-diastolic and -systolic volumes. EPA+DHA resulted in a dose-dependent increase in the anti-inflammatory adipokine adiponectin, and there was a strong correlation between the prevention of LV chamber enlargement and plasma levels of adiponectin (r = −0.78). Supplementation with EPA+DHA had anti-aggregatory and anti-inflammatory effects as evidenced by decreases in urinary thromboxane B2 and serum tumour necrosis factor-α.
Conclusion
Dietary supplementation with ω-3 PUFA derived from fish, but not from vegetable sources, increased plasma adiponectin, suppressed inflammation, and prevented cardiac remodelling and dysfunction under pressure overload conditions.
doi:10.1093/cvr/cvn310
PMCID: PMC2721645  PMID: 19015135
α-linolenic acid; Diet; Docosahexaenoic acid; Eicosapentaenoic acid; Heart failure
3.  Omega-3-Acid Ethyl Esters Block the Pro-tumorigenic Effects of Obesity in Mouse Models of Postmenopausal Basal-Like and Claudin-Low Breast Cancer 
Obesity induces chronic inflammation and is an established risk and progression factor for triple-negative breast cancers, including basal-like (BL) and claudin-low (CL) subtypes. We tested the effects of dietary supplementation with ethyl esters of the marine-derived anti-inflammatory omega-3 fatty acids eicosapentaenoic and docosahexaenoic acid (EPA+DHA; Lovaza®) on growth of murine BL and CL mammary tumors. Female ovariectomized C57BL/6 mice were fed a control diet or a diet-induced obesity (DIO) diet with or without EPA+DHA (0.025%, resulting in blood levels of EPA and DHA comparable to women taking Lovaza 4 g/day) for 6 weeks. All mice were then orthotopically injected with Wnt-1 cells (a BL tumor cell suspension derived from MMTV-Wnt-1 transgenic mouse mammary tumors) or M-Wnt cells (a CL tumor cell line cloned from the Wnt-1 tumor cell suspension). Mice were killed when tumors were 1 cm in diameter. EPA+DHA supplementation did not significantly impact Wnt-1 or M-Wnt mammary tumor growth in normoweight control mice. However, EPA+DHA supplementation in DIO mice reduced growth of Wnt-1 and M-Wnt tumors; reduced leptin:adiponectin ratio and pro-inflammatory eicosanoids in the serum; improved insulin sensitivity; and decreased tumoral expression of cyclooxygenase-2 and phospho-p65. Thus, EPA+DHA supplementation in mouse models of postmenopausal BL and CL breast cancer offsets many of the pro-tumorigenic effects of obesity. These preclinical findings, in combination with results from parallel biomarker studies in women, suggest EPA+DHA supplementation may reduce the burden of BL and CL breast cancer in obese women.
doi:10.1158/1940-6207.CAPR-15-0018
PMCID: PMC5024781  PMID: 26100521
basal-like breast cancer; claudin-low breast cancer; diet and cancer; inflammation; omega-3 fatty acids; animal/transgenic models in promotion and prevention
4.  Inhibitory effects of docosahexaenoic acid on colon carcinoma 26 metastasis to the lung. 
British Journal of Cancer  1997;75(5):650-655.
Unsaturated fatty acids, including n-3 polyunsaturated fatty acids (PUFAs) such as docosahexaenoic acid (C22:6, DHA) and eicosapentaenoic acid (C20:5, EPA), and a series of n-6 PUFAs were investigated for their anti-tumour and antimetastatic effects in a subcutaneous (s.c.) implanted highly metastatic colon carcinoma 26 (Co 26Lu) model. EPA and DHA exerted significant inhibitory effects on tumour growth at the implantation site and significantly decreased the numbers of lung metastatic nodules. Oleic acid also significantly inhibited lung metastatic nodules. Treatment with arachidonic acid showed a tendency for reduction in colonization. However, treatment with high doses of fatty acids, especially linoleic acid, increased the numbers of lung metastatic nodules. DHA and EPA only inhibited lung colonizations when administered together with the tumour cells, suggesting that their incorporation is necessary for an influence to be exerted. Chromatography confirmed that contents of fatty acids in both tumour tissues and plasma were indeed affected by the treatments. Tumour cells pretreated with fatty acids in vivo, in particular DHA, also showed a low potential for lung colony formation when transferred to new hosts. Thus, DHA treatment exerted marked antimetastatic activity associated with pronounced change in the fatty acid component of tumour cells. The results indicate that uptake of DHA into tumour cells results in altered tumour cell membrane characteristics and a decreased ability to metastasize.
PMCID: PMC2063338  PMID: 9043019
5.  Short term effects of different omega-3 fatty acid formulation on lipid metabolism in mice fed high or low fat diet 
Background
Bioactivities of Docosahexaenoic acid (DHA) and Eicosapentaenoic acid (EPA) depend on their chemical forms. The present study was to investigate short term effects of triglyceride (TG), ethyl ester (EE), free fatty acid (FFA) and phospholipid (PL) forms of omega-3 fatty acid (FA) on lipid metabolism in mice, fed high fat or low fat diet.
Method
Male Balb/c mice were fed with 0.7% different Omega-3 fatty acid formulation: DHA bound free fatty acid (DHA-FFA), DHA bound triglyceride (DHA-TG), DHA bound ethyl ester (DHA-EE) and DHA bound phospholipid (DHA-PL) for 1 week, with dietary fat levels at 5% and 22.5%. Serum and hepatic lipid concentrations were analyzed, as well as the fatty acid composition of liver and brain.
