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1.  Plasma Phospholipid Fatty Acid Concentration and Incident Coronary Heart Disease in Men and Women: The EPIC-Norfolk Prospective Study 
PLoS Medicine  2012;9(7):e1001255.
Kay-Tee Khaw and colleagues analyze data from a prospective cohort study and show associations between plasma concentrations of saturated phospholipid fatty acids and risk of coronary heart disease, and an inverse association between omega-6 polyunsaturated phospholipid fatty acids and risk of coronary heart disease.
Background
The lack of association found in several cohort studies between dietary saturated fat and coronary heart disease (CHD) risk has renewed debate over the link between dietary fats and CHD.
Methods and Findings
We assessed the relationship between plasma phospholipid fatty acid (PFA) concentration and incident CHD using a nested case control design within a prospective study (EPIC-Norfolk) of 25,639 individuals aged 40–79 years examined in 1993–1997 and followed up to 2009. Plasma PFA concentrations were measured by gas chromatography in baseline samples retrieved from frozen storage. In 2,424 men and women with incident CHD compared with 4,930 controls alive and free of cardiovascular disease, mean follow-up 13 years, saturated PFA (14:0, 16:0,18:0) plasma concentrations were significantly associated with increased CHD risk (odds ratio [OR] 1.75, 95% CI 1.27–2.41, p<0.0001), in top compared to bottom quartiles (Q), and omega-6 polyunsaturated PFA concentrations were inversely related (OR 0.77, 0.60–0.99, p<0.05) after adjusting for age, sex, body mass index, blood pressure, smoking, alcohol intake, plasma vitamin C, social class, education, and other PFAs. Monounsaturated PFA, omega-3 PFA, and trans PFA concentrations were not significantly associated with CHD. Odd chain PFA (15:0, 17:0) concentrations were significantly inversely associated with CHD (OR 0.73, 0.59–0.91, p<0.001, Q4 versus Q1). Within families of saturated PFA or polyunsaturated PFA, significantly heterogeneous relationships with CHD were observed for individual fatty acids.
Conclusions
In this study, plasma concentrations of even chain saturated PFA were found to be positively and omega-6 polyunsaturated PFA inversely related to subsequent coronary heart disease risk. These findings are consistent with accumulating evidence suggesting a protective role of omega-6 fats substituting for saturated fats for CHD prevention.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Coronary heart disease (CHD) is a condition caused by a build-up of fatty deposits on the inner walls of the blood vessels that supply the heart, causing the affected person to experience pain, usually on exertion (angina). A complete occlusion of the vessel by deposits causes a heart attack (myocardial infarction). Lifestyle factors, such as diet (particularly one high in fat), contribute to causing CHD. There are different types of fat, some of which are thought to increase risk of CHD, such as saturated fat, typically found in meat and dairy foods. However, others, such as unsaturated fats (polyunsaturated and monounsaturated fats) found in foods such as vegetable oils, fish, and nuts, may actually help prevent this condition.
Why Was This Study Done?
Although there have been many studies investigating the role of different types of dietary fat in coronary heart disease, it is still not clear whether coronary heart disease can be prevented by changing the type of dietary fat consumed from saturated to unsaturated fats or by lowering all types of dietary fat. Furthermore, many of these studies have relied on participants recalling their dietary intake in questionnaires, which is an unreliable method for different fats. So in this study, the researchers used an established UK cohort to measure the levels of different types of fatty acids in blood to investigate whether a diet high in saturated fatty acids and low in unsaturated fatty acids increases CHD risk.
What Did the Researchers Do and Find?
The researchers used a selection of 10,000 participants (all men and women aged 40–79 years) from the prospective European Prospective Investigation into Cancer (EPIC)-Norfolk cohort. Blood samples from the selected participants taken at the start of the study in 1993–1997 were analyzed to determine levels of specific fatty acids. Participants were followed up till 2011. The researchers identified 2,424 participants who were subsequently diagnosed with CHD using death certificates and hospital discharge data and matched these with 4,930 controls who were still alive and free of known coronary disease. The researchers grouped the type of blood fatty acids identified in the blood samples into six families (even chain saturated fatty acid, odd chain saturated fatty acid, omega-6 polyunsaturated fatty acid, omega-3 polyunsaturated fatty acid, monounsaturated fatty acid, and trans-fatty acid), which represented saturated and unsaturated fatty acids. Using statistical methods, the researchers then compared the risks of developing CHD between cases and controls by the concentration of fatty acid families after adjusting for age and sex and other factors, such as body mass index, physical activity, and smoking. Using these methods, the researchers found that there was no overall significant relationship between total blood fatty acid concentration and CHD but there was a positive association with increasing blood saturated fatty acid concentration after adjusting for other fatty acid concentrations, with an odds ratio of 1.83 comparing higher versus lower concentrations. This risk was attenuated after adjusting for cholesterol levels, indicating that much of the association between saturated fatty acid and CHD is likely to be mediated through blood cholesterol levels. In contrast, blood omega-6 poly-unsaturated fatty acid concentrations were associated with lower CHD risk. Blood monounsaturated fatty acids, omega-3 poly-unsaturated fatty acids, and trans-fatty acids were not consistently associated with CHD risk. The authors also noted that within families of fatty acids, individual fatty acids related differently to CHD risk.
What Do These Findings Mean?
These findings suggest that plasma concentrations of saturated fatty acids are associated with increased risk of CHD and that concentrations of omega-6 poly-unsaturated fatty acids are associated with decreased risk of CHD. These findings are consistent with other studies and with current dietary advice for preventing CHD, which encourages substituting foods high in saturated fat with n-6 polyunsaturated fats. The results also suggest that different fatty acids may relate differently to CHD risk and that the overall balance between different fatty acids is important. However, there are limitations to this study, such as that factors other than diet (genetic differences in metabolism, for example) may cause changes to blood fatty acid levels so a major question is to identify what factors influence blood fatty acid concentrations. Nevertheless, these findings suggest that individual fatty acids play a role in increasing or decreasing risks of CHD.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001255.
