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1.  Dietary Omega-3 Fatty Acids, Other Fat Intake, Genetic Susceptibility and Progression to Incident Geographic Atrophy 
Ophthalmology  2013;120(5):1020-1028.
To investigate associations between dietary omega-3 fatty acids and other fat intake, genes related to age-related macular degeneration (AMD) and progression to geographic atrophy (GA).
Observational analysis of a prospective cohort.
2531 individuals from the Age-Related Eye Disease Study, among which 525 eyes progressed to GA and 4165 eyes did not.
Eyes without advanced AMD (GA or neovascular disease) at baseline were evaluated for progression to GA. Behavioral data, including smoking and body mass index measurements were collected at baseline using questionnaires. Dietary data was collected from food frequency questionnaires (FFQ) at baseline. Dietary fats, including omega-3 fatty acids (docosahexaenoic acid or DHA and eicosapentaenoic acid or EPA), omega-6 fatty acids, monounsaturated, saturated, polyunsaturated and total fat were sex and calorie adjusted and divided into quintiles. Eight single nucleotide polymorphisms (SNPs) in 7 genes: CFH, ARMS2/HTRA1, CFB, C2, C3, CFI, LIPC were genotyped. Cox proportional hazards models were used to test for associations between incident GA and intake of dietary lipids, and interaction effects between dietary fat intake and genetic variation on risk of GA.
Main Outcome Measures
Associations between dietary fat intake reported from FFQs, genetic variants and incident GA.
Increased intake of DHA was significantly associated with reduced risk of progression to GA in multivariate models with behavioral factors (Model A) and behavioral factors with genetic variants (Model B) (P-trend=0.008 and 0.03, respectively). Total omega-3 long chain polyunsaturated (DHA + EPA) fatty acid intake was significantly associated with reduced risk of progression in Model B variants (P-trend =0.02). Monounsaturated fat was associated with increased risk in Model A (P=0.05).. DHA intake in the 5th quintile was significantly associated with reduced risk of incident GA among those with the ARMS2/HTRA1 homozygous risk genotype (HR = 0.4, P = 0.002, P – interaction between gene and fat intake = 0.05), whereas DHA was not associated with reduced risk of GA among those with the homozygous non-risk genotype (HR = 1.0, P= 0.90).
Increased self- reported dietary intake of omega-3 fatty acids is associated with reduced risk of GA and may modify genetic susceptibility for progression to GA.
PMCID: PMC3758110  PMID: 23481534
2.  Animal Nutrition and Lipids in Animal Products and Their Contribution to Human Intake and Health 
Nutrients  2009;1(1):71-82.
Few EU countries meet targets for saturated fatty acid (SFA) intake. Dairy products usually represent the single largest source of SFA, yet evidence indicates that milk has cardioprotective properties. Options for replacing some of the SFA in milk fat with cis-monounsaturated fatty acids (MUFA) through alteration of the cow’s diet are examined. Also, few people achieve minimum recommended intakes (~450–500 mg/d) of the long chain n-3 polyunsaturated fatty acids (PUFA) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Enrichment of EPA+DHA in poultry meat via bird nutrition is described and how this would impact on habitual intake is discussed.
PMCID: PMC3257589  PMID: 22253968
lipids; animal nutrition
3.  Eicosapentaenoic acid/docosahexaenoic acid 1:1 ratio improves histological alterations in obese rats with metabolic syndrome 
Marine polyunsaturated fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been associated with improvement in the Metabolic Syndrome (MS). The aim of this study is to evaluate how three fish-oil diets with different eicosapentaenoic acid/docosahexaenoic acid ratios (EPA/DHA ratio) affect the histology of liver, kidney, adipose tissue and aorta in a preliminary morphological study. This work uses an animal model of metabolic syndrome in comparison with healthy animals in order to provide information about the best EPA:DHA ratio to prevent or to improve metabolic syndrome symptoms.
35 Wistar rats, as a control, and 35 spontaneously hypertensive obese rats (SHROB) were fed for 13 weeks with 3 different suplemmentation of fish oil containing EPA and DHA ratios (1:1, 2:1 and 1:2, respectively). All samples were stained with haematoxylin/eosin stain, except aorta samples, which were stained also with Verhoeff and van Gieson’s stain. A histological study was carried out to evaluate changes. These changes were statistically analyzed using SPSS IBM 19 software. The quantitative data were expressed by mean ± SD and were compared among groups and treatments using ANOVA with post-hoc tests for parametric data and the U-Mann–Whitney for non-parametric data. Qualitative data were expressed in frequencies, and compared with contingency tables using χ2 statistics.
EPA:DHA 1:1 treatment tended to improve the density and the wrinkling of elastic layers in SHROB rats. Only Wistar rats fed with EPA:DHA 1:1 treatment did not show mast cells in adipose tissue and has less kidney atrophy. In both strains EPA:DHA 1:1 treatment improved inflammation related parameters in liver and kidney.
EPA:DHA 1:1 treatment was the most beneficial treatment since improved many histological parameters in both groups of rats.
PMCID: PMC3927584  PMID: 24512213
Metabolic syndrome; Omega-3-polyunsaturated fatty acids; EPA/DHA ratio; Histology; SHROB rats; Fish oils
4.  Omega-3 and omega-6 fatty acid intakes and endometrial cancer risk in a population-based case–control study 
European journal of nutrition  2012;52(3):1251-1260.
Animal and laboratory studies suggest that long-chain omega-3 (n-3) fatty acids, a type of polyunsaturated fat found in fatty fish, may protect against carcinogenesis, but human studies on dietary intake of polyunsaturated fats and fish with endometrial cancer risk show mixed results.