Result
At low fat level, serum total cholesterol (TC) level in mice fed diets with DHA-FFA, DHA-EE and DHA-PL were significantly lower than that in the control group (P < 0.05). Hepatic TG level decreased significantly in mice fed diets with DHA-TG (P < 0.05), DHA-EE (P < 0.05) and DHA-PL (P < 0.05), while TC level in liver was significantly lower in mice fed diets with TG and EE compared with the control group (P < 0.05). At high fat level, mice fed diets with DHA-EE and DHA-PL had significantly lower hepatic TC level compared with the control diet (P < 0.05). Hepatic PL concentration experienced a significant increase in mice fed the diet with PL at high fat level (P < 0.05). Furthermore, both at low and high fat levels, hepatic DHA level significantly increased and AA level significantly decreased in all forms of DHA groups (P < 0.05), compared to control groups at two different fat levels, respectively. Additionally, cerebral DHA level in mice fed diets with DHA-FFA, DHA-EE and DHA-PL significantly increased compared with the control at high fat level (P < 0.05), but no significant differences were observed among dietary treatments for mice fed diets with low fat level.
Conclusion
The present study suggested that not only total dietary fat content but also the molecular forms of omega-3 fatty acids contributed to lipid metabolism in mice. DHA-PL showed effective bioactivity in decreasing hepatic and serum TC, TG levels and increasing omega-3 concentration in liver and brain.
doi:10.1186/1476-511X-11-70
PMCID: PMC3393618  PMID: 22676394
Omega-3 fatty acid; DHA; EPA; Lipid metabolism; Triglycerides; Ethyl ester; Phospholipids
6.  Dietary ω-3 Fatty Acids Alter Cardiac Mitochondrial Phospholipid Composition and Delay Ca2+-Induced Permeability Transition 
Consumption of ω-3 fatty acids from fish oil, specifically eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), decreases risk for heart failure and attenuates pathologic cardiac remodeling in response to pressure overload. Dietary supplementation with EPA+DHA may also impact cardiac mitochondrial function and energetics through alteration of membrane phospholipids. We assessed the role of EPA+DHA supplementation on left ventricular (LV) function, cardiac mitochondrial membrane phospholipid composition, respiration, and sensitivity to mitochondrial permeability transition pore (MPTP) opening in normal and infarcted myocardium. Rats were subjected to sham surgery or myocardial infarction by coronary artery ligation (n=10–14), and fed a standard diet, or supplemented with EPA+DHA (2.3% of energy intake) for 12 weeks. EPA+DHA altered fatty acid composition of total mitochondrial phospholipids and cardiolipin by reducing arachidonic acid content and increasing DHA incorporation. EPA+DHA significantly increased calcium uptake capacity in both subsarcolemmal and intrafibrillar mitochondria from sham rats. This treatment effect persisted with the addition of cyclosporin A, and was not accompanied by changes in mitochondrial respiration or coupling, or cyclophilin D protein expression. Myocardial infarction resulted in heart failure as evidenced by LV dilation and contractile dysfunction. Infarcted LV myocardium had decreased mitochondrial protein yield and activity of mitochondrial marker enzymes, however respiratory function of isolated mitochondria was normal. EPA+DHA had no effect on LV function, mitochondrial respiration, or MPTP opening in rats with heart failure. In conclusion, dietary supplementation with EPA+DHA altered mitochondrial membrane phospholipid fatty acid composition in normal and infarcted hearts, but delayed MPTP opening only in normal hearts.
doi:10.1016/j.yjmcc.2009.08.014
PMCID: PMC2783943  PMID: 19703463
eicosapentaenoic acid; docosahexaenoic acid; myocardial infarction; mitochondrial permeability transition pore
7.  Effects of n-3 fatty acids during neoplastic progression and comparison of in vitro and in vivo sensitivity of two human tumour cell lines. 
British Journal of Cancer  1995;71(4):691-696.
Several studies have shown that dietary lipid exerts an effect on carcinogenesis. We report here that progression to malignancy in vitro is associated with changes in the response to fatty acids (FAs). Tumorigenic (THKE) cells were more sensitive to the n-3 FAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) than immortalised (IHKE) cells. The growth of THKE cells was inhibited 25% more than the growth of IHKE cells at 80 microM EPA (P < 0.01) and 35% more at 40 microM DHA (P < 0.001). Furthermore, the results indicate that there is a wide cell type variation in the response to FAs. We found that the in vitro inhibition by FAs correlated with the reduction in the growth rate of the tumour in nude mice fed K85 (55% EPA and 30% DHA). A significant difference in tumour latency was observed for the A427 cell tumour groups (10 days, P < 0.05). Tumours in the animals fed n-3 FA exhibited significantly higher levels of EPA and DHA; the level of arachidonic acid (ARA) was significantly lower in THKE tumours and the level of linoleic acid (LA) was significantly lower in A427 tumours than in controls fed corn oil. The higher sensitivity of the A427 cell line was not explained by higher uptake of EPA/DHA.
PMCID: PMC2033729  PMID: 7710930
8.  Reduced ratio of eicosapentaenoic acid and docosahexaenoic acid to arachidonic acid is associated with early onset of acute coronary syndrome 
Nutrition Journal  2015;14:111.
Background
The hospitalization rate for acute coronary syndrome (ACS) for people aged ≤50 has remained stable over the past decade. Increased serum levels of n-3 polyunsaturated fatty acids (PUFAs), such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are associated with a decreased incidence of cardiovascular events and mortality in older patients; however, it is currently unknown whether reduced serum levels of n-3 PUFAs is also a risk factor for ACS in patients aged ≤50 years.
Methods and results
We retrospectively reviewed 102 (male/ female 73/29) Japanese ACS patients whose serum levels of EPA/arachidonic acid (AA) and DHA/AA were evaluated on admission. The EPA/AA ratio was the lowest in patients aged ≤50 compared to patients aged 51–74 and ≥75. Pearson correlation analysis showed that early ACS onset was associated with low EPA/AA and DHA/AA ratios, and multiple regression analysis determined that decreased ratios of EPA/AA and DHA/AA, and male sex, current smoker status, increased body mass index and triglyceride levels, independently correlated with early ACS onset. Conversely, low-density and high-density lipoproteins, glycated hemoglobin, and hypertension did not correlate with early ACS onset. Subgroup analyses of male patients revealed that decreased ratios of EPA/AA and DHA/AA independently correlated with early ACS onset.
Conclusion
Decreased EPA/AA and DHA/AA ratios may be risk factors for early onset of ACS, suggesting that reduced EPA/AA and DHA/AA may represent targets for preventing ACS in Japanese young people.