Information about the EPIC-Norfolk study is available
The American Heart Foundation provides patient-friendly information about different dietary fats as does Medline
The British Heart Foundation also provides patient-friendly information on heart conditions
doi:10.1371/journal.pmed.1001255
PMCID: PMC3389034  PMID: 22802735
2.  Dietary Omega-3 Fatty Acids, Other Fat Intake, Genetic Susceptibility and Progression to Incident Geographic Atrophy 
Ophthalmology  2013;120(5):1020-1028.
Objective
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).
Design
Observational analysis of a prospective cohort.
Participants
2531 individuals from the Age-Related Eye Disease Study, among which 525 eyes progressed to GA and 4165 eyes did not.
Methods
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.
Results
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).
Conclusions
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.
doi:10.1016/j.ophtha.2012.10.020
PMCID: PMC3758110  PMID: 23481534
3.  Effect of Physical Inactivity on the Oxidation of Saturated and Monounsaturated Dietary Fatty Acids: Results of a Randomized Trial  
PLoS Clinical Trials  2006;1(5):e27.
Objectives:
Changes in the way dietary fat is metabolized can be considered causative in obesity. The role of sedentary behavior in this defect has not been determined. We hypothesized that physical inactivity partitions dietary fats toward storage and that a resistance exercise training program mitigates storage.
Design:
We used bed rest, with randomization to resistance training, as a model of physical inactivity.
Setting:
The trial took place at the Space Clinic (Toulouse, France).
Participants:
A total of 18 healthy male volunteers, of mean age ± standard deviation 32.6 ± 4.0 y and body mass index 23.6 ± 0.7 kg/m2, were enrolled.
Interventions:
An initial 15 d of baseline data collection were followed by 3 mo of strict bed-rest alone (control group, n = 9) or with the addition of supine resistance exercise training every 3 d (exercise group, n = 9).
Outcome measures:
Oxidation of labeled [d31]palmitate (the main saturated fatty acid of human diet) and [1-13C]oleate (the main monounsaturated fatty acid), body composition, net substrate use, and plasma hormones and metabolites were measured.
Results:
Between-group comparisons showed that exercise training did not affect oxidation of both oleate (mean difference 5.6%; 95% confidence interval [95% CI], −3.3% to 14.5%; p = 0.20) and palmitate (mean difference −0.2%; 95% CI, −4.1% to 3.6%; p = 0.89). Within-group comparisons, however, showed that inactivity changed oxidation of palmitate in the control group by −11.0% (95% CI, −19.0% to −2.9%; p = 0.01) and in the exercise group by −11.3% (95% CI, −18.4% to −4.2%; p = 0.008). In contrast, bed rest did not significantly affect oleate oxidation within groups. In the control group, the mean difference in oleate oxidation was 3.2% (95% CI, −4.2% to 10.5%; p = 0.34) and 6.8% (95% CI, −1.2% to 14.7%; p = 0.08) in the exercise group.
Conclusions:
Independent of changes in energy balance (intake and/or output), physical inactivity decreased the oxidation of saturated but not monounsaturated dietary fat. The effect is apparently not compensated by resistance exercise training. These results suggest that Mediterranean diets should be recommended in sedentary subjects and recumbent patients.
Editorial Commentary
Background: Obesity is an important contributor to the burden of chronic diseases, particularly type II diabetes, cardiovascular disease, hypertension, and stroke. Being inactive is a risk factor for all of these conditions. However, the physiological effects of inactivity are not well understood. In this trial, supported by the European Space Agency, a group of researchers aimed to further understand the effects of physical inactivity on the way that fat from the diet is metabolized (i.e., broken down to generate energy). 18 healthy male volunteers were randomized into two groups, both of whom underwent 90 days of bed rest, aiming to mimic sedentary behavior. One group also received an exercise training program during the 90 days' bed rest. The researchers examined to what extent two different types of fatty acids common in the diet were metabolized over the duration of the trial: oleate (monounsaturated fat) and palmitate (saturated fat). As secondary objectives of the study, body weight, water, fat, and energy expenditure were also examined in the participants.
What this trial shows: The researchers did not see any statistically significant changes between the groups—that is, participants receiving bed rest, and those receiving bed rest plus exercise training—for any of the primary or secondary outcomes, except for resting metabolic rate, which was higher in the exercise group. However, they did see physiologically relevant changes in fat metabolism of one of the fatty acids, palmitate, over the course of the trial within both groups studied. Although metabolism of oleate (monounsaturated fat) did not show significant changes over the course of the trial, metabolism of palmitate (saturated fat) dropped by nearly 10% in both groups (bed rest, and bed rest plus exercise).
Strengths and limitations: The study design was appropriate to the questions being posed, and the techniques for examining fat metabolism were relevant. Although the number of participants was very small, this problem is true of many such studies due to the cost and complexity of the interventions. The model for inactivity used in this trial—90 days' bed rest—is very extreme. Very few studies of this type have been performed, with most of the evidence relating to activity and fat handling coming from training studies in otherwise sedentary people.
Contribution to the evidence: It is already known that physical activity has numerous health benefits, including the prevention of obesity. This trial provides data showing that inactivity lowers the ability to metabolize fat, specifically saturated fat, from the diet, which would therefore be more likely to be stored in the body.
doi:10.1371/journal.pctr.0010027
PMCID: PMC1584255  PMID: 17016547
4.  Postprandial enrichment of triacylglycerol-rich lipoproteins with omega-3 fatty acids: lack of an interaction with apolipoprotein E genotype? 