We evaluated the associations between endometrial cancer risk and intake of fatty acids and fish in a population-based sample of 556 incident cancer cases and 533 age-matched controls using multivariate unconditional logistic regression methods.
Although total n-3 fatty acid intake was not associated with endometrial cancer risk, higher intakes of eicosapentaenoic (EPA 20:5) and docosahexaenoic (DHA 22:6) fatty acids were significantly associated with lower risks (OR = 0.57, 95 % CI: 0.39–0.84; OR = 0.64, 95 % CI: 0.44–0.94; respectively) comparing extreme quartiles. The ratio of n-3:n-6 fatty acids was inversely associated with risk only on a continuous scale (OR = 0.84, 95 % CI: 0.71–0.99), while total fish intake was not associated with risk. Fish oil supplement use was significantly associated with reduced risk of endometrial cancer: OR = 0.63 (95 % CI: 0.45–0.88).
Our results suggest that dietary intake of the long-chain polyunsaturated fatty acids EPA and DHA in foods and supplements may have protective associations against the development of endometrial cancer.
PMCID: PMC3548981  PMID: 22915050
Endometrial cancer; Fatty acids; Fish oil; Fish; Case–control study
5.  Omega-3 fatty acids for treatment of non-alcoholic fatty liver disease: design and rationale of randomized controlled trial 
BMC Pediatrics  2013;13:85.
Non-alcoholic fatty liver disease (NAFLD) is a liver manifestation of metabolic syndrome since obesity and insulin resistance are the main pathogenic contributors for both conditions. NAFLD carries increased risk of atherosclerosis and cardiovascular diseases. There is an urgent need to find effective and safe therapy for children and adults with NAFLD. Data from research and clinical studies suggest that omega-3 fatty acids may be beneficial in metabolic syndrome-related conditions and can reduce the risk of cardiovascular disease.
We are conducting a randomized, multicenter, double-blind, placebo-controlled trial of treatment with omega-3 fatty acids in children with NAFLD. Patients are randomized to receive either omega-3 fatty acids containing docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) or placebo for 24 weeks. The dose of omega-3 (DHA+ EPA) ranges from 450 to 1300 mg daily. Low calorie diet and increased physical activity are advised and monitored using validated questionnaires. The primary outcome of the trial is the number of patients who decreased ALT activity by ≥ 0,3 of upper limit of normal. The main secondary outcomes are improvement in the laboratory liver tests, liver steatosis on ultrasound, markers of insulin resistance and difference in fat/lean body mass composition after 6 months of intervention.
Potential efficacy of omega-3 fatty acids in the treatment of NAFLD will provide needed rationale for use of this safe diet supplement together with weight reduction therapy in the growing population of children with NAFLD.
Trial registration
PMCID: PMC3672084  PMID: 23702094
Non-alcoholic fatty liver disease; Omega-3 fatty acids; Polyunsaturated fatty acids; Randomized controlled trial; Children
6.  Fish, Fish-Derived n-3 Fatty Acids, and Risk of Incident Atrial Fibrillation in the Atherosclerosis Risk in Communities (ARIC) Study 
PLoS ONE  2012;7(5):e36686.
Results of observational and experimental studies investigating the association between intake of long-chain n-3 polyunsaturated fatty acids (PUFAs) and risk of atrial fibrillation (AF) have been inconsistent.
We studied the association of fish and the fish-derived n-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) with the risk of incident AF in individuals aged 45–64 from the Atherosclerosis Risk in Communities (ARIC) cohort (n = 14,222, 27% African Americans). Intake of fish and of DHA and EPA were measured via food frequency questionnaire. Plasma levels of DHA and EPA were measured in phospholipids in a subset of participants (n = 3,757). Incident AF was identified through the end of 2008 using ECGs, hospital discharge codes and death certificates. Cox proportional hazards regression was used to estimate hazard ratios of AF by quartiles of n-3 PUFAs or by fish intake.
During the average follow-up of 17.6 years, 1,604 AF events were identified. In multivariable analyses, total fish intake and dietary DHA and EPA were not associated with AF risk. Higher intake of oily fish and canned tuna was associated with a nonsignificant lower risk of AF (p for trend = 0.09). Phospholipid levels of DHA+EPA were not related to incident AF. However, DHA and EPA showed differential associations with AF risk when analyzed separately, with lower risk of AF in those with higher levels of DHA but no association between EPA levels and AF risk.
In this racially diverse sample, dietary intake of fish and fish-derived n-3 fatty acids, as well as plasma biomarkers of fish intake, were not associated with AF risk.
PMCID: PMC3343018  PMID: 22570739
7.  Acute appearance of fatty acids in human plasma – a comparative study between polar-lipid rich oil from the microalgae Nannochloropsis oculata and krill oil in healthy young males 
The long-chain n-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have human health benefits. Alternatives to fish as sources of EPA and DHA are needed. Oil from the micro-algae Nannochloropsis oculata contains a significant amount of EPA conjugated to phospholipids and glycolipids and no DHA. Krill oil contains EPA and DHA conjugated to phospholipids. We compare the appearance of fatty acids in blood plasma of healthy humans after consuming a high fat meal followed by either algal oil or krill oil.