Electronic supplementary material
The online version of this article (doi:10.1186/s12937-015-0102-4) contains supplementary material, which is available to authorized users.
doi:10.1186/s12937-015-0102-4
PMCID: PMC4627394  PMID: 26514181
Polyunsaturated fatty acids (PUFA); Eicosapentaenoic acid (EPA); Docosahexaenoic acid (DHA); Acute coronary syndrome (ACS)
9.  Dietary fish oil (MaxEPA) enhances pancreatic carcinogenesis in azaserine-treated rats. 
British Journal of Cancer  1996;73(1):36-43.
In the present study the putative chemopreventive effect of dietary fish oil (MaxEPA) on azaserine-induced pancreatic carcinogenesis in rats was investigated. Groups of rats were maintained on a semipurified low-fat (LF; 5 wt%) diet or on semipurified high-fat (HF; 25 wt%) diets containing 5 wt% linoleic acid (LA) and including 0.0, 1.2, 2.4, 4.7, 7.1 or 9.4 wt% MaxEPA. Animals fed a HF diet developed significantly higher mean numbers of atypical acinar cell nodules (AACNs), adenomas and carcinomas than animals fed a LF diet. Dietary MaxEPA caused a significant (P < 0.01) dose-related increase in mean number of AACNs (0.5 < phi < 3.0 mm). The mean number of adenomas and carcinomas remained similar among the groups. Cell proliferation was significantly lower in AACNs from animals fed HF containing 9.4% MaxEPA in comparison with HF without MaxEPA and with LF. LA levels had increased and arachidonic acid (AA) levels had decreased in blood plasma and pancreas with increasing dietary MaxEPA. Feeding MaxEPA resulted in significant decreases in 6-keto-prostaglandin (PG) F1 alpha (P < 0.05) and PGF2 alpha (P < 0.01) in non-tumorous pancreas, whereas PGE2, PGF2 alpha and thromboxane B2 (TXB2) levels were significantly (P < 0.001) higher in pancreatic tumour tissue than in non-tumorous pancreatic tissue. It is concluded that (i) dietary MaxEPA enhances dose-relatively growth of putative preneoplastic AACNs in the pancreas of azaserine-treated rats; (ii) dietary MaxEPA inhibits the conversion of LA to AA, as well as the conversion of AA to TXB2 or PGF2 alpha in non-tumorous pancreatic tissue; (iii) the high levels of PGE2, PGF2 alpha and TXB2 in pancreatic adenocarcinomas indicate a possible role for these eicosanoids in modulation of tumour growth.
PMCID: PMC2074299  PMID: 8554980
10.  Effect of n-3 fatty acids on the expression of inflammatory genes in THP-1 macrophages 
Background
Uncontrolled inflammation participates in the development of inflammatory diseases. Beneficial effects of polyunsaturated fatty acids belonging to the n-3 family such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on inflammation have been reported.
The present study investigates the basal effects of EPA, DHA and a mixture EPA + DHA on the expression of 10 genes (AKT1, MAPK, NFKB, TNFA, IL1Β, MCP1, ALOX5, PTGS2, MGST1and NOS2) related to inflammation in unstimulated cultured THP1 macrophages. Cells were incubated for 24 h with n-3 PUFAs (50 μM and 10 μM EPA, DHA, EPA + DHA). Expression levels of inflammatory genes were analyzed by real-time PCR.
Results
50 μM, 10 μM EPA and 50 μM EPA + DHA decreased the expression of genes involved in the NF-κB pathway (MAPK, AKT1, and NFKB). Treatment with 50 μM, 10 μM EPA, 50 μM DHA and EPA + DHA decreased expression levels of cytokines genes IL1Β and MCP1. TNFA expression was decreased by 50 μM, 10 μM of EPA, DHA and with 50 μM EPA + DHA. Two genes involved in the fatty acid metabolism (PTGS2 and ALOX5) were also modulated by the n-3 FAs. 50 μM of DHA and EPA + DHA inhibited PTGS2 expression when the two concentrations of EPA, 50 μM DHA and EPA + DHA inhibited ALOX5 expression. Finally, the effects of n-3 FAs were studied among genes involved in the oxidative stress. 50 μM of each fatty acid increased MGST1 expression. Both concentration of EPA and 50 μM DHA decreased NOS2 expression.
Conclusion
EPA seems to be more effective than DHA and EPA + DHA in modulating expression levels of selected inflammatory genes. The concentration of 50 μM was globally more effective than 10 μM.
doi:10.1186/s12944-016-0241-4
PMCID: PMC4820929  PMID: 27044314
Omega-3; Eicosapentaenoic acid; Docosahexaenoic acid; Inflammation; THP-1; Genes
11.  Dietary Supplementation with Docosahexaenoic Acid, but Not Eicosapentanoic Acid, Dramatically Alters Cardiac Mitochondrial Phospholipid Fatty Acid Composition and Prevents Permeability Transition 
Biochimica et biophysica acta  2010;1797(8):1555-1562.
Treatment with the ω-3 polyunsaturated fatty acids (PUFAs) docosahexanoic acid (DHA) and eicosapentanoic acid (EPA) exerts cardioprotective effects, and suppresses Ca2+-induced opening of the mitochondrial permeability transition pore (MPTP). These effects are associated with increased DHA and EPA, and lower arachidonic acid (ARA) in cardiac phospholipids. While clinical studies suggest the triglyceride lowering effects of DHA and EPA are equivalent, little is known about the independent effects of DHA and EPA on mitochondria function. We compared the effects of dietary supplementation with the ω-3 PUFAs DHA and EPA on cardiac mitochondrial phospholipid fatty acid composition and Ca2+-induced MPTP opening. Rats were fed a standard lab diet with either normal low levels of ω-3 PUFA, or DHA or EPA at 2.5% of energy intake for 8 weeks, and cardiac mitochondria were isolated and analyzed for Ca2+-induced MPTP opening and phospholipid fatty acyl composition. DHA supplementation increased both DHA and EPA and decreased ARA in mitochondrial phospholipid, and significantly delayed MPTP opening as assessed by increased Ca2+ retention capacity and decreased Ca2+-induced mitochondria swelling. EPA supplementation increased EPA in mitochondrial phospholipids, but did not affect DHA, only modestly lowered ARA, and did not affect MPTP opening. In summary, dietary supplementation with DHA but not EPA, profoundly altered mitochondrial phospholipid fatty acid composition and delayed Ca2+-induced MPTP opening.
doi:10.1016/j.bbabio.2010.05.007
PMCID: PMC3071681  PMID: 20471951
cardiac; eicosapentaenoic acid; docosahexaenoic acid; fish oil; heart; mitochondrial permeability transition pore
12.  n-3 and n-6 fatty acid processing and growth effects in neoplastic and non-cancerous human mammary epithelial cell lines. 