Background
We have previously demonstrated that carrying the apolipoprotein (apo) E epsilon 4 (E4+) genotype disrupts omega-3 fatty acids (n − 3 PUFA) metabolism. Here we hypothesise that the postprandial clearance of n − 3 PUFA from the circulation is faster in E4+ compared to non-carriers (E4−). The objective of the study was to investigate the fasted and postprandial fatty acid (FA) profile of triacylglycerol-rich lipoprotein (TRL) fractions: Sf >400 (predominately chylomicron CM), Sf 60 − 400 (VLDL1), and Sf 20 − 60 (VLDL2) according to APOE genotype.
Methods
Postprandial TRL fractions were obtained in 11 E4+ (ϵ3/ϵ4) and 12 E4− (ϵ3/ϵ3) male from the SATgenϵ study following high saturated fat diet + 3.45 g/d of docosahexaenoic acid (DHA) for 8-wk. Blood samples were taken at fasting and 5-h after consuming a test-meal representative of the dietary intervention. FA were characterized by gas chromatography.
Results
At fasting, there was a 2-fold higher ratio of eicosapentaenoic acid (EPA) to arachidonic acid (P = 0.046) as well as a trend towards higher relative% of EPA (P = 0.063) in the Sf >400 fraction of E4+. Total n − 3 PUFA in the Sf 60 − 400 and Sf 20 − 60 fractions were not APOE genotype dependant. At 5 h, there was a trend towards a time × genotype interaction (P = 0.081) for EPA in the Sf >400 fraction. When sub-groups were form based on the level of EPA at baseline within the Sf >400 fraction, postprandial EPA (%) was significantly reduced only in the high-EPA group. EPA at baseline significantly predicted the postprandial response in EPA only in E4+ subjects (R2 = 0.816).
Conclusion
Despite the DHA supplement contain very low levels of EPA, E4+ subjects with high EPA at fasting potentially have disrupted postprandial n − 3 PUFA metabolism after receiving a high-dose of DHA.
Trial registration
Registered at clinicaltrials.gov/show/NCT01544855.
doi:10.1186/1476-511X-13-148
PMCID: PMC4177609  PMID: 25227179
APOE4 carriers; Chylomicrons; n − 3 PUFA metabolism; VLDL; Fish-oil supplementation; Postprandial lipemia
5.  Eicosapentaenoic acid-enriched phospholipid ameliorates insulin resistance and lipid metabolism in diet-induced-obese mice 
Background
Over the past two decades, a striking increase in the number of people with metabolic syndrome (MS) has taken place worldwide. With the elevated risk of not only diabetes but also cardiovascular morbidity and mortality, there is urgent need for strategies to prevent this emerging global epidemic. The present study was undertaken to investigate the effects of dietary eicosapentaenoic acid-enriched phospholipid (EPA-PL) on metabolic disorders.
Methods
Male C57BL/6J mice (n = 7) were fed one of the following 4 diets for a period of 4 weeks: 1) a modified AIN-96G diet with 5% corn oil (control diet); 2) a high fat (20%, wt/wt) and high fructose (20%, wt/wt) diet (HF diet); 3) the HF diet containing 1% SOY-PL (SOY-PL diet); 4) the HF diet containing 1% EPA-PL (EPA-PL diet). The oral glucose tolerance test was performed. Plasma TG, TC, glucose, NEFA, insulin, leptin, adiponectin, TNF-α and IL-6 levels were assessed. In addition, hepatic lipid levels, lipogenic, and lipidolytic enzyme activities and gene expressions were evaluated.
Results
Both EPA-PL and SOY-PL significantly inhibited body weight gain and white adipose tissue accumulation, alleviated glucose intolerance, and lowered both serum fasting glucose and NEFA levels substantially. Only EPA-PL significantly reduced serum TNF-α and IL-6 levels, and increased serum adiponectin level. EPA-PL was more effective in reducing hepatic and serum TG and TC levels than SOY-PL. Both EPA-PL and SOY-PL reduced the activities of hepatic lipogenic enzymes, such as FAS and G6PDH, but only EPA-PL significantly increased CPT, peroxisomal β-oxidation enzymes activities and CPT-1a mRNA level. Alterations of hepatic lipogenic gene expressions, such as FAS, G6PDH, ACC, SCD-1 and SREBP-1c were consistent with changes in related enzyme activities.
Conclusions
According to our study, EPA-PL supplementation was efficacious in suppressing body fat accumulation, and alleviating insulin resistance and hepatic steatosis by modulating the secretion of adipocytokines and inflammatory cytokines, suppression of SREBP-1c mediated lipogenesis and enhancement of fatty acid β-oxidation. These results demonstrate that EPA-PL is a novel beneficial food component for the prevention and improvement of metabolic disorders.
doi:10.1186/1476-511X-12-109
PMCID: PMC3728066  PMID: 23876229
Eicosapentaenoic acid; Phospholipid; Metabolic syndrome; Obesity; Insulin resistance; Lipid metabolism
6.  The role of Odontella aurita, a marine diatom rich in EPA, as a dietary supplement in dyslipidemia, platelet function and oxidative stress in high-fat fed rats 
Background
Dietary changes are a major factor in determining cardiovascular risk. n-3 polyunsaturated fatty acids modulate the risk factors for metabolic syndrome via multiple mechanisms, including the regulation of the lipid metabolism. We therefore investigated the effect of Odontella aurita, a microalga rich in EPA, which is already used as a food supplement, on the risk factors for high-fat diet induced metabolic syndrome in rats.
Methods
Male Wistar rats were divided into 4 groups and were fed with a standard diet (control); with the standard diet supplemented with 3% freeze-dried O. aurita (COA); with a high-fat diet (HF); or with the high-fat diet supplemented with 3% of freeze-dried O. aurita (HFOA) for 7 weeks. In this study we evaluated the impact of these different diets on the risk factors for metabolic syndrome, such as hyperlipidemia, platelet aggregation, thromboxane B2 production, and oxidative stress.
Results
After 7 weeks of treatment, high fat feeding had increased final body weight, glycemia, triacylglycerol, and total cholesterol levels in plasma and liver compared to the control diet. Collagen-induced platelet aggregation and basal platelet thromboxane B2 were also higher in the high-fat fed rats than in those in the control group. In the liver, oxidative stress was greater in the HF group than in the control group. O. aurita intake in HFOA-fed rats resulted in lower glycemia and lipid levels in the plasma and liver relative than in the HF group. Thus, in the HFOA group, n-3 polyunsaturated fatty acid levels in the tissues studied (plasma, liver, and platelets) were higher than in the HF group. Platelet hyper-aggregability tended to decrease in HFOA-fed rats as basal platelet thromboxane B2 production decreased. Finally, O. aurita reduced oxidative stress in the liver, with lower malondialdehyde levels and increased glutathione peroxidase activity.
Conclusions
O. aurita is a marine diatom rich in EPA as well as in other bioactive molecules, such as pigments. The synergistic effect of these microalgal compounds, displayed a beneficial effect in reducing the risk factors for high-fat induced metabolic syndrome: hyperlipidemia, platelet aggregation, and oxidative stress.
doi:10.1186/1476-511X-11-147
PMCID: PMC3543224  PMID: 23110391
Odontella aurita; n-3 PUFA; Platelet aggregation; Metabolic syndrome; Oxidative stress
7.  A Taiwanese food frequency questionnaire correlates with plasma docosahexaenoic acid but not with plasma eicosapentaenoic acid levels: questionnaires and plasma biomarkers 
Background
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.
Methods
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.
Results
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).
Conclusions
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.
doi:10.1186/1471-2288-13-23
PMCID: PMC3598308  PMID: 23414574
N-3 fatty acid; Biomarker; Food frequency questionnaire
8.  Eicosapentaenoic Acid and Docosahexaenoic Acid in Whole Blood Are Differentially and Sex-Specifically Associated with Cardiometabolic Risk Markers in 8–11-Year-Old Danish Children 
PLoS ONE  2014;9(10):e109368.
n-3 long-chain polyunsaturated fatty acids improve cardiovascular risk markers in adults. These effects may differ between eicosapentaenoic acid (EPA, 20∶5n-3) and docosahexaenoic acid (DHA, 22∶6n-3), but we lack evidence in children. Using baseline data from the OPUS School Meal Study we 1) investigated associations between EPA and DHA in whole blood and early cardiometabolic risk markers in 713 children aged 8–11 years and 2) explored potential mediation through waist circumference and physical activity and potential dietary confounding. We collected data on parental education, pubertal stage, 7-day dietary records, physical activity by accelerometry and measured anthropometry, blood pressure, and heart rate. Blood samples were analyzed for whole blood fatty acid composition, cholesterols, triacylglycerol, insulin resistance by the homeostatic model of assessment (HOMA-IR), and inflammatory markers. Whole blood EPA was associated with a 2.7 mmHg (95% CI 0.4; 5.1) higher diastolic blood pressure per weight% EPA, but only in boys. Heart rate was negatively associated with both EPA and DHA status (P = 0.02 and P = 0.002, respectively). Whole blood EPA was negatively associated with triacylglycerol (P = 0.003) and positively with total cholesterol, low density and high density lipoprotein (HDL) cholesterol and HDL:triacylglycerol (all P<0.01) whereas DHA was negatively associated with insulin and HOMA-IR (P = 0.003) and tended to be negatively associated with a metabolic syndrome-score (P = 0.05). Adjustment for waist circumference and physical activity did not change the associations. The association between DHA and HOMA-IR was attenuated but remained after adjustment for fiber intake and none of the other associations were confounded by dietary fat, protein, fiber or energy intake. This study showed that EPA status was negatively associated with triacylglycerol and positively with cholesterols whereas DHA was negatively associated with insulin resistance, and both were inversely associated with heart rate in children. The sex-specific associations with blood pressure confirm our previous findings and warrant further investigation.
doi:10.1371/journal.pone.0109368
PMCID: PMC4198100  PMID: 25330302
9.  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 
Background
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1186/1476-511X-12-102
PMCID: PMC3718725  PMID: 23855409
Omega-3; Eicosapentaenoic acid; Docosahexaenoic acid; Algal oil; Krill oil; Polar lipids; Glycolipids; Phospholipids
10.  Low serum eicosapentaenoic acid / arachidonic acid ratio in male subjects with visceral obesity 
Background
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.
Findings
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).
Conclusions
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
UMIN000002271
doi:10.1186/1743-7075-10-25
PMCID: PMC3606329  PMID: 23497138
Arachidonic acid; Eicosapentaenoic acid; Docosahexaenoic acid; Visceral fat; Metabolic syndrome; Obesity
11.  Effects of EPA supplementation on plasma fatty acids composition in hypertriglyceridemic subjects with FABP2 and PPARα genotypes 
Background
Fatty acid binding protein 2 (FABP2) and peroxisome proliferator-activated receptor α (PPARα) are involved in cellular uptake and metabolism of fatty acids. Polymorphism of FABP2 and PPARα may influence plasma levels of fatty acids in those who take supplemental eicosapentaenoic acid (EPA). The purpose of this study was to study the potential associations between the Ala54/Thr polymorphism in FABP2 protein and the Leu162/Val in exon 5 and G/C in intron 7 of PPARα with plasma fatty acids composition after EPA supplementation.