Ten healthy males aged 18-45 years consumed a standard high fat (55 g) breakfast followed by either algal oil (providing 1.5 g EPA and no DHA) or krill oil (providing 1.02 g EPA and 0.54 g DHA). All participants consumed both oils in random order and separated by 7 days. Blood samples were collected before the breakfast and at several time points up to 10 hours after taking the oils. Fatty acid concentrations (μg/ml) in plasma were determined by gas chromatography.
Fatty acids derived mainly from the breakfast appeared rapidly in plasma, peaking about 3 hours after consuming the breakfast, and in a pattern that reflected their content in the breakfast. There were time-dependent increases in the concentrations of both EPA and DHA with both algal oil (P < 0.001 for EPA; P = 0.027 for DHA) and krill oil (P < 0.001 for both EPA and DHA). The concentration of EPA was higher with algal oil than with krill oil at several time points. DHA concentration did not differ between oils at any time point. The maximum concentration of EPA was higher with algal oil (P = 0.010) and both the area under the concentration curve (AUC) and the incremental AUC for EPA were greater with algal oil (P = 0.020 and 0.006). There was no difference between oils in the AUC or the incremental AUC for DHA.
This study in healthy young men given a single dose of oil indicates that the polar-lipid rich oil from the algae Nannochloropis oculata is a good source of EPA in humans.
PMCID: PMC3718725  PMID: 23855409
Omega-3; Eicosapentaenoic acid; Docosahexaenoic acid; Algal oil; Krill oil; Polar lipids; Glycolipids; Phospholipids
8.  Reduction in Dietary Omega-6 Polyunsaturated Fatty Acids:Eicosapentaenoic Acid plus Docosahexaenoic Acid Ratio Minimizes Atherosclerotic Lesion Formation and Inflammatory Response in the LDL Receptor Null Mouse 
Atherosclerosis  2008;204(1):147-155.
Dietary very long chain omega (ω)-3 polyunsaturated fatty acids (PUFA) have been associated with reduced CVD risk, the mechanisms of which have yet to be fully elucidated. LDL receptor null mice (LDLr-/-) were used to assess the effect of different ratios of dietary ω-6 PUFA to eicosapentaenoic acid plus docosahexaenoic acid (ω-6:EPA+DHA) on atherogenesis and inflammatory response. Mice were fed high saturated fat diets without EPA and DHA (HSF ω-6), or with ω-6:EPA+DHA at ratios of 20:1 (HSF R=20:1), 4:1 (HSF R=4:1), and 1:1 (HSF R=1:1) for 32 weeks. Mice fed the lowest ω-6:EPA+DHA ratio diet had lower circulating concentrations of non-HDL cholesterol (25%, P<0.05) and interleukin-6 (IL-6) (44%, P<0.05) compared to mice fed the HSF ω-6 diet. Aortic and elicited peritoneal macrophage (Mϕ) total cholesterol were 24% (P=0.07) and 25% (P<0.05) lower, respectively, in HSF R=1:1 compared to HSF ω-6 fed mice. MCP-1 mRNA levels and secretion were 37% (P<0.05) and 38% (P<0.05) lower, respectively, in elicited peritoneal Mϕ isolated from HSF R=1:1 compared to HSF ω-6 fed mice. mRNA and protein levels of ATP-binding cassette A1, and mRNA levels of TNFα were significantly lower in elicited peritoneal Mϕ isolated from HSF R=1:1 fed mice, whereas there was no significant effect of diets with different ω-6:EPA+DHA ratios on CD36, Mϕ scavenger receptor 1, scavenger receptor B1 and IL-6 mRNA or protein levels. These data suggest that lower ω-6:EPA+DHA ratio diets lowered some measures of inflammation and Mϕ cholesterol accumulation, which was associated with less aortic lesion formation in LDLr-/- mice.
PMCID: PMC2826705  PMID: 18842266
ω-6:EPA+DHA ratio; ω-3 fatty acids; atherosclerosis; inflammation; macrophage cholesterol accumulation; LDLr-/- mouse; diet; elicited peritoneal Mϕ
9.  Short term effects of different omega-3 fatty acid formulation on lipid metabolism in mice fed high or low fat diet 
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.
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.
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.
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.
PMCID: PMC3393618  PMID: 22676394
Omega-3 fatty acid; DHA; EPA; Lipid metabolism; Triglycerides; Ethyl ester; Phospholipids
10.  A defect in Δ6 and Δ5 desaturases may be a factor in the initiation and progression of insulin resistance, the metabolic syndrome and ischemic heart disease in South Asians 
The high incidence of insulin resistance and the metabolic syndrome in South Asians remains unexplained. I propose that a defect in the activity of Δ6 and Δ5 desaturases and consequent low plasma and tissue concentrations of polyunsaturated fatty acids such as γ-linolenic acid (GLA), dihomo-γ-linolenic acid (DGLA), arachidonic acid (AA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and formation of their anti-inflammatory products prostaglandin E1 (PGE1), prostacyclin (PGI2), PGI3, lipoxins, resolvins, protectins, maresins and nitrolipids could be responsible for the high incidence of insulin resistance, the metabolic syndrome and ischemic heart disease (IHD) in South Asians. This proposal is supported by the observation that South Asian Indians have lower plasma and tissue concentrations of GLA, DGLA, AA, EPA and DHA, the precursors of PGE1, PGI2, PGI3, lipoxins, resolvins, protectins, and nitrolipids, the endogenous molecules that prevent platelet aggregation, vasoconstriction, thrombus formation, leukocyte activation and possess anti-inflammatory action and thus, are capable of preventing the development of insulin resistance, atherosclerosis, hypertension, type 2 diabetes mellitus and premature ischemic heart disease. Genetic predisposition, high carbohydrate intake, lack of exercise, tobacco use and low birth weight due to maternal malnutrition suppress the activity of Δ6 and Δ5 desaturases that leads to low plasma and tissue concentrations of polyunsaturated fatty acids and their products. This implies that adequate provision of polyunsaturated fatty acids and co-factors needed for their metabolism, and efforts to enhance the formation of their beneficial metabolites PGE1, PGI2, PGI3, lipoxins, resolvins, protectins, maresins and nitrolipids could form a novel approach in the prevention and management of these diseases in this high-risk population.
PMCID: PMC2987992  PMID: 21062475
11.  A Taiwanese food frequency questionnaire correlates with plasma docosahexaenoic acid but not with plasma eicosapentaenoic acid levels: questionnaires and plasma biomarkers 
Little evidence is available for the validity of dietary fish and polyunsaturated fatty acid intake derived from interviewer-administered questionnaires and plasma docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) concentration.
We estimated the correlation of DHA and EPA intake from both questionnaires and biochemical measurements. Ethnic Chinese adults with a mean (± SD) age of 59.8 (±12.8) years (n = 297) (47% women) who completed a 38-item semi-quantitative food-frequency questionnaire and provided a plasma sample were enrolled. Plasma fatty acids were analyzed by capillary gas chromatography.
The Spearmen rank correlation coefficients between the intake of various types of fish and marine n-3 fatty acids as well as plasma DHA were significant, ranging from 0.20 to 0.33 (P < 0.001). In addition, dietary EPA, C22:5 n-3 and DHA were significantly correlated with the levels of marine n-3 fatty acids and DHA, with the Spearman rank correlation coefficients ranging from 0.26 to 0.35 (P < 0.001). Moreover, compared with those in the lowest fish intake quintile, participants in the highest quintile had a significantly higher DHA level (adjusted mean difference, 0.99 ± 0.10%, test for trend, P < 0.001). Similar patterns between dietary DHA intake and plasma DHA levels were found. However, the association between dietary fish intake and plasma EPA was not significant (test for trend, P = 0.69).
The dietary intakes of fish and of long chain n-3 fatty acids, as determined by the food frequency questionnaire, were correlated with the percentages of these fatty acids in plasma, and in particular with plasma DHA. Plasma DHA levels were correlated to dietary intake of long-chain n-3 fatty acids.
PMCID: PMC3598308  PMID: 23414574
N-3 fatty acid; Biomarker; Food frequency questionnaire
12.  Low serum eicosapentaenoic acid / arachidonic acid ratio in male subjects with visceral obesity 
Visceral fat accumulation is caused by over-nutrition and physical inactivity. Excess accumulation of visceral fat associates with atherosclerosis. Polyunsaturated fatty acids have an important role in human nutrition, but imbalance of dietary long-chain polyunsaturated fatty acids, especially low eicosapentaenoic acid (EPA) / arachidonic acid (AA) ratio, is associated with increased risk of cardiovascular disease. The present study investigated the correlation between EPA, docosahexaenoic acid (DHA), AA parameters and clinical features in male subjects.
The study subjects were 134 Japanese with diabetes, hypertension and/or dyslipidemia who underwent measurement of visceral fat area (eVFA) by the bioelectrical impedance method and serum levels of EPA, DHA and AA. EPA/AA ratio correlated positively with age, and negatively with waist circumference and eVFA. Stepwise regression analysis demonstrated that age and eVFA correlated significantly and independently with serum EPA/AA ratio. Serum EPA/AA ratio, but not serum DHA/AA and (EPA+DHA)/AA ratios, was significantly lower in subjects with eVFA ≥100 cm2, compared to those with eVFA <100 cm2 (p=0.049). Subjects with eVFA ≥100 cm2 were significantly more likely to have the metabolic syndrome and history of cardiovascular diseases, compared to those with eVFA <100 cm2 (p<0.001, p=0.028, respectively).
Imbalance of dietary long-chain polyunsaturated fatty acids (low serum EPA/AA ratio) correlated with visceral fat accumulation in male subjects.
Clinical trial registration number
PMCID: PMC3606329  PMID: 23497138
Arachidonic acid; Eicosapentaenoic acid; Docosahexaenoic acid; Visceral fat; Metabolic syndrome; Obesity
13.  Ingestion of a single serving of saury alters postprandial levels of plasma n-3 polyunsaturated fatty acids and long-chain monounsaturated fatty acids in healthy human adults 
Saury oil contains considerable amounts of n-3 polyunsaturated fatty acids (PUFA) and monounsaturated fatty acids (MUFA) with long aliphatic tails (>18C atoms). Ingestion of saury oil reduces the risk of developing metabolic syndrome concomitant with increases in n-3 PUFA and long-chain MUFA in plasma and organs of mice. We therefore evaluated changes in postprandial plasma fatty acid levels and plasma parameters in healthy human subjects after ingestion of a single meal of saury.
Five healthy human adults ingested 150 g of grilled saury. Blood was collected before the meal and at 2, 6, and 24 hr after the meal, and plasma was prepared. Plasma levels of eicosapentaenoic acid, docosahexaenoic acid, and long-chain MUFA (C20:1 and C22:1 isomers combined) increased significantly throughout the postprandial period compared with the pre-meal baseline. Postprandial plasma insulin concentration increased notably, and plasma levels of glucose and free fatty acids decreased significantly and subsequently returned to the pre-meal levels.
Our study suggests that a single saury meal may alter the postprandial plasma levels of n-3 PUFA and long-chain MUFA in healthy human subjects.
PMCID: PMC3485116  PMID: 22846384
Saury; n-3 PUFA; MUFA; Eicosapentaenoic acid (EPA); Docosahexaenoic acid (DHA)
14.  Red blood cell omega-3 fatty acid levels and markers of accelerated brain aging 
Neurology  2012;78(9):658-664.
Higher dietary intake and circulating levels of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) have been related to a reduced risk for dementia, but the pathways underlying this association remain unclear. We examined the cross-sectional relation of red blood cell (RBC) fatty acid levels to subclinical imaging and cognitive markers of dementia risk in a middle-aged to elderly community-based cohort.
We related RBC DHA and EPA levels in dementia-free Framingham Study participants (n = 1,575; 854 women, age 67 ± 9 years) to performance on cognitive tests and to volumetric brain MRI, with serial adjustments for age, sex, and education (model A, primary model), additionally for APOE ϵ4 and plasma homocysteine (model B), and also for physical activity and body mass index (model C), or for traditional vascular risk factors (model D).
Participants with RBC DHA levels in the lowest quartile (Q1) when compared to others (Q2–4) had lower total brain and greater white matter hyperintensity volumes (for model A: β ± SE = −0.49 ± 0.19; p = 0.009, and 0.12 ± 0.06; p = 0.049, respectively) with persistence of the association with total brain volume in multivariable analyses. Participants with lower DHA and ω-3 index (RBC DHA+EPA) levels (Q1 vs Q2–4) also had lower scores on tests of visual memory (β ± SE = −0.47 ± 0.18; p = 0.008), executive function (β ± SE = −0.07 ± 0.03; p = 0.004), and abstract thinking (β ± SE = −0.52 ± 0.18; p = 0.004) in model A, the results remaining significant in all models.
Lower RBC DHA levels are associated with smaller brain volumes and a “vascular” pattern of cognitive impairment even in persons free of clinical dementia.
PMCID: PMC3286229  PMID: 22371413
15.  Fatty acid profiles of muscle from large yellow croaker (Pseudosciaena crocea R.) of different age 
We investigated the fatty acid profiles of muscle from large yellow croaker (Pseudosciaena crocea R.) of different age. One- and two-year-old fish were cultured in floating net cages and sampled randomly for analysis. Moisture, protein, lipid and ash contents were determined by methods of Association of Analytical Chemist (AOAC) International. Fatty acid profile was determined by gas chromatography. Crude protein, fat, moisture and ash contents showed no significant differences between the two age groups. The contents of total polyunsaturated fatty acids and docosahexaenoic acid (DHA) were significantly higher and eicosapentaenoic acid (EPA) content was significantly lower in the two-year-old large yellow croaker than in the one-year-old (P<0.05). No significant differences were observed in the contents of total saturated fatty acids and monounsaturated fatty acids, or the ratio of n-3/n-6 fatty acids among the large yellow croakers of the two age groups. We conclude that large yellow croakers are good food sources of EPA and DHA.
PMCID: PMC2644757  PMID: 19235275
Fatty acid; Large yellow croaker; Age
16.  Dietary intake of specific fatty acids and breast cancer risk among postmenopausal women in the VITAL cohort 
Nutrition and cancer  2012;64(8):1131-1142.
Studies of dietary fat intake and breast cancer have been inconsistent and few have examined specific fatty acids. We examined the association between specific monounsaturated (MUFA), polyunsaturated (PUFA), saturated (SFA), and trans-fatty acids (TFA) and breast cancer risk. Participants, 50–76y, were female members of the VITamins And Lifestyle (VITAL) Cohort, who were postmenopausal at baseline. In 2000–2002, participants completed a food frequency questionnaire. 772 incident, primary breast cancer cases were identified using a population-based cancer registry. Cox proportional hazard models estimated hazard ratios (HR) and 95% confidence intervals (95% CI) for the association between fatty acid intake and breast cancer risk. Intake of total MUFAs (Highest vs. lowest quintile: HR=1.61, 95% CI: 1.08–2.38, P-trend=0.02), particularly myristoleic and erucic acids, was associated with increased breast cancer risk. Whereas total SFA was suggestive of an increased risk (HR=1.47, 95% CI: 1.00–2.15, P-trend=0.09), strong associations were observed for palmitic, margaric, and stearic acids. Total TFA and PUFA intake were not associated with breast cancer. However, among TFAs, linolelaidic acid was positively associated with risk; among PUFAs, intake of eicosapentaenoic and docosahexaenoic acids were inversely associated with risk. Our findings show that fatty acids are heterogeneous in their association with postmenopausal breast cancer risk.
PMCID: PMC3633593  PMID: 23137008
17.  Red blood cell stearidonic acid and other omega-3 fatty acids and coronary heart disease in the Physicians’ Health Study 
The British journal of nutrition  2012;109(11):2044-2049.
Intake of marine- based omega-3 fatty acids [eicosapentaenoic acids (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acids (DHA)] is recommended to prevent coronary heart disease (CHD). Stearidonic acid (SDA), a plant- based omega-3 fatty acid (FA), is a precursor of EPA and may be more readily converted to EPA than alpha-linolenic acid (ALA). While transgenic soybean might supply SDA at low costs, it is unclear whether SDA is associated with CHD risk. Furthermore, associations of other omega-3 FAs with CHD risk remain inconsistent. This ancillary study examined the association of red blood cell SDA as well as other omega-3 FAs with the risk of CHD. In a prospective nested case-control study of the Physicians’ Health Study, we randomly selected 1,000 pairs of incident CHD with matching controls. Red blood cell FAs were measured using gas chromatography. We used conditional logistic regression to estimate relative risks.
Mean age was 68.7±8.7 y. In a multivariable model controlling for matching factors and established CHD risk factors, odds ratio for CHD for each standard deviation increase of log-SDA was 1.03 (95% CI: 0.90, 1.18). Corresponding values for log ALA and log-marine omega-3 FAs were 1.04 (95% CI: 0.94, 1.16) and 0.97 (95% CI: 0.88, 1.07), respectively.
In conclusion, our data did not show an association between red blood cell SDA, ALA, or marine omega-3 FAs and the risk of CHD in male physicians.
PMCID: PMC3657297  PMID: 23098619
Stearidonic acid (SDA); omega-3 fatty acids; alpha-linolenic acid (ALA); coronary heart disease
18.  Effect of different types of heat processing on chemical changes in tuna 
The chemical changes in skipjack tuna (Katsuwonus pelamis) subjected to cooking, frying, canning and microwave heating were studied. Raw tuna contained an unusual fatty acid C16:3 in high proportion (29.3%) followed by C18:2, C24:1, C16:0 and C18:3. Health beneficial fatty acids, eicosapentaenoic acid (EPA) (1.67%) and docosahexaenoic acid (DHA) (2.50%), were quite low with ω-3/ω-6 ratio 0.28. The total saturated fatty acids suffered major loss in fried (70%) and canned tuna (40%) due to loss of C16:0, C14:0 and C22:0. The monounsaturated fatty acids content increased (38%) in cooked and microwave heated tuna due to C24:1. The polyunsaturated fatty acids content increased in fried (50%) and canned (25%) tuna due to the uptake of frying and filling oil, respectively during processing. The loss of health beneficial ω-3 fatty acids, EPA and DHA were minimum in cooked tuna followed by microwave heated tuna. Canning totally destroyed these fatty acids. In fried tuna, the losses of EPA and DHA were 70 and 85%, respectively. Thiobarbituric acid — reactive substances values increased in heat processed tuna. Cholesterol increased in canned and microwave heated tuna but not in cooked tuna. Reduction of cholesterol in fried tuna was due to its migration into frying oil. This study indicated that cooking and microwave heating are the better processing methods to retain the health beneficial ω-3 fatty acids in comparison to frying and canning.
PMCID: PMC3550962  PMID: 23572621
Tuna; Katsuwonus pelamis; ω-3 Fatty acids; Thiobarbituric acid; Cholesterol; Thermal processing
19.  Mechanism of Growth Inhibition of Human Cancer Cells by Conjugated Eicosapentaenoic Acid, an Inhibitor of DNA Polymerase and Topoisomerase 
DNA topoisomerases (topos) and DNA polymerases (pols) are involved in many aspects of DNA metabolism such as replication reactions. We found that long chain unsaturated fatty acids such as polyunsaturated fatty acids (PUFA) (i.e., eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)) inhibited the activities of eukaryotic pols and topos in vitro, and the inhibitory effect of conjugated fatty acids converted from EPA and DHA (cEPA and cDHA) on pols and topos was stronger than that of normal EPA and DHA. cEPA and cDHA did not affect the activities of plant and prokaryotic pols or other DNA metabolic enzymes tested. cEPA was a stronger inhibitor than cDHA with IC50 values for mammalian pols and human topos of 11.0 – 31.8 and 0.5 – 2.5 μM, respectively. cEPA inhibited the proliferation of two human leukemia cell lines, NALM-6, which is a p53-wild type, and HL-60, which is a p53-null mutant, and the inhibitory effect was stronger than that of normal EPA. In both cell lines, cEPA arrested in the G1 phase, and increased cyclin E protein levels, indicating that it blocks the primary step of in vivo DNA replication by inhibiting the activity of replicative pols rather than topos. DNA replication-related proteins, such as RPA70, ATR and phosphorylated-Chk1/2, were increased by cEPA treatment in the cell lines, suggesting that cEPA led to DNA replication fork stress inhibiting the activities of pols and topos, and the ATR-dependent DNA damage response pathway could respond to the inhibitor of DNA replication. The compound induced cell apoptosis through both p53-dependent and p53-independent pathways in cell lines NALM-6 and HL-60, respectively. These results suggested the therapeutic potential of conjugated PUFA, such as cEPA, as a leading anti-cancer compound that inhibited pols and topos activities.
PMCID: PMC3871801
conjugated eicosapentaenoic acid (cEPA); DNA polymerase; DNA topoisomerase; enzyme inhibitor; DNA replication; cell proliferation; cell cycle arrest; p53; apoptosis
20.  Effects of Pure Eicosapentaenoic and Docosahexaenoic Acids on Oxidative Stress, Inflammation and Body Fat Mass in Patients with Type 2 Diabetes 
N-3 Fatty acids reduce the risk of cardiovascular disease. Previous studies have shown that they may reduce inflammation, oxidative stress, and fat mass in patients with type 2 diabetes, but the results are inconclusive, due, in part, to type of omega-3 fatty acids used. The aim of this study was to determine the effects of pure eicosapentaenoic (EPA) and docosahexaenoic acids (DHA), the two major omega-3 fatty acids, on inflammation, oxidative stress, and fat mass in patients with type 2 diabetes.
Sixty patients with DM-II were randomly allocated to receive daily either ~1 gr EPA or ~1 gr DHA, or a canola oil as placebo for 12 weeks in a randomized triple-blind, placebo-controlled trial. Serum MDA, CRP, body weight, BMI, and fat mass were measured at baseline and after intervention.
Forty-five patients with a mean (±SD) age of 54.9 ± 8.2 years with BMI of 27.6 ± 4.1 kg/m2 and fasting blood glucose 96.0 ± 16.2 mg/dl completed the intervention. Neither EPA nor DHA had significant effects on serum FBS, C-reactive protein, body weight, BMI, and fat mass after intervention (P > 0.05). In addition, while MDA increased 18% in the placebo group (P = 0.009), it did not change in the EPA or DHA group (P > 0.05).
Twelve weeks of supplementation with 1gr/d EPA or DHA prevent increasing oxidative stress without changing marker of inflammation. This study is the first report demonstrating that neither EPA nor DHA have effects on body fat mass in type 2 diabetic patients.
PMCID: PMC3775170  PMID: 24049619
Inflammation; omega 3 fatty acids; oxidative stress; type 2 diabetes mellitus
21.  Prescription n-3 Fatty Acids, But Not Eicosapentaenoic Acid Alone, Improve Reference Memory-Related Learning Ability by Increasing Brain-Derived Neurotrophic Factor Levels in SHR.Cg-Leprcp/NDmcr rats, A Metabolic Syndrome Model 
Neurochemical Research  2013;38:2124-2135.
Metabolic syndrome is implicated in the decline of cognitive ability. We investigated whether the prescription n-3 fatty acid administration improves cognitive learning ability in SHR.Cg-Leprcp/NDmcr (SHR-cp) rats, a metabolic syndrome model, in comparison with administration of eicosapentaenoic acid (EPA, C20:5, n-3) alone. Administration of TAK-085 [highly purified and concentrated n-3 fatty acid formulation containing EPA ethyl ester and docosahexaenoic acid (DHA, C22:6, n-3) ethyl ester] at 300 mg/kg body weight per day for 13 weeks reduced the number of reference memory-related errors in SHR-cp rats, but EPA alone had no effect, suggesting that long-term TAK-085 administration improves cognitive learning ability in a rat model of metabolic syndrome. However, the working memory-related errors were not affected in either of the rat groups. TAK-085 and EPA administration increased plasma EPA and DHA levels of SHR-cp rats, associating with an increase in EPA and DHA in the cerebral cortex. The TAK-085 administration decreased the lipid peroxide levels and reactive oxygen species in the cerebral cortex and hippocampus of SHR-cp rats, suggesting that TAK-085 increases antioxidative defenses. Its administration also increased the brain-derived neurotrophic factor levels in the cortical and hippocampal tissues of TAK-085-administered rats. The present study suggests that long-term TAK-085 administration is a possible therapeutic strategy for protecting against metabolic syndrome-induced learning decline.
PMCID: PMC3778907  PMID: 23963508
Metabolic syndrome; Memory; BDNF; Docosahexaenoic acid; Eicosapentaenoic acid
22.  DHA derivatives of fish oil as dietary supplements: a nutrition-based drug discovery approach for therapies to prevent metabolic cardiotoxicity 
Expert opinion on drug discovery  2012;7(8):711-721.
During the early 1970s, Danish physicians Jorn Dyerberg and colleagues observed that Greenland Eskimos consuming fatty fishes exhibited low incidences of heart disease. Fish oil is now one of the most commonly consumed dietary supplements. In 2004, concentrated fish oil was approved as a drug by the FDA for the treatment of hyperlipidemia. Fish oil contains two major omega-3 fatty acids: eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). With advancements in lipid concentration and purification techniques, EPA- or DHA-enriched products are now commercially available, and the availability of these components in isolation allows their individual effects to be examined. Newly synthesized derivatives and endogenously discovered metabolites of DHA exhibit therapeutic utility for obesity, metabolic syndrome and cardiovascular disease.
Areas covered
This review summarizes our current knowledge on the distinct effects of EPA and DHA to prevent metabolic syndrome and reduce cardiotoxicity risk. Since EPA is an integral component of fish oil, we will briefly review EPA effects, but our main theme will be to summarize effects of the DHA derivatives that are available today. We focus on using nutrition-based drug discovery to explore the potential of DHA derivatives for the treatment of obesity, metabolic syndrome and cardiovascular diseases.
Expert opinion
The safety and efficacy evaluation of DHA derivatives will provide novel biomolecules for the drug discovery arsenal. Novel nutritional-based drug discoveries of DHA derivatives or metabolites may provide realistic and alternative strategies for the treatment of metabolic and cardiovascular disease.
PMCID: PMC3969443  PMID: 22724444
cardiovascular disease; dietary supplement; docosahexaenoic acid; eicosapentaenoic acid; fish oil; metabolic syndrome; obesity
23.  Lipid content in hepatic and gonadal adipose tissue parallel aortic cholesterol accumulation in mice fed diets with different omega-6 PUFA to EPA plus DHA ratios 
Background & aims
Diets with low omega (ω)-6 polyunsaturated fatty acids (PUFA) to eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA) ratios have been shown to decrease aortic cholesterol accumulation and have been suggested to promote weight loss. The involvement of the liver and gonadal adipose tissue (GAT) in mediating these effects is not well understood. LDL receptor null mice were used to assess the effect of an atherogenic diet with different ω-6:EPA+DHA ratios on weight gain, hepatic and GAT lipid accumulation, and their relationship to atherosclerosis.
Four groups of mice were fed a high saturated fat and cholesterol diet (HSF ω-6) alone, or with ω-6 PUFA to EPA+DHA ratios up to 1:1 for 32 weeks. Liver and GAT were collected for lipid and gene expression analysis.
The fatty acid profile of liver and GAT reflected the diets. All diets resulted in similar weight gains. Compared to HSF ω-6 diet, the 1:1 ratio diet resulted in lower hepatic total cholesterol (TC) content. Aortic TC was positively correlated with hepatic and GAT TC and triglyceride. These differences were accompanied by significantly lower expression of CD36, ATP-transporter cassette A1, scavenger receptor B class 1, 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), acetyl-CoA carboxylase alpha, acyl-CoA synthetase long-chain family member 5, and stearoyl-coenzyme A desaturase 1 (SCD1) in GAT, and HMGCR, SCD1 and cytochrome P450 7A1 in liver.
Dietary ω-6:EPA+DHA ratios did not affect body weight, but lower ω-6:EPA+DHA ratio diets decreased liver lipid accumulation, which possibly contributed to the lower aortic cholesterol accumulation.
PMCID: PMC4005276  PMID: 23672804
Atherosclerosis; Liver; Gonadal adipose tissue; Fatty acids; Lipid metabolism; Omega-3 fatty acids
24.  Metabolic Effects of n-3 PUFA as Phospholipids Are Superior to Triglycerides in Mice Fed a High-Fat Diet: Possible Role of Endocannabinoids 
PLoS ONE  2012;7(6):e38834.
n-3 polyunsaturated fatty acids, namely docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), reduce the risk of cardiovascular disease and can ameliorate many of obesity-associated disorders. We hypothesised that the latter effect will be more pronounced when DHA/EPA is supplemented as phospholipids rather than as triglycerides.
Methodology/Principal Findings
In a ‘prevention study’, C57BL/6J mice were fed for 9 weeks on either a corn oil-based high-fat obesogenic diet (cHF; lipids ∼35% wt/wt), or cHF-based diets in which corn oil was partially replaced by DHA/EPA, admixed either as phospholipids or triglycerides from marine fish. The reversal of obesity was studied in mice subjected to the preceding cHF-feeding for 4 months. DHA/EPA administered as phospholipids prevented glucose intolerance and tended to reduce obesity better than triglycerides. Lipemia and hepatosteatosis were suppressed more in response to dietary phospholipids, in correlation with better bioavailability of DHA and EPA, and a higher DHA accumulation in the liver, white adipose tissue (WAT), and muscle phospholipids. In dietary obese mice, both DHA/EPA concentrates prevented a further weight gain, reduced plasma lipid levels to a similar extent, and tended to improve glucose tolerance. Importantly, only the phospholipid form reduced plasma insulin and adipocyte hypertrophy, while being more effective in reducing hepatic steatosis and low-grade inflammation of WAT. These beneficial effects were correlated with changes of endocannabinoid metabolome in WAT, where phospholipids reduced 2-arachidonoylglycerol, and were more effective in increasing anti-inflammatory lipids such as N-docosahexaenoylethanolamine.
Compared with triglycerides, dietary DHA/EPA administered as phospholipids are superior in preserving a healthy metabolic profile under obesogenic conditions, possibly reflecting better bioavalability and improved modulation of the endocannabinoid system activity in WAT.
PMCID: PMC3372498  PMID: 22701720
25.  Fish oil and krill oil supplementations differentially regulate lipid catabolic and synthetic pathways in mice 
Marine derived oils are rich in long-chain polyunsaturated omega-3 fatty acids, in particular eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which have long been associated with health promoting effects such as reduced plasma lipid levels and anti-inflammatory effects. Krill oil (KO) is a novel marine oil on the market and is also rich in EPA and DHA, but the fatty acids are incorporated mainly into phospholipids (PLs) rather than triacylglycerols (TAG). This study compares the effects of fish oil (FO) and KO on gene regulation that influences plasma and liver lipids in a high fat diet mouse model.
Male C57BL/6J mice were fed either a high-fat diet (HF) containing 24% (wt/wt) fat (21.3% lard and 2.3% soy oil), or the HF diet supplemented with FO (15.7% lard, 2.3% soy oil and 5.8% FO) or KO (15.6% lard, 2.3% soy oil and 5.7% KO) for 6 weeks. Total levels of cholesterol, TAG, PLs, and fatty acid composition were measured in plasma and liver. Gene regulation was investigated using quantitative PCR in liver and intestinal epithelium.
Plasma cholesterol (esterified and unesterified), TAG and PLs were significantly decreased with FO. Analysis of the plasma lipoprotein particles indicated that the lipid lowering effect by FO is at least in part due to decreased very low density lipoprotein (VLDL) content in plasma with subsequent liver lipid accumulation. KO lowered plasma non-esterified fatty acids (NEFA) with a minor effect on fatty acid accumulation in the liver. In spite of a lower omega-3 fatty acid content in the KO supplemented diet, plasma and liver PLs omega-3 levels were similar in the two groups, indicating a higher bioavailability of omega-3 fatty acids from KO. KO more efficiently decreased arachidonic acid and its elongation/desaturation products in plasma and liver. FO mainly increased the expression of several genes involved in fatty acid metabolism, while KO specifically decreased the expression of genes involved in the early steps of isoprenoid/cholesterol and lipid synthesis.
The data show that both FO and KO promote lowering of plasma lipids and regulate lipid homeostasis, but with different efficiency and partially via different mechanisms.
PMCID: PMC4021563  PMID: 24834104
Omega-3 fatty acids; Plasma lipids; High-fat diet; Gene regulation; Krill oil

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