British Journal of Cancer  1994;70(2):219-227.
The type rather than the amount of dietary fat may be more important in breast carcinogenesis. While animal studies support this view, little is known about the effects of essential fatty acids (EFAs) at the cellular level. The MCF-7 breast cancer and the MCF-10A non-cancerous human mammary epithelial cell lines are compared in terms of growth response to EFAs and ability to incorporate and process the EFAs. Eicosapentaenoic (EPA, n-3) and docosahexaenoic (DHA, n-3) acids, presented bound to albumin, inhibited the growth of MCF-7 cells by as much as 50% in a dose-dependent manner (6-30 microM) in medium containing 0.5% serum. alpha-Linolenic (LNA, n-3) and arachidonic (AA, n-6) acids inhibited growth less extensively, while linoleic acid (LA, n-6) had no effect. In contrast, MCF-10A cells were not inhibited by any of the EFAs at levels below 24 microM. The differential effects of AA, EPA and DHA on MCF-7 and MCF-10A cells support a protective role of highly unsaturated essential fatty acids against breast cancer. The EFAs were primarily incorporated into phosphoglycerides. MCF-7 cells showed chain elongations and possibly delta 8 desaturation, but no AA was formed from LA, nor EPA or DHA from LNA. In contrast, MCF-10A cells desaturated and elongated the exogenous EFAs via all the known pathways. These findings suggest defects in the desaturating enzymes of MCF-7 cells. LNA, DHA and AA presented to MCF-7 cells in phospholipid liposomes inhibited growth as extensively as albumin-bound free acids, but were less extensively incorporated, suggesting different mechanisms of inhibition for the two methods.
PMCID: PMC2033515  PMID: 8054269
13.  The Cardioprotective Effects of Fish Oil During Pressure Overload Are Blocked by High Fat Intake 
Hypertension  2009;54(3):605-611.
Supplementation with eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) from fish oil may prevent development of heart failure through alterations in cardiac phospholipids that favorably impact inflammation and energy metabolism. A high-fat diet may block these effects in chronically stressed myocardium. Pathological left ventricle (LV) hypertrophy was generated by subjecting rats to pressure overload by constriction of the abdominal aorta. Animals were fed: (1) standard diet (10% of energy from fat), (2) standard diet with EPA+DHA (2.3% of energy intake as EPA+DHA), (3) high fat (60% fat); or (4) high fat with EPA+DHA. Pressure overload increased LV mass by ≈40% in both standard and high-fat diets without fish oil. Supplementation with fish oil increased their incorporation into cardiac phospholipids, and decreased the proinflammatory fatty acid arachidonic acid and urine thromboxane B2 with both the standard and high-fat diet. Linoleic acid and tetralinoloyl cardiolipin (an essential mitochondrial phospholipid) were decreased with pressure overload on standard diet, which was prevented by fish oil. Animals fed high-fat diet had decreased linoleic acid and tetralinoloyl cardiolipin regardless of fish oil supplemention. Fish oil limited LV hypertrophy on the standard diet, and prevented upregulation of fetal genes associated with heart failure (myosin heavy chain-β and atrial natriuetic factor). These beneficial effects of fish oil were absent in animals on the high-fat diet. In conclusion, whereas treatment with EPA+DHA prevented tetralinoloyl cardiolipin depletion, LV hypertrophy, and abnormal genes expression with pressure overload, these effects were absent with a high-fat diet.
doi:10.1161/HYPERTENSIONAHA.109.135806
PMCID: PMC3103889  PMID: 19597033
Omega-3 fatty acids; cardiac hypertrophy; heart failure; cardiolipin; phospolipids
14.  A Transgenic Camelina sativa Seed Oil Effectively Replaces Fish Oil as a Dietary Source of Eicosapentaenoic Acid in Mice123 
The Journal of Nutrition  2016;146(2):227-235.
Background: Fish currently supplies only 40% of the eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) required to allow all individuals globally to meet the minimum intake recommendation of 500 mg/d. Therefore, alternative sustainable sources are needed.
Objective: The main objective was to investigate the ability of genetically engineered Camelina sativa (20% EPA) oil (CO) to enrich tissue EPA and DHA relative to an EPA-rich fish oil (FO) in mammals.
Methods: Six-week-old male C57BL/6J mice were fed for 10 wk either a palm oil–containing control (C) diet or diets supplemented with EPA-CO or FO, with the C, low-EPA CO (COL), high-EPA CO (COH), low-EPA FO (FOL), and high-EPA FO (FOH) diets providing 0, 0.4, 3.4, 0.3, and 2.9 g EPA/kg diet, respectively. Liver, muscle, and brain were collected for fatty acid analysis, and blood glucose and serum lipids were quantified. The expression of selected hepatic genes involved in EPA and DHA biosynthesis and in modulating their cellular impact was determined.
Results: The oils were well tolerated, with significantly greater weight gain in the COH and FOH groups relative to the C group (P < 0.001). Significantly lower (36–38%) blood glucose concentrations were evident in the FOH and COH mice relative to C mice (P < 0.01). Hepatic EPA concentrations were higher in all EPA groups relative to the C group (P < 0.001), with concentrations of 0.0, 0.4, 2.9, 0.2, and 3.6 g/100 g liver total lipids in the C, COL, COH, FOL, and FOH groups, respectively. Comparable dose-independent enrichments of liver DHA were observed in mice fed CO and FO diets (P < 0.001). Relative to the C group, lower fatty acid desaturase 1 (Fads1) expression (P < 0.005) was observed in the COH and FOH groups. Higher fatty acid desaturase 2 (Fads2), peroxisome proliferator–activated receptor α (Ppara), and peroxisome proliferator–activated receptor γ (Pparg) (P < 0.005) expressions were induced by CO. No impact of treatment on liver X receptor α (Lxra) or sterol regulatory element-binding protein 1c (Srebp1c) was evident.
Conclusions: Oil from transgenic Camelina is a bioavailable source of EPA in mice. These data provide support for the future assessment of this oil in a human feeding trial.
doi:10.3945/jn.115.223941
PMCID: PMC4725436  PMID: 26791554
n–3 PUFA; EPA; DHA; Camelina oil; fish oil; sustainability; desaturation; Fads; transgenic; TG sn-2
15.  Elevated Ratio of Arachidonic acid to Long-Chain Omega-3 Fatty Acids Predicts Depression Development Following Interferon-alpha Treatment: Relationship with Interleukin-6 
Cross-sectional studies have found that an elevated ratio of arachidonic acid to omega-3 fatty acid is associated with depression, and controlled intervention studies have found that decreasing this ratio through administration of omega-3 fatty acids can alleviate depressive symptoms. Additionally, arachidonic acid and omega-3 fatty acids have opposing effects on inflammatory signaling. Exogenous administration of the inflammatory cytokine interferon-alpha (IFN-α) can trigger a depressive episode in a subset of vulnerable people, though associated risk factors remain poorly understood. Using a within-subject prospective design of 138 subjects, we examined whether baseline long-chain omega-3 (docosahexaenoic acid – DHA; eicosapentaenoic acid – EPA) and omega-6 (arachidonic acid – AA; di-homo-gamma-linolenic acid – DGLA) fatty acid status was associated with depression vulnerability in hepatitis C patients treated with IFN-α. Based on the literature, we had specific a priori interest in the AA/EPA+DHA ratio. Lower baseline DHA predicted depression incidence (p=0.04), as did elevated DGLA (p=0.02) and an elevated AA/EPA+DHA ratio (p=0.007). The AA/EPA+DHA ratio predicted depression even when controlling for other critical variables such as sleep quality and race. A higher AA/EPA+DHA ratio was positively associated with both increasing Montgomery-Asperg Depression Rating Scores over time (F=4.0; p<0.05) as well as interleukin-6 levels (F=107.4; p<0.05) but not C-reactive protein. Importantly, omega-3 and omega-6 fatty acid status was not associated with sustained viral response to IFN-α treatment. These prospective data support the role of fatty acid status in depression vulnerability and indicate a potential role for omega-3 fatty acids in the prevention of inflammation-induced depression.
doi:10.1016/j.bbi.2012.08.007
PMCID: PMC3552059  PMID: 22926083
Omega-3 fatty acids; Inflammation; Arachidonic acid; Cytokine; Interleukin-6; C-reactive protein; Major depressive disorder
16.  Effect of fish oils containing different amounts of EPA, DHA, and antioxidants on plasma and brain fatty acids and brain nitric oxide synthase activity in rats 
Upsala Journal of Medical Sciences  2009;114(4):206-213.
Background
The interest in n-3 polyunsaturated fatty acids (PUFAs) has expanded significantly in the last few years, due to their many positive effects described. Consequently, the interest in fish oil supplementation has also increased, and many different types of fish oil supplements can be found on the market. Also, it is well known that these types of fatty acids are very easily oxidized, and that stability among supplements varies greatly.
Aims of the study
In this pilot study we investigated the effects of two different types of natural fish oils containing different amounts of the n-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and antioxidants on plasma and brain fatty acids, blood lipids, vitamin E, and in vivo lipid peroxidation, as well as brain nitric oxide synthase (NOS) activity, an enzyme which has been shown to be important for memory and learning ability.
Methods
Sprague-Dawley rats were divided into four groups and fed regular rat chow pellets enriched with 5% (w/w) of butter (control group), a natural fish oil (17.4% EPA and 11.7% DHA, referred to as EPA-rich), and a natural fish oil rich in DHA (7.7% EPA and 28.0% DHA, referred to as DHA-rich). Both of the fish oils were stabilized by a commercial antioxidant protection system (Pufanox®) at production. The fourth group received the same DHA-rich oil, but without Pufanox® stabilization (referred to as unstable). As an index of stability of the oils, their peroxide values were repeatedly measured during 9 weeks. The dietary treatments continued until sacrifice, after 10 days.
Results
Stability of the oils varied greatly. It took the two stabilized oils 9 weeks to reach the same peroxide value as the unstable oil reached after only a few days. Both the stabilized EPA- and DHA-rich diets lowered the triacylglycerols and total cholesterol compared to control (-45%, P < 0.05 and -54%, P < 0.001; -31%, P < 0.05 and -25%, P < 0.01) and so did the unstable oil, but less efficiently. Only the unstable oil increased in vivo lipid peroxidation significantly compared to control (+40%, P < 0.001). Most of the fatty acids in the plasma phospholipids were significantly affected by both the EPA- and DHA-rich diets compared to control, reflecting their specific fatty acid pattern. The unstable oil diet resulted in smaller changes, especially in n-3 PUFAs. In the brain phospholipids the changes were less pronounced, and only the diet enriched with the stabilized DHA-rich oil resulted in a significantly greater incorporation of DHA (+13%, P < 0.01), as well as total n-3 PUFAs (+13%, P < 0.01) compared to control. Only the stabilized DHA-rich oil increased the brain NOS activity (+33%, P < 0.01).
Conclusions
Both the EPA- and DHA-rich diets affected the blood lipids in a similarly positive manner, and they both had a large impact on plasma phospholipid fatty acids. It was only the unstable oil that increased in vivo lipid peroxidation. However, the intake of DHA was more important than that of EPA for brain phospholipid DHA enrichment and brain NOS activity, and the stability of the fish oil was also important for these effects.
doi:10.3109/03009730903268958
PMCID: PMC2852776  PMID: 19961266
Antioxidants; brain; DHA; EPA; fish oil; lipid peroxidation; nitric oxide synthase
17.  Effects of Eicosapentaenoic Acid and Docosahexaenoic Acid on Prostate Cancer Cell Migration and Invasion Induced by Tumor-Associated Macrophages 
PLoS ONE  2014;9(6):e99630.
Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are the major n-3 polyunsaturated fatty acids (PUFAs) in fish oil that decrease the risk of prostate cancer. Tumor-associated macrophages (TAMs) are the main leukocytes of intratumoral infiltration, and increased TAMs correlates with poor prostate cancer prognosis. However, the mechanism of n-3 PUFAs on prostate cancer cell progression induced by TAMs is not well understood. In this study, we investigated the effects of EPA and DHA on modulating of migration and invasion of prostate cancer cells induced by TAMs-like M2-type macrophages. PC-3 prostate cancer cells were pretreated with EPA, DHA, or the peroxisome proliferator-activated receptor (PPAR)-γ antagonist, GW9662, before exposure to conditioned medium (CM). CM was derived from M2-polarized THP-1 macrophages. The migratory and invasive abilities of PC-3 cells were evaluated using a coculture system of M2-type macrophages and PC-3 cells. EPA/DHA administration decreased migration and invasion of PC-3 cells. The PPAR-γ DNA-binding activity and cytosolic inhibitory factor κBα (IκBα) protein expression increased while the nuclear factor (NF)-κB p65 transcriptional activity and nuclear NF-κB p65 protein level decreased in PC-3 cells incubated with CM in the presence of EPA/DHA. Further, EPA/DHA downregulated mRNA expressions of matrix metalloproteinase-9, cyclooxygenase-2, vascular endothelial growth factor, and macrophage colony-stimulating factor. Pretreatment with GW9662 abolished the favorable effects of EPA/DHA on PC-3 cells. These results indicate that EPA/DHA administration reduced migration, invasion and macrophage chemotaxis of PC-3 cells induced by TAM-like M2-type macrophages, which may partly be explained by activation of PPAR-γ and decreased NF-κB p65 transcriptional activity.
doi:10.1371/journal.pone.0099630
PMCID: PMC4055683  PMID: 24925287
18.  Omega-3 polyunsaturated fatty acids selectively inhibit growth in neoplastic oral keratinocytes by differentially activating ERK1/2 
Carcinogenesis  2013;34(12):2716-2725.
The long-chain omega-3 polyunsaturated fatty acids (n-3 PUFAs)—eicosapentaenoic acid (EPA) and its metabolite docosahexaenoic acid (DHA)—inhibit cancer formation in vivo, but their mechanism of action is unclear. Extracellular signal-regulated kinase 1/2 (ERK1/2) activation and inhibition have both been associated with the induction of tumour cell apoptosis by n-3 PUFAs. We show here that low doses of EPA, in particular, inhibited the growth of premalignant and malignant keratinocytes more than the growth of normal counterparts by a combination of cell cycle arrest and apoptosis. The growth inhibition of the oral squamous cell carcinoma (SCC) lines, but not normal keratinocytes, by both n-3 PUFAs was associated with epidermal growth factor receptor (EGFR) autophosphorylation, a sustained phosphorylation of ERK1/2 and its downstream target p90RSK but not with phosphorylation of the PI3 kinase target Akt. Inhibition of EGFR with either the EGFR kinase inhibitor AG1478 or an EGFR-blocking antibody inhibited ERK1/2 phosphorylation, and the blocking antibody partially antagonized growth inhibition by EPA but not by DHA. DHA generated more reactive oxygen species and activated more c-jun N-terminal kinase than EPA, potentially explaining its increased toxicity to normal keratinocytes. Our results show that, in part, EPA specifically inhibits SCC growth and development by creating a sustained signalling imbalance to amplify the EGFR/ERK/p90RSK pathway in neoplastic keratinocytes to a supraoptimal level, supporting the chemopreventive potential of EPA, whose toxicity to normal cells might be reduced further by blocking its metabolism to DHA. Furthermore, ERK1/2 phosphorylation may have potential as a biomarker of n-3 PUFA function in vivo.
doi:10.1093/carcin/bgt257
PMCID: PMC3845892  PMID: 23892603
19.  On the potential application of polar and temperate marine microalgae for EPA and DHA production 
AMB Express  2013;3:26.
Long chain polyunsaturated fatty acids (LC-PUFAs) such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are considered essential omega-3 fatty acids in human nutrition. In marine microalgae EPA and/or DHA are allegedly involved in the regulation of membrane fluidity and thylakoid membrane functioning. The cellular content of EPA and DHA may therefore be enhanced at low temperature and irradiance conditions. As a result, polar and cold temperate marine microalgal species might potentially be suitable candidates for commercial EPA and DHA production, given their adaptation to low temperature and irradiance habitats.
In the present study we investigated inter- and intraspecific EPA and DHA variability in five polar and (cold) temperate microalgae. Intraspecific EPA and DHA content did not vary significantly in an Antarctic (Chaetoceros brevis) and a temperate (Thalassiosira weissflogii) centric diatom after acclimation to a range of irradiance levels at two temperatures. Interspecific variability was investigated for two Antarctic (Chaetoceros brevis and Pyramimonas sp. (Prasinophyceae)) and three cold-temperate species (Thalassiosira weissflogii, Emiliania huxleyi (Prymnesiophyceae) and Fibrocapsa japonica (Raphidophyceae)) during exponential growth. Interspecific variability was shown to be much more important than intraspecific variability. Highest relative and absolute levels of DHA were measured in the prymnesiophyte E. huxleyi and the prasinophyte Pyramimonas sp., while levels of EPA were high in the raphidophyte F. japonica and the diatoms C. brevis and T. weissflogii. Yet, no significant differences in LC-PUFA content were found between polar and cold-temperate species. Also, EPA and DHA production rates varied strongly between species. Highest EPA production rate (174 μg L-1 day-1) was found in the Antarctic diatom Chaetoceros brevis, while DHA production was highest in the cold-temperate prymnesiophyte Emiliania huxleyi (164 μg L-1 day-1). We show that, following careful species selection, effective mass cultivation of marine microalgae for EPA and DHA production may be possible under low temperature and irradiance conditions.
doi:10.1186/2191-0855-3-26
PMCID: PMC3671209  PMID: 23673135
Eicosapentaenoic acid; Docosahexaenoic acid; Thalassiosira weissflogii; Chaetoceros brevis; Fibrocapsa japonica; Emiliania huxleyi; Pyramimonas sp.
20.  Omega-3 fatty acids for breast cancer prevention and survivorship 
Women with evidence of high intake ratios of the marine omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) relative to the omega-6 arachidonic acid have been found to have a reduced risk of breast cancer compared with those with low ratios in some but not all case–control and cohort studies. If increasing EPA and DHA relative to arachidonic acid is effective in reducing breast cancer risk, likely mechanisms include reduction in proinflammatory lipid derivatives, inhibition of nuclear factor-κB-induced cytokine production, and decreased growth factor receptor signaling as a result of alteration in membrane lipid rafts. Primary prevention trials with either risk biomarkers or cancer incidence as endpoints are underway but final results of these trials are currently unavailable. EPA and DHA supplementation is also being explored in an effort to help prevent or alleviate common problems after a breast cancer diagnosis, including cardiac and cognitive dysfunction and chemotherapy-induced peripheral neuropathy. The insulin-sensitizing and anabolic properties of EPA and DHA also suggest supplementation studies to determine whether these omega-3 fatty acids might reduce chemotherapy-associated loss of muscle mass and weight gain. We will briefly review relevant omega-3 fatty acid metabolism, and early investigations in breast cancer prevention and survivorship.
doi:10.1186/s13058-015-0571-6
PMCID: PMC4418048  PMID: 25936773
21.  Dose Response Effects of Marine Omega-3 Fatty Acids on Apolipoproteins, Apolipoprotein-Defined Lipoprotein Subclasses, and Lp-PLA2 in Individuals with Moderate Hypertriglyceridemia 
Journal of clinical lipidology  2014;9(3):360-367.
Background
Apolipoprotein (apo) distribution and lipoprotein (Lp)-associated markers of inflammation, such as lipoprotein-associated phospholipase A2 (Lp-PLA2), influence the atherogenicity of circulating lipids and lipoproteins. Little evidence exists regarding the dose-response effects of the marine omega-3 fatty acids eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids on apos, apo-defined Lps, and Lp-PLA2.
Objective
The purpose of this study was to compare the effects of 0 g/d, 0.85 g/d and 3.4 g/d of EPA + DHA on Lp-PLA2 mass and activity in individuals with moderate hypertriglyceridemia. We also measured effects on concentrations of apo AI, AII, B, C, D, and E-defined Lp subclasses.
Methods
The study was a randomized, double-blind crossover design with 8-week treatment periods and 6-week washout periods. During the 3 treatment periods, subjects (n = 25) received 0 g/d EPA + DHA, 0.85 g/d EPA + DHA (low dose), and 3.4 g/d EPA + DHA (high dose) in random order.
Results
Apo B and apo C-III were significantly decreased by the high dose relative to placebo and low dose (p < 0.01), as was very low density lipoprotein-cholesterol (VLDL-C, p < 0.005). The low dose had no effect on Lp outcomes compared to placebo. The high and low dose effects differed significantly for heparin-precipitated apo C-III, LpB, LpA-I, and apo B/apo A-I ratio (p < 0.05). There was a trend for a decreased Lp-PLA2 mass with the high dose (p = 0.1).
Conclusion
The effects of 3.4 g/d EPA + DHA on apo B and apo C-III may reduce atherosclerotic plaque progression in individuals with elevated triglycerides.
doi:10.1016/j.jacl.2014.12.001
PMCID: PMC4677829  PMID: 26073395
apolipoproteins; lipoproteins; Lp-PLA2; omega-3; docosahexaenoic acid; eicosapentaenoic acid; triglycerides; fish oil
22.  Omega-3 Fatty Acids: Anti-Arrhythmic, Pro-Arrhythmic, or Both? 
This review focuses on developments after 2008, when the topic was last reviewed by the author. Pertinent publications were found by medline searches and in the author’s personal data base. Prevention of atrial fibrillation (AF) was investigated in a number of trials, sparked by one positive report on the effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), considerations of upstream therapy, data from electrophysiologic laboratories and animal experiments. If EPA + DHA prevent postoperative AF, the effect is probably smaller than initially expected. The same is probably true for maintenance of sinus rhythm after cardioversion and for new-onset AF. Larger trials are currently ongoing. Prevention of ventricular arrhythmias was studied in carriers of an implanted cardioverter-defibrillator, with no clear results. This might have been due to a broad definition of the primary endpoint, including any ventricular arrhythmia and any action of the device. Epidemiologic studies support the contention that high levels of EPA + DHA prevent sudden cardiac death (SCD). However, since SCD is a rare occurrence, it is difficult to conduct an adequately powered trial. In patients with congestive heart failure, EPA + DHA reduced total mortality and rehospitalizations, but not SCD or presumed arrhythmic death. Of three trials in patients after a myocardial infarction, two were inadequately powered, and in one, the dose might have been too low. Taken together, while epidemiologic studies support an inverse relation between EPA + DHA and occurrence of SCD or arrhythmic death, demonstrating this effect in intervention trials remained elusive so far. A pro-arrhythmic effect of EPA + DHA has not been seen in intervention studies, and results of epidemiologic and animal studies also rather argue against such an effect. A different, and probably more productive, perspective is provided by a standardized analytical assessment of a person’s status in EPA + DHA by use of the omega-3 index, EPA + DHA in red cell fatty acids. In populations with a high omega-3 index, SCD is rare. Intervention trials can become more effective by including a low omega-3 index into the inclusion criteria, thus creating a study population more likely to demonstrate an effect of EPA + DHA. This is especially relevant in case of rare endpoints, like new-onset AF or SCD.
doi:10.3389/fphys.2012.00088
PMCID: PMC3327892  PMID: 22529815
eicosapentaenoic acid; docosahexaenoic acid; omega-3 fatty acids; omega-3 index; atrial fibrillation; ventricular tachycardia; ventricular fibrillation; sudden cardiac death
23.  Compared with Daily, Weekly n–3 PUFA Intake Affects the Incorporation of Eicosapentaenoic Acid and Docosahexaenoic Acid into Platelets and Mononuclear Cells in Humans123 
The Journal of Nutrition  2014;144(5):667-672.
Consumption of oily fish is sporadic, whereas controlled intervention studies of n–3 (ω-3) fatty acids usually provide capsules containing eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) as a daily dose. This methodologic study explored whether there are differences in the short-, medium-, and long-term incorporation of EPA and DHA into blood plasma and cells with the provision of identical amounts of EPA and DHA, equivalent to 2 oily fish servings per week (or 6.54 g/wk EPA and DHA), either intermittently (i.e., 1 portion twice per week) or continuously (i.e., divided into daily amounts). The study was part of a randomized, double-blind controlled intervention lasting 12 mo, with participants stratified by age and sex. There were 5 intervention groups, 2 of which are reported here: the 2 intermittent portions (2I) and 2 continuous portions (2C) groups. EPA and DHA were measured in plasma phosphatidylcholine, platelets, and blood mononuclear cells (MNCs) at 9 time points. Sixty-five participants completed the study (2I group, n = 30, mean age of 49.2 y; 2C group, n = 35, mean age of 50.6 y). The incorporation pattern over the 12-mo intervention was different between the 2 groups in all samples (P < 0.0001, time × treatment interaction). At the end of the 12-mo intervention, the 2C group had higher EPA, DHA, and EPA + DHA in platelets (all P < 0.01) and higher EPA and EPA + DHA in MNCs (both P < 0.05) compared with the 2I group. No significant differences were shown for plasma phosphatidylcholine EPA (P = 0.1), DHA (P = 0.15), EPA + DHA (P = 0.07), or MNC DHA (P = 0.06). In conclusion, the pattern of consumption does affect the incorporation of EPA and DHA into cells used as biomarkers of intake. The differences identified here need to be considered in the design of studies and when extrapolating results from continuous capsule-based intervention studies to dietary guidelines for oily fish consumption. This trial was registered at www.controlled-trials.com as ISRCTN48398526.
doi:10.3945/jn.113.186346
PMCID: PMC3985823  PMID: 24647395
24.  Omega-3 Fatty Acids and Inflammatory Processes 
Nutrients  2010;2(3):355-374.
Long chain fatty acids influence inflammation through a variety of mechanisms; many of these are mediated by, or at least associated with, changes in fatty acid composition of cell membranes. Changes in these compositions can modify membrane fluidity, cell signaling leading to altered gene expression, and the pattern of lipid mediator production. Cell involved in the inflammatory response are typically rich in the n-6 fatty acid arachidonic acid, but the contents of arachidonic acid and of the n-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) can be altered through oral administration of EPA and DHA. Eicosanoids produced from arachidonic acid have roles in inflammation. EPA also gives rise to eicosanoids and these often have differing properties from those of arachidonic acid-derived eicosanoids. EPA and DHA give rise to newly discovered resolvins which are anti-inflammatory and inflammation resolving. Increased membrane content of EPA and DHA (and decreased arachidonic acid content) results in a changed pattern of production of eicosanoids and resolvins. Changing the fatty acid composition of cells involved in the inflammatory response also affects production of peptide mediators of inflammation (adhesion molecules, cytokines etc.). Thus, the fatty acid composition of cells involved in the inflammatory response influences their function; the contents of arachidonic acid, EPA and DHA appear to be especially important. The anti-inflammatory effects of marine n-3 PUFAs suggest that they may be useful as therapeutic agents in disorders with an inflammatory component.
doi:10.3390/nu2030355
PMCID: PMC3257651  PMID: 22254027
leukocyte; neutrophil; macrophage; monocyte; eicosanoid; cytokine; interleukin; fish oil
25.  Effects of Omega-3 Fatty Acid Supplementation on Heart Rate Variability at Rest and During Acute Stress in Adults With Moderate Hypertriglyceridemia 
Psychosomatic medicine  2013;75(4):382-389.
Objective
This study examined the dose-dependent effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) supplementation on heart rate variability (HRV) at rest and during standard laboratory stress tasks. We also investigated whether EPA + DHA supplementation was associated with changes in mood state.
Methods
This placebo-controlled, double-blind, randomized, three-period crossover trial (8-week treatment, 6-week washout) compared two doses of EPA + DHA supplementation (0.85 and 3.4 g/d) in 26 adults with elevated triglycerides. After each treatment period, HRV was assessed during an acute stress protocol that included a resting baseline, standard laboratory stress tasks (speech task and cold pressor), and recovery periods. In addition, mood state was assessed.
Results
Root mean square of successive differences in interbeat interval and total power increased 9.9% and 20.6%, respectively, after the high dose relative to placebo (Tukey p = .016 and .012, respectively). The low dose was not significantly different from the high dose or placebo dose. There was a trend for a treatment effect on high-frequency HRV (p = .058), with 21.0% greater power observed after the high dose compared with placebo (Tukey p = .052). Mood did not differ between treatments, and there was no association between mood state and HRV.
Conclusions
In healthy adults with elevated triglycerides, supplementation of 3.4 g/d EPA + DHA resulted in greater HRV, whereas 0.85 g/d EPA + DHA had no effect. These results indicate that EPA + DHA supplementation may improve autonomic tone in adults at increased risk for cardiovascular disease within 8 weeks.
Trial Registration
NCT00504309 (ClinicalTrials.gov).
doi:10.1097/PSY.0b013e318290a107
PMCID: PMC3681100  PMID: 23592752
heart rate variability; acute stress; omega-3 fatty acids; eicosapentaenoic acid; docosahexaenoic acid

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