Methods
Twenty three FABP2 Ala54 and twenty three Thr54 carriers with hypertriglyceridemia were enrolled in this study. Participants took 2 g of pure EPA daily for 8 wks. Plasma fatty acids composition was determined and changes from the baseline were measured.
Results
Although EPA supplementation increased the level of plasma EPA and ω-3 fatty acids in both carriers of FABP2 and PPARα genes, these effects were more pronounced in Thr54 and Val162 carriers. EPA supplementation decreased the level of some n-6 fatty acids such as arachidonic acid.
Conclusion
EPA consumption has more favorable effects on blood n-3 fatty acids and can change the level of plasma n-3 fatty acids, particularly EPA. Because the FABP2 Thr54 polymorphism appears to be prevalent in hypertriglyceridemic subjects, increasing EPA intake in these subjects could be an effective strategy for preventing cardiovascular diseases. Finally, diets and micronutrient recommendations should be individualized for high risk people.
doi:10.1186/2251-6581-11-25
PMCID: PMC3620558  PMID: 23497599
Plasma fatty acids composition; Eicosapentaenoic acid; Polymorphism; Fatty acid binding protein-2; Peroxisome proliferator-activated receptor
12.  Antiobesity Effect of Eicosapentaenoic Acid in High-Fat/High-Sucrose Diet–Induced Obesity 
Diabetes  2010;59(10):2495-2504.
OBJECTIVE
Given the pleiotropic effect of eicosapentaenoic acid (EPA), it is interesting to know whether EPA is capable of improving obesity. Here we examined the anti-obesity effect of EPA in mice with two distinct models of obesity.
RESEARCH DESIGN AND METHODS
Male C57BL/6J mice were fed a high-fat/high-sucrose diet (25.0% [w/w] fat, 32.5% [w/w] sucrose) (HF/HS group) or a high-fat diet (38.1% [w/w] fat, 8.5% [w/w] sucrose) (HF group) for 4–20 weeks. A total of 5% EPA was administered by partially substituting EPA for fat in the HF/HS + EPA and HF + EPA groups.
RESULTS
Both the HF/HS and HF groups similarly developed obesity. EPA treatment strongly suppresses body weight gain and obesity-related hyperglycemia and hyperinsulinemia in HF/HS-fed mice (HF/HS + EPA group), where hepatic triglyceride content and lipogenic enzymes are increased. There is no appreciable effect of EPA on body weight in HF-fed mice (HF + EPA group) without enhanced expression of hepatic lipogenic enzymes. Moreover, EPA is capable of reducing hepatic triglyceride secretion and changing VLDL fatty acid composition in the HF/HS group. By indirect calorimetry analysis, we also found that EPA is capable of increasing energy consumption in the HF/HS + EPA group.
CONCLUSIONS
This study is the first demonstration that the anti-obesity effect of EPA in HF/HS-induced obesity is associated with the suppression of hepatic lipogenesis and steatosis. Because the metabolic syndrome is often associated with hepatic lipogenesis and steatosis, the data suggest that EPA is suited for treatment of the metabolic syndrome.
doi:10.2337/db09-1554
PMCID: PMC3279525  PMID: 20682690
13.  Effects of Step-Wise Increases in Dietary Carbohydrate on Circulating Saturated Fatty Acids and Palmitoleic Acid in Adults with Metabolic Syndrome 
PLoS ONE  2014;9(11):e113605.
Recent meta-analyses have found no association between heart disease and dietary saturated fat; however, higher proportions of plasma saturated fatty acids (SFA) predict greater risk for developing type-2 diabetes and heart disease. These observations suggest a disconnect between dietary saturated fat and plasma SFA, but few controlled feeding studies have specifically examined how varying saturated fat intake across a broad range affects circulating SFA levels. Sixteen adults with metabolic syndrome (age 44.9±9.9 yr, BMI 37.9±6.3 kg/m2) were fed six 3-wk diets that progressively increased carbohydrate (from 47 to 346 g/day) with concomitant decreases in total and saturated fat. Despite a distinct increase in saturated fat intake from baseline to the low-carbohydrate diet (46 to 84 g/day), and then a gradual decrease in saturated fat to 32 g/day at the highest carbohydrate phase, there were no significant changes in the proportion of total SFA in any plasma lipid fractions. Whereas plasma saturated fat remained relatively stable, the proportion of palmitoleic acid in plasma triglyceride and cholesteryl ester was significantly and uniformly reduced as carbohydrate intake decreased, and then gradually increased as dietary carbohydrate was re-introduced. The results show that dietary and plasma saturated fat are not related, and that increasing dietary carbohydrate across a range of intakes promotes incremental increases in plasma palmitoleic acid, a biomarker consistently associated with adverse health outcomes.
doi:10.1371/journal.pone.0113605
PMCID: PMC4240601  PMID: 25415333
14.  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.
doi:10.1080/01635581.2012.718033
PMCID: PMC3633593  PMID: 23137008
15.  Dietary intakes and food sources of fat and fatty acids in Guatemalan schoolchildren: A cross-sectional study 
Nutrition Journal  2010;9:20.
Background
Consumption of healthy diets that contribute with adequate amounts of fat and fatty acids is needed for children. Among Guatemalan children, there is little information about fat intakes. Therefore, the present study sought to assess intakes of dietary fats and examine food sources of those fats in Guatemalan children.
Methods
The study subjects consisted of a convenience sample of 449 third- and fourth-grade schoolchildren (8-10 y), attending public or private schools in Quetzaltenango City, Guatemala. Dietary data was obtained by means of a single pictorial 24-h record.
Results
The percentages of total energy (%E) from total fat, saturated fat (SFA) and monounsaturated fat (MUFA) reached 29%E for total fat and 10%E for each SFA and MUFA, without gender differences. %E from fats in high vs. low-socio economic status (SES) children were significantly higher for boys, but not for girls, for total fat (p = 0.002) and SFA (p < 0.001). Large proportions of the children had low levels of intakes of some fatty acids (FA), particularly for n-3 FA, with >97% of all groups consuming less than 1%E from this fats. Fried eggs, sweet rolls, whole milk and cheese were main sources of total fat and, SFA. Whole milk and sweet bread were important sources of n-3 FA for high- and low-SES boys and girls, respectively. Fried plantain was the main source of n-3 FA for girls in the high-SES group. Fried fish, seafood soup, and shrimp, consumed only by boys in low amounts, were sources of eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids, which may explain the low intakes of these nutrients.
Conclusions
α-linolenic acid, EPA and DHA were the most limiting fatty acids in diets of Guatemalan schoolchildren, which could be partially explained by the low consumption of sources of these nutrients, particularly fish and seafood (for EPA and DHA). This population will benefit from a higher consumption of culturally acceptable foods that are rich in these limiting nutrients.
doi:10.1186/1475-2891-9-20
PMCID: PMC2868781  PMID: 20416064
16.  Plasma Phospholipid Long-Chain Omega-3 Fatty Acids and Total and Cause-Specific Mortality in Older Adults: the Cardiovascular Health Study 
Annals of internal medicine  2013;158(7):515-525.
Background
Long-chain n-3 polyunsaturated fatty acids (n3-PUFA), including eicosapentaenoic acid (EPA/20:5n-3), docosapentaenoic acid (DPA/22:5n-3), and docosahexaenoic acid (DHA/22:6n-3), experimentally reduce cardiovascular risk. Yet, effects on cause-specific and total mortality and potential dose-responses remain controversial. Most observational studies have assessed self-reported dietary intakes, rather than objective biomarkers; while most randomized trials have tested effects of adding supplements to background dietary intake and evaluated secondary prevention, limiting inference for dietary n3-PUFA or primary prevention.
Objective
We investigated associations of plasma phospholipid EPA, DPA, DHA, and total n-3 PUFA with total and cause-specific mortality among generally healthy older adults not taking fish oil supplements.
Design
Prospective cohort, 1992–2008.
Setting
Four U.S. communities.
Participants
2,692 U.S. adults age 75±5 years, free of prevalent coronary heart disease (CHD), stroke, or heart failure.
Measurements
Phospholipid fatty acids and cardiovascular risk factors were measured in 1992 using standardized methods. Relationships with total and cause-specific mortality through 2008, and incident total (fatal+nonfatal) CHD and stroke, were assessed using Cox proportional-hazards.
Results
During 30,829 person-years, 1,625 deaths (including 570 cardiovascular deaths), 359 fatal and 371 nonfatal CHD events, and 130 fatal and 276 nonfatal strokes occurred. After multivariable-adjustment, n3-PUFA biomarkers associated with lower total mortality, with extreme-quintile hazard ratios (95% CI) of 0.83 for EPA (0.71–0.98), 0.77 for DPA (0.66–0.90), 0.80 for DHA (0.67–0.94), and 0.73 for total n3-PUFA (0.61–0.86) (P-trend≤0.008 each). Lower risk was largely attributable to fewer cardiovascular, rather than noncardiovascular, deaths, in particular fewer arrhythmic cardiac deaths (total n3-PUFA: hazard ratio=0.52, 95%CI=0.31–0.86; P-trend=0.008). Based on relations with total mortality, individuals in the highest quintile of phospholipid n3-PUFA, versus the lowest, experienced 2.22 greater years of life (95%CI=0.75–3.13) after age 65.
Limitations
Temporal changes in fatty acid levels and misclassification of death causes may cause underestimated associations; and unmeasured/imperfectly measured covariates, residual confounding.
Conclusions
Circulating individual and total n3-PUFA are associated with lower total mortality, especially CHD death, in older adults.
Primary Funding Source
National Institutes of Health.
doi:10.7326/0003-4819-158-7-201304020-00003
PMCID: PMC3698844  PMID: 23546563
17.  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.
Background
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.
Conclusions/Significance
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.
doi:10.1371/journal.pone.0038834
PMCID: PMC3372498  PMID: 22701720
18.  Immunologic effects of national cholesterol education panel step-2 diets with and without fish-derived N-3 fatty acid enrichment. 
Journal of Clinical Investigation  1993;92(1):105-113.
Reductions in dietary fat, saturated fat, and cholesterol have been recommended to reduce the risk of heart disease in our society. The effects of these modifications on human cytokine production and immune responses have not been well studied. 22 subjects > 40 yr of age were fed a diet approximating that of the current American (14.1% of calories as saturated fatty acids, [SFA], 14.5% monounsaturated fatty acids [MUFA], 6.1% [n-6] polyunsaturated fatty acids [PUFA], 0.8% [n-3] PUFA, and 147 mg cholesterol/1,000 calories) for 6 wk, after which time they consumed (11 in each group) one of the two low-fat, low-cholesterol, high-PUFA diets based on National Cholesterol Education Panel (NCEP) Step 2 recommendations (4.0-4.5% SFA, 10.8-11.6% MUFA, 10.3-10.5% PUFA, 45-61 mg cholesterol/1,000 calories) for 24 wk. One of the NCEP Step 2 diets was enriched in fish-derived (n-3) PUFA (low-fat, high-fish: 0.54% or 1.23 g/d eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA] [121-188 g fish/d]) and the other low in fish-derived (n-3) PUFA (low-fat, low-fish [0.13% or 0.27 g/d EPA and DHA] [33 g fish/d]). Measurements of in vivo and in vitro indexes of immune responses were taken after each dietary period. Long-term feeding of low-fat, low-fish diet enriched in plant-derived PUFA increased blood mononuclear cell mitogenic response to the T cell mitogen Con A, IL-1 beta, and TNF production and had no effect on delayed-type hypersensitivity skin response, IL-6, GM-CSF, or PGE2 production. In contrast, the low-fat, high-fish diet significantly decreased the percentage of helper T cells whereas the percentage of suppressor T cells increased. Mitogenic responses to Con A and delayed-type hypersensitivity skin response as well as the production of cytokines IL-1 beta, TNF, and IL-6 by mononuclear cells were significantly reduced after the consumption of the low-fat, high-fish diet (24, 40, 45, 35, and 34%, respectively; P < 0.05 by two-tailed Student's t test except for IL-1 beta and TNF, which is by one-tailed t test). Our data are consistent with the concept that the NCEP Step 2 diet that is high in fish significantly decreases various parameters of the immune response in contrast to this diet when it is low in fish. Such alterations may be beneficial for the prevention and treatment of atherosclerotic and inflammatory diseases but may be detrimental with regard to host defense against invading pathogens.
PMCID: PMC293543  PMID: 8325975
19.  Steady-state bioavailability of prescription omega-3 on a low-fat diet is significantly improved with a free fatty acid formulation compared with an ethyl ester formulation: the ECLIPSE II study 
The systemic bioavailability of free fatty acid (FFA) forms of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) compared with ethyl ester (EE) forms is dependent on the presence of intestinal lipases and is highest during consumption of high-fat meals. Given that patients with cardiovascular disease are advised to reduce dietary fat intake, potentially lowering the bioavailability and therapeutic benefit, the hypothesis that FFA forms provide for higher bioavailability compared with EE forms under low-fat diet conditions was tested where the pharmacokinetics of the FFA form (Epanova™) were compared with those of an ethyl ester form (Lovaza®) following repeat dosing. Fifty-two healthy male and female subjects were equally allocated to one of two open-label, parallel-group cohorts. Following a Therapeutic Lifestyle Changes diet for a minimum of 7 days, blood samples were drawn for endogenous values for EPA and DHA over a 24-hour period. Subjects were then administered 4 × 1 g capsules of either Epanova (OM3 FFA) or Lovaza (OM3 EE) once daily for 14 days, following which serial blood samples were drawn over a 24-hour period to characterize the bioavailability of EPA and DHA from the respective formulations. In addition, changes from baseline in lipid profile were explored. Systemic bioavailability, as measured by area under the curve from time zero to 24 hours (AUC0-τ) and the maximum measured plasma concentrations during the 0–24 hour dosing interval (Cmax,ss) of unadjusted total plasma EPA + DHA were approximately 3-fold and 3.9-fold higher, respectively, for Epanova relative to Lovaza. Following baseline adjustment, the magnitude of difference in bioavailability was approximately 5.8-fold and 6.5-fold higher in AUC0-τ and Cmax, respectively, for Epanova relative to Lovaza. Serum triglycerides were reduced by a significantly greater extent (P = 0.013) for Epanova relative to Lovaza (21% versus 8%). The bioavailability of the FFA forms of EPA and DHA in Epanova are significantly greater than the bioavailability from the EE forms present in Lovaza under low-fat dietary conditions normally recommended for patients with cardiovascular disease. This increased bioavailability may lead to improved triglyceride-lowering in patients with hypertriglyceridemia.
doi:10.2147/VHRM.S50464
PMCID: PMC3794864  PMID: 24124374
hypertriglyceridemia; eicosapentaenoic acid; docosahexaenoic acid; pharmacokinetics
20.  Fish oil and krill oil supplementations differentially regulate lipid catabolic and synthetic pathways in mice 
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1186/1743-7075-11-20
PMCID: PMC4021563  PMID: 24834104
Omega-3 fatty acids; Plasma lipids; High-fat diet; Gene regulation; Krill oil
21.  Omega-3 fatty acids for treatment of non-alcoholic fatty liver disease: design and rationale of randomized controlled trial 
BMC Pediatrics  2013;13:85.
Background
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.
Methods/design
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.
Discussion
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
NCT01547910
doi:10.1186/1471-2431-13-85
PMCID: PMC3672084  PMID: 23702094
Non-alcoholic fatty liver disease; Omega-3 fatty acids; Polyunsaturated fatty acids; Randomized controlled trial; Children
22.  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.
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1371/journal.pone.0036686
PMCID: PMC3343018  PMID: 22570739
23.  Long-chain omega-3 polyunsaturated fatty acids are inversely associated with depressive symptoms in women 
Objective
Experimental and observational data suggest higher dietary intake of long-chain omega-3 polyunsaturated acids may lead to decreased risk of depressive disorders. We assessed multivariable-adjusted associations of fish consumption and dietary intakes of eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA] with depressive symptoms in a population-based sample of 3,317 African American and Caucasian men and women from the Coronary Artery Risk Development in Young Adults study (CARDIA).
Methods
Diet was assessed in Year 7 (1992–93) and depressive symptoms were measured in Years 10 (1995–96), 15 (2000–01), and 20 (2005–06) by the 20-item Center for Epidemiological Studies Depression Scale (CES-D). Depressive symptoms were defined as CES-D score ≥ 16 or self-reported use of antidepressant medication.
Results
In the entire cohort, the highest quintiles of intakes of EPA (at least 0.03% energy), DHA (at least 0.05% energy), and EPA+DHA (at least 0.08% energy) were associated with lower risk of depressive symptoms at Year 10 (p-trends: 0.16, 0.10, 0.03, respectively). The observed inverse associations were more pronounced in women. For the total number of occasions with depressive symptoms, the multivariable adjusted odds ratios (95% confidence interval) in women were 0.75 (0.55–1.01) for fish intake; 0.66 (0.50–0.89), for EPA; 0.66 (0.49–0.89) for DHA; and 0.71 (0.52–0.95) for EPA+DHA, when comparing highest to lowest quintiles. Analyses of continuous CES-D scores revealed inverse associations with fourth root transformed omega-3 variables in women.
Conclusions
Our findings suggest that dietary intakes of fish and long-chain omega-3 fatty acids may be inversely associated with chronic depressive symptoms in women.
doi:10.1016/j.nut.2008.12.008
PMCID: PMC2798585  PMID: 19195841
omega-3 fatty acids; depressive symptoms; EPA; DHA; fish
24.  Plasma fatty acid composition and incident ischemic stroke in middle-aged adults: the Atherosclerosis Risk in Communities (ARIC) Study 
Cerebrovascular diseases (Basel, Switzerland)  2013;36(1):10.1159/000351205.
Background
The association of individual fatty acids with ischemic stroke has not been thoroughly studied, and results have been inconsistent. Few prospective studies have systematically explored the association of biomarkers of fatty acid intake with stroke. The aim of this study was to explore which individual plasma fatty acids would be associated with higher risk of ischemic stroke among whites.
Methods
We studied 3,870 white men and women from the Minneapolis field center of the Atherosclerosis Risk in Communities (ARIC) Study, aged 45–64 at baseline (1987–89) who had plasma cholesterol ester (CE) and phospholipid (PL) fatty acids measured. Participants were followed through 2008 for incident ischemic stroke. Hazard ratios (HRs) with 95% confidence intervals (CIs) across quartiles of each fatty acid, measured as the percentage of total fatty acids, were calculated using Cox proportional hazards model.
Results
During a maximum of 22-years of follow-up, we identified 168 cases of ischemic stroke. After adjustment for age and sex, plasma levels of saturated fatty acids were associated positively: HR (95%CI) of the highest quartile vs the lowest quartile for CE fraction was 1.93 (1.23–3.04), p for trend =0.01 and that for PL fraction was 1.64 (1.05–2.57), p for trend =0.03. There was also a positive linear association with monounsaturated fatty acids, especially with palmitoleic acid: HR (95%CI) of the highest quartile vs the lowest quartile for CE fraction was 1.86 (1.20–2.87), p for trend =0.003 for CE; and those for PL fraction was 1.52 (0.99–2.34), p for trend =0.005. No associations of ω-3 and ω-6 polyunsaturated fatty acids with ischemic stroke were observed, but linoleic acid was inversely and nonlinearly associated with ischemic stroke: HR (95%CI) of the highest quartile vs the lowest quartile for CE fraction was 0.64 (0.43–0.97), p for trend =0.13 and that for PL fraction was 0.69 (0.45–1.05), p for trend =0.24. These associations were generally unchanged after adjustment for cardiovascular risk factors.
Conclusions
In this US cohort of whites, we found significant positive associations of plasma saturated and monounsaturated fatty acids, especially of palmitoleic acid, with ischemic stroke. We also found an inverse nonlinear association between linoleic acid and ischemic stroke.
doi:10.1159/000351205
PMCID: PMC3875134  PMID: 23920478
longitudinal study; epidemiology; fat; biomarkers; risk factors
25.  Dietary intakes of fat and total mortality among Japanese populations with a low fat intake: the Japan Collaborative Cohort (JACC) Study 
Background
It may be useful to examine associations of fat intakes with total mortality as a basis for dietary recommendations. We aimed to elucidate associations between dietary fat and total mortality among Japanese populations with low fat intake.
Methods
We conducted a prospective study consisting of 58,672 men and women aged 40 to 79 years. Fat intakes were estimated using a food frequency questionnaire. Multivariate-adjusted hazard ratios (HRs) for mortality by sex were computed according to quintiles of energy-adjusted fat intakes.
Results
During the follow-up period (median duration, 19.3 years), 11,656 deaths were recorded. In men, we found no clear association between total fat and total mortality. HRs across quintiles of total fat intake were 1.00, 1.03 (95% confidence interval [CI], 0.95–1.12), 1.02 (0.94–1.10), 0.98 (0.90–1.07), and 1.07 (0.98–1.17). No significant association was detected in regard to types of fat. In women, HR was lowest in the fourth quintile of total fat intake followed by the top quintile; HRs across quintiles were 1.00, 1.03 (0.94–1.11), 1.00 (0.92–1.09), 0.88 (0.81–0.96), and 0.94 (0.86–1.03). Regarding types of fat in women, total mortality was inversely associated with intakes of saturated fatty acids (SFA), monounsaturated fatty acids (MUFA), and polyunsaturated fatty acids (PUFA); the lowest HR was in the top quintile of intake for SFA, MUFA, and PUFA: 0.91 (95% CI, 0.83–1.00), 0.91 (0.83–0.99) and 0.88 (0.80 - 0.97), respectively (trend P across quintiles, 0.020, 0.012, and 0.029, respectively). Causes of death other than cancer and cardiovascular disease contributed most to decreases in HRs for total and types of fat. In women, analysis with finer categories revealed that the lowest risk for total mortality appeared at total fat intake of 28% of energy.
Conclusions
Our findings from a large cohort study among populations with relatively low fat intake provide evidence regarding optimal levels of fat intakes.
doi:10.1186/1743-7075-11-12
PMCID: PMC3973975  PMID: 24597664
Fat; Fatty acids; Saturated fatty acids; Monounsaturated fatty acids; Polyunsaturated fatty acids; Total mortality; Cohort studies; Japan

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