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1.  Omega‐3 polyunsaturated fatty acids and inflammatory processes: nutrition or pharmacology? 
Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are n‐3 fatty acids found in oily fish and fish oil supplements. These fatty acids are able to inhibit partly a number of aspects of inflammation including leucocyte chemotaxis, adhesion molecule expression and leucocyte‐endothelial adhesive interactions, production of eicosanoids like prostaglandins and leukotrienes from the n‐6 fatty acid arachidonic acid, production of inflammatory cytokines and T cell reactivity. In parallel, EPA gives rise to eicosanoids that often have lower biological potency than those produced from arachidonioc acid and EPA and DHA give rise to anti‐inflammatory and inflammation resolving resolvins and protectins. Mechanisms underlying the anti‐inflammatory actions of n‐3 fatty acids include altered cell membrane phospholipid fatty acid composition, disruption of lipid rafts, inhibition of activation of the pro‐inflammatory transcription factor nuclear factor kappa B so reducing expression of inflammatory genes, activation of the anti‐inflammatory transcription factor NR1C3 (i.e. peroxisome proliferator activated receptor γ) and binding to the G protein coupled receptor GPR120. These mechanisms are interlinked. In adult humans, an EPA plus DHA intake greater than 2 g day–1 seems to be required to elicit anti‐inflammatory actions, but few dose finding studies have been performed. Animal models demonstrate benefit from n‐3 fatty acids in rheumatoid arthritis (RA), inflammatory bowel disease (IBD) and asthma. Clinical trials of fish oil in patients with RA demonstrate benefit supported by meta‐analyses of the data. Clinical trails of fish oil in patients with IBD and asthma are inconsistent with no overall clear evidence of efficacy.
doi:10.1111/j.1365-2125.2012.04374.x
PMCID: PMC3575932  PMID: 22765297
cytokine; docosahexaenoic acid; eicosanoid; eicosapentaenoic acid; fish oil; leucocyte
2.  Increased Intake of Foods with High Nutrient Density Can Help to Break the Intergenerational Cycle of Malnutrition and Obesity 
Nutrients  2015;7(7):6016-6037.
A workshop held at the University Medical Center in Groningen, The Netherlands, aimed at discussing the nutritional situation of the population in general and the role diet plays during critical windows in the life course, during which the body is programmed for the development of non-communicable diseases (NCDs). NCDs are increasingly prevalent as our society ages, and nutrition is well known to play an important role in determining the risk and the time of onset of many common NCDs. Even in affluent countries, people have difficulties to achieve adequate intakes for a range of nutrients: Economic constraints as well as modern lifestyles lead people to consume diets with a positive energy balance, but low in micronutrients, resulting in increasing prevalence of obesity and suboptimal nutritional status. Information about nutrient density, which refers to the content of micronutrients relative to energy in food or diets, can help identify foods that have a low calorie to nutrient ratio. It thus allows the consumption of diets that cover nutritional needs without increasing the risk of becoming obese. Given the impact a nutrient dense, low energy diet can have on health, researchers, food industry and governments jointly should develop options for affordable, appealing nutrient-rich food products, which, in combination with physical activity, allow for optimal health throughout the life-course.
doi:10.3390/nu7075266
PMCID: PMC4517043  PMID: 26197337
nutrient density; vitamin; PUFA; life cycle; non-communicable diseases; obesity
3.  Balancing omega-6 and omega-3 fatty acids in ready-to-use therapeutic foods (RUTF) 
BMC Medicine  2015;13:117.
Ready-to-use therapeutic foods (RUTFs) are a key component of a life-saving treatment for young children who present with uncomplicated severe acute malnutrition in resource limited settings. Increasing recognition of the role of balanced dietary omega-6 and omega-3 polyunsaturated fatty acids (PUFA) in neurocognitive and immune development led two independent groups to evaluate RUTFs. Jones et al. (BMC Med 13:93, 2015), in a study in BMC Medicine, and Hsieh et al. (J Pediatr Gastroenterol Nutr 2015), in a study in the Journal of Pediatric Gastroenterology and Nutrition, reformulated RUTFs with altered PUFA content and looked at the effects on circulating omega-3 docosahexaenoic acid (DHA) status as a measure of overall omega-3 status. Supplemental oral administration of omega-3 DHA or reduction of RUTF omega-6 linoleic acid using high oleic peanuts improved DHA status, whereas increasing omega-3 alpha-linolenic acid in RUTF did not. The results of these two small studies are consistent with well-established effects in animal studies and highlight the need for basic and operational research to improve fat composition in support of omega-3-specific development in young children as RUTF use expands.
Please see related article: http://www.biomedcentral.com/1741-7015/13/93
doi:10.1186/s12916-015-0352-1
PMCID: PMC4433071  PMID: 25980919
Docosahexaenoic acid supplementation; High oleic peanuts; Omega-3 fatty acids; Ready-to-use therapeutic foods; Severe acute malnutrition
4.  Ready-to-use therapeutic food with elevated n-3 polyunsaturated fatty acid content, with or without fish oil, to treat severe acute malnutrition: a randomized controlled trial 
BMC Medicine  2015;13:93.
Background
Ready-to-use therapeutic foods (RUTF) are lipid-based pastes widely used in the treatment of acute malnutrition. Current specifications for RUTF permit a high n-6 polyunsaturated fatty acid (PUFA) content and low n-3 PUFA, with no stipulated requirements for preformed long-chain n-3 PUFA. The objective of this study was to develop an RUTF with elevated short-chain n-3 PUFA and measure its impact, with and without fish oil supplementation, on children’s PUFA status during treatment of severe acute malnutrition.
Methods
This randomized controlled trial in children with severe acute malnutrition in rural Kenya included 60 children aged 6 to 50 months who were randomized to receive i) RUTF with standard composition; ii) RUTF with elevated short chain n-3 PUFA; or iii) RUTF with elevated short chain n-3 PUFA plus fish oil capsules. Participants were followed-up for 3 months. The primary outcome was erythrocyte PUFA composition.
Results
Erythrocyte docosahexaenoic acid (DHA) content declined from baseline in the two arms not receiving fish oil. Erythrocyte long-chain n-3 PUFA content following treatment was significantly higher for participants in the arm receiving fish oil than for those in the arms receiving RUTF with elevated short chain n-3 PUFA or standard RUTF alone: 3 months after enrolment, DHA content was 6.3% (interquartile range 6.0–7.3), 4.5% (3.9–4.9), and 3.9% (2.4–5.7) of total erythrocyte fatty acids (P <0.001), respectively, while eicosapentaenoic acid (EPA) content was 2.0% (1.5–2.6), 0.7% (0.6–0.8), and 0.4% (0.3–0.5) (P <0.001). RUTF with elevated short chain n-3 PUFA and fish oil capsules were acceptable to participants and carers, and there were no significant differences in safety outcomes.
Conclusions
PUFA requirements of children with SAM are not met by current formulations of RUTF, or by an RUTF with elevated short-chain n-3 PUFA without additional preformed long-chain n-3 PUFA. Clinical and growth implications of revised formulations need to be addressed in large clinical trials.
Trial registration
Clinicaltrials.gov NCT01593969. Registered 4 May 2012.
Electronic supplementary material
The online version of this article (doi:10.1186/s12916-015-0315-6) contains supplementary material, which is available to authorized users.
doi:10.1186/s12916-015-0315-6
PMCID: PMC4407555  PMID: 25902844
Fatty acid; Fish oils; Growth; Omega-3; Ready-to-use therapeutic food; Severe acute malnutrition
5.  Dietary Docosahexaenoic Acid and Eicosapentaenoic Acid Influence Liver Triacylglycerol and Insulin Resistance in Rats Fed a High-Fructose Diet 
Marine Drugs  2015;13(4):1864-1881.
This study aimed to examine the benefits of different amounts of omega-3 (n-3) polyunsaturated fatty acids from fish oil (FO) on lipid metabolism, insulin resistance and gene expression in rats fed a high-fructose diet. Male Wistar rats were separated into two groups: Control (C, n = 6) and Fructose (Fr, n = 32), the latter receiving a diet containing 63% by weight fructose for 60 days. After this period, 24 animals from Fr group were allocated to three groups: FrFO2 (n = 8) receiving 63% fructose and 2% FO plus 5% soybean oil; FrFO5 (n = 8) receiving 63% fructose and 5% FO plus 2% soybean oil; and FrFO7 (n = 8) receiving 63% fructose and 7% FO. Animals were fed these diets for 30 days. Fructose led to an increase in liver weight, hepatic and serum triacylglycerol, serum alanine aminotransferase and HOMA1-IR index. These alterations were reversed by 5% and 7% FO. FO had a dose-dependent effect on expression of genes related to hepatic β-oxidation (increased) and hepatic lipogenesis (decreased). The group receiving the highest FO amount had increased markers of oxidative stress. It is concluded that n-3 fatty acids may be able to reverse the adverse metabolic effects induced by a high fructose diet.
doi:10.3390/md13041864
PMCID: PMC4413191  PMID: 25837985
fish oil; fructose; metabolic syndrome; omega-3 fatty acids
6.  Age and sex differences in the incorporation of EPA and DHA into plasma fractions, cells and adipose tissue in humans 
The British journal of nutrition  2013;111(4):679-689.
The aims of this study were to determine whether age and sex influence both the status and the incorporation of EPA and DHA into blood plasma, cells and tissues. The study was a double-blind, randomised, controlled intervention, providing EPA+DHA equivalent to 0, 1, 2 or 4 portions of oily fish per week, for 12 months. Participants were stratified by age and sex. A linear regression model was used to analyse baseline outcomes, with covariates for age or sex groups, and adjusting for BMI. The change from baseline to 12 months in outcome was analysed with additional adjusting of treatment and average compliance. Fatty acid profiles were determined in plasma phosphatidylcholine (PC), cholesteryl esters (CE), NEFA and TAG, mononuclear cells (MNC), erythrocyte membranes (RBC), platelets (PLAT), buccal cells (BU) and adipose tissue (AT). At baseline, EPA concentration in plasma NEFA and DHA concentration in MNC, BU and AT was higher in females than males (all P<0.05). EPA in AT (P=0.003) and DHA in plasma TAG (P<0.01) and AT (P<0.001) were higher with increasing age. Following 12 months supplementation with EPA+DHA, adjusted mean difference for change in EPA in plasma TAG was significantly higher in females than males (P<0.05) and was greater with increasing age (P=0.02). Adjusted mean difference for change in DHA in AT was significantly smaller with increasing age (P=0.02). Although small differences in incorporation with age and sex were identified, these were not of sufficient magnitude to warrant a move away from population-level diet recommendations for n-3 PUFA.
doi:10.1017/S0007114513002985
PMCID: PMC4351921  PMID: 24063767
Fish oil; EPA; DHA; n-3 polyunsaturated fatty acids
7.  Fish Oil Decreases Hepatic Lipogenic Genes in Rats Fasted and Refed on a High Fructose Diet 
Nutrients  2015;7(3):1644-1656.
Fasting and then refeeding on a high-carbohydrate diet increases serum and hepatic triacylglycerol (TAG) concentrations compared to standard diets. Fructose is a lipogenic monosaccharide which stimulates de novo fatty acid synthesis. Omega-3 (n-3) fatty acids stimulate hepatic β-oxidation, partitioning fatty acids away from TAG synthesis. This study investigated whether dietary n-3 fatty acids from fish oil (FO) improve the hepatic lipid metabolic response seen in rats fasted and then refed on a high-fructose diet. During the post-prandial (fed) period, rats fed a FO rich diet showed an increase in hepatic peroxisome proliferator-activated receptor α (PPAR-α) gene expression and decreased expression of carbohydrate responsive element binding protein (ChREBP), fatty acid synthase (FAS) and microsomal triglyceride transfer protein (MTTP). Feeding a FO rich diet for 7 days prior to 48 h of fasting resulted in lower hepatic TAG, lower PPAR-α expression and maintenance of hepatic n-3 fatty acid content. Refeeding on a high fructose diet promoted an increase in hepatic and serum TAG and in hepatic PPAR-α, ChREBP and MTTP expression. FO did not prevent the increase in serum and hepatic TAG after fructose refeeding, but did decrease hepatic expression of lipogenic genes and increased the n-3 fatty acid content of the liver. n-3 Fatty acids can modify some components of the hepatic lipid metabolic response to later feeding with a high fructose diet.
doi:10.3390/nu7031644
PMCID: PMC4377871  PMID: 25751821
fish oil; omega-3; fructose; fasting; refeeding; liver
9.  Increased dietary α-linolenic acid has sex-specific effects upon eicosapentaenoic acid status in humans: re-examination of data from a randomised, placebo-controlled, parallel study 
Nutrition Journal  2014;13:113.
Background
There is a metabolic pathway by which mammals can convert the omega-3 (n-3) essential fatty acid α-linolenic acid (ALA) into longer-chain n-3 polyunsaturated fatty acids (LC n-3 PUFA) including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). As far as we know there are currently no studies that have specifically examined sex differences in the LC n-3 PUFA response to increased dietary ALA intake in humans, although acute studies with isotope-labelled ALA identified that women have a significantly greater capacity to synthesise EPA and DHA from ALA compared to men.
Findings
Available data from a placebo-controlled, randomised study were re-examined to identify whether there are sex differences in the LC n-3 PUFA response to increased dietary ALA intake in humans. There was a significant difference between sexes in the response to increased dietary ALA, with women having a significantly greater increase in the EPA content of plasma phospholipids (mean +2.0% of total fatty acids) after six months of an ALA-rich diet compared to men (mean +0.7%, P = 0.039). Age and BMI were identified as predictors of response to dietary ALA among women.
Conclusions
Women show a greater increase in circulating EPA than men during increased dietary ALA consumption. Further understanding of individual variation in the response to dietary ALA could inform nutrition advice, with recommendations being specifically tailored according to habitual diet, sex, age and BMI.
doi:10.1186/1475-2891-13-113
PMCID: PMC4274685  PMID: 25496415
α-linolenic acid; Sex; Eicosapentaenoic acid
10.  A randomised controlled trial of a preconceptional dietary intervention in women undergoing IVF treatment (PREPARE trial) 
BMC Women's Health  2014;14:130.
Background
In vitro fertilisation (IVF) treatment provides an opportunity to study early developmental responses to periconceptional dietary interventions. Retrospective studies have suggested links between preconception diet and fertility, and more recently, a "Mediterranean" diet has been reported to increase pregnancy rates by up to 40%. In addition, a prospective study examining increased intake of omega-3 polyunsaturated fats demonstrated a quickened rate of embryo development after IVF. However, up to now, few prospective randomised controlled trials have investigated the impact of periconceptional dietary interventions on fertility outcomes.
Methods and design
The study is a randomised controlled trial of a dietary intervention consisting of olive oil for cooking, an olive oil based spread, and a daily supplement drink enriched with Vitamin D (10 microgram daily) and marine omega-3 fatty acids (2 g daily) for 6 weeks preconception versus a control diet of sunflower seed oil for cooking, a sunflower oil based spread, and a daily supplement drink without added Vitamin D or marine omega-3 fatty acids. Couples undergoing IVF will be randomised to either the intervention or control group (55 in each arm). The primary endpoint is embryo developmental competency in vitro, measured by validated morphokinetic markers. Secondary outcomes will include the effect of the dietary intervention on the nutritional content of the intrauterine environment.
Discussion
This approach will enable rigorous examination of the impact of the dietary intervention on early embryo development, together with the influence of the peri-implantation intra-uterine nutritional environment.
Trial registration
ISRCTN50956936
doi:10.1186/1472-6874-14-130
PMCID: PMC4289275  PMID: 25407227
11.  Supplementation with N-3 Long-Chain Polyunsaturated Fatty Acids or Olive Oil in Men and Women with Renal Disease Induces Differential Changes in the DNA Methylation of FADS2 and ELOVL5 in Peripheral Blood Mononuclear Cells 
PLoS ONE  2014;9(10):e109896.
Background
Studies in animal models and in cultured cells have shown that fatty acids can induce alterations in the DNA methylation of specific genes. There have been no studies of the effects of fatty acid supplementation on the epigenetic regulation of genes in adult humans.
Methods and Results
We investigated the effect of supplementing renal patients with 4 g daily of either n-3 long-chain polyunsaturated fatty acids (n-3 LCPUFA) or olive oil (OO) for 8 weeks on the methylation status of individual CpG loci in the 5′ regulatory region of genes involved in PUFA biosynthesis in peripheral blood mononuclear cells from men and women (aged 53 to 63 years). OO and n-3 LCPUFA each altered (>10% difference in methylation) 2/22 fatty acid desaturase (FADS)-2 CpGs, while n-3 LCPUFA, but not OO, altered (>10%) 1/12 ELOVL5 CpGs in men. OO altered (>6%) 8/22 FADS2 CpGs and (>3%) 3/12 elongase (ELOVL)-5 CpGs, while n-3 LCPUFA altered (>5%) 3/22 FADS2 CpGs and 2/12 (>3%) ELOVL5 CpGs in women. FADS1 or ELOVL2 methylation was unchanged. The n-3 PUFA supplementation findings were replicated in blood DNA from healthy adults (aged 23 to 30 years). The methylation status of the altered CpGs in FADS2 and ELOVL5 was associated negatively with the level of their transcripts.
Conclusions
These findings show that modest fatty acid supplementation can induce altered methylation of specific CpG loci in adult humans, contingent on the nature of the supplement and on sex. This has implications for understanding the effect of fatty acids on PUFA metabolism and cell function.
doi:10.1371/journal.pone.0109896
PMCID: PMC4201459  PMID: 25329159
12.  Effects of Perioperative Supplementation with Omega-3 Fatty Acids on Leukotriene B4 and Leukotriene B5 Production by Stimulated Neutrophils in Patients with Colorectal Cancer: A Randomized, Placebo-Controlled Intervention Trial 
Nutrients  2014;6(10):4043-4057.
Omega-3 fatty acids (n-3 FA) may have beneficial clinical and immune-modulating effects in surgical patients. In a randomized, double-blind, prospective, placebo-controlled trial, 148 patients referred for elective colorectal cancer surgery received an n-3 FA-enriched oral nutritional supplement (ONS) providing 2.0 g of eicosapentaenoic acid (EPA) and 1.0 g of docosahexaenoic acid (DHA) per day or a standard ONS for seven days before surgery. On the day of operation, there was a significant increase in the production of leukotriene B5 (LTB5) (p < 0.01) and 5-hydroxyeicosapentaenoic acid (5-HEPE) (p < 0.01), a significant decrease in the production of leukotriene B4 (LTB4) (p < 0.01) and a trend for a decrease in the production of 5-hydroxyeicosatetraenoic acid (5-HETE) (p < 0.1) from stimulated neutrophils in the active group compared with controls. There was no association between LTB4 values and postoperative complications. In conclusion, oral n-3 FA exerts anti-inflammatory effects in surgical patients, without reducing the risk of postoperative complications.
doi:10.3390/nu6104043
PMCID: PMC4210906  PMID: 25268838
colorectal cancer; omega-3 fatty acids; immunomodulation; fish oil; leukotrienes
13.  Compared with Daily, Weekly n–3 PUFA Intake Affects the Incorporation of Eicosapentaenoic Acid and Docosahexaenoic Acid into Platelets and Mononuclear Cells in Humans123 
The Journal of Nutrition  2014;144(5):667-672.
Consumption of oily fish is sporadic, whereas controlled intervention studies of n–3 (ω-3) fatty acids usually provide capsules containing eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) as a daily dose. This methodologic study explored whether there are differences in the short-, medium-, and long-term incorporation of EPA and DHA into blood plasma and cells with the provision of identical amounts of EPA and DHA, equivalent to 2 oily fish servings per week (or 6.54 g/wk EPA and DHA), either intermittently (i.e., 1 portion twice per week) or continuously (i.e., divided into daily amounts). The study was part of a randomized, double-blind controlled intervention lasting 12 mo, with participants stratified by age and sex. There were 5 intervention groups, 2 of which are reported here: the 2 intermittent portions (2I) and 2 continuous portions (2C) groups. EPA and DHA were measured in plasma phosphatidylcholine, platelets, and blood mononuclear cells (MNCs) at 9 time points. Sixty-five participants completed the study (2I group, n = 30, mean age of 49.2 y; 2C group, n = 35, mean age of 50.6 y). The incorporation pattern over the 12-mo intervention was different between the 2 groups in all samples (P < 0.0001, time × treatment interaction). At the end of the 12-mo intervention, the 2C group had higher EPA, DHA, and EPA + DHA in platelets (all P < 0.01) and higher EPA and EPA + DHA in MNCs (both P < 0.05) compared with the 2I group. No significant differences were shown for plasma phosphatidylcholine EPA (P = 0.1), DHA (P = 0.15), EPA + DHA (P = 0.07), or MNC DHA (P = 0.06). In conclusion, the pattern of consumption does affect the incorporation of EPA and DHA into cells used as biomarkers of intake. The differences identified here need to be considered in the design of studies and when extrapolating results from continuous capsule-based intervention studies to dietary guidelines for oily fish consumption. This trial was registered at www.controlled-trials.com as ISRCTN48398526.
doi:10.3945/jn.113.186346
PMCID: PMC3985823  PMID: 24647395
14.  Parenteral omega-3 fatty acids: pouring oil on troubled waters? 
Critical Care  2012;16(6):172.
A meta-analysis of parenteral fish oil in 23 studies in intensive care unit (ICU) and non-ICU patients reported a reduced infection rate (significant in ICU patients) and shorter lengths of ICU and hospital stays (both non-ICU and ICU patients). Parenteral fish oil reduced inflammation and improved oxygenation index and liver function. The findings of the meta-analysis are discussed in this report.
doi:10.1186/cc11848
PMCID: PMC3672587  PMID: 23146333
15.  Altered Colonic Mucosal Polyunsaturated Fatty Acid (PUFA) Derived Lipid Mediators in Ulcerative Colitis: New Insight into Relationship with Disease Activity and Pathophysiology 
PLoS ONE  2013;8(10):e76532.
Objectives
Ulcerative colitis (UC) is a relapsing inflammatory disorder of unconfirmed aetiology, variable severity and clinical course, characterised by progressive histological inflammation and with elevation of eicosanoids which have a known pathophysiological role in inflammation. Therapeutic interventions targetting eicosanoids (5-aminosalicylates (ASA)) are effective first line and adjunctive treatments in mild-moderate UC for achieving and sustaining clinical remission. However, the variable clinical response to 5-ASA and frequent deterioration in response to cyclo-oxygenase (COX) inhibitors, has prompted an in depth simultaneous evaluation of multiple lipid mediators (including eicosanoids) within the inflammatory milieu in UC. We hypothesised that severity of inflammation is associated with alteration of lipid mediators, in relapsing UC.
Design
Study was case-control design. Mucosal lipid mediators were determined by LC-MS/MS lipidomics analysis on mucosal biopsies taken from patients attending outpatients with relapsing UC. Univariate and multivariate statistical analyses were used to investigate the association of mucosal lipid mediators, with the disease state and severity graded histologically.
Results
Levels of PGE2, PGD2, TXB2, 5-HETE, 11-HETE, 12-HETE and 15-HETE are significantly elevated in inflamed mucosa and correlate with severity of inflammation, determined using validated histological scoring systems.
Conclusions
Our approach of capturing inflammatory mediator signature at different stages of UC by combining comprehensive lipidomics analysis and computational modelling could be used to classify and predict mild-moderate inflammation; however, predictive index is diminished in severe inflammation. This new technical approach could be developed to tailor drug treatments to patients with active UC, based on the mucosal lipid mediator profile.
doi:10.1371/journal.pone.0076532
PMCID: PMC3799829  PMID: 24204637
16.  Limited Impact of 2 g/day Omega-3 Fatty Acid Ethyl Esters (Omacor®) on Plasma Lipids and Inflammatory Markers in Patients Awaiting Carotid Endarterectomy 
Marine Drugs  2013;11(9):3569-3581.
The objective of this study was to determine the effects of prescription omega-3 (n-3) fatty acid ethyl esters (Omacor®) on blood pressure, plasma lipids, and inflammatory marker concentrations in patients awaiting carotid endarterectomy. Patients awaiting carotid endarterectomy (n = 121) were randomised to Omacor® or olive oil as placebo (2 g/day) until surgery (median 21 days). Blood pressure, plasma lipids, and plasma inflammatory markers were determined. There were significant decreases in systolic and diastolic blood pressure and in plasma triglyceride, total cholesterol, low density lipoprotein-cholesterol, soluble vascular cellular adhesion molecule 1, and matrix metalloproteinase 2 concentrations, in both groups. The extent of triglyceride lowering was greater with Omacor® (25%) compared with placebo (9%). Soluble E-selectin concentration was significantly decreased in the Omacor® group but increased in the placebo group. At the end of the supplementation period there were no differences in blood pressure or in plasma lipid and inflammatory marker concentrations between the two groups. It is concluded that Omacor® given at 2 g/day for an average of 21 days to patients with advanced carotid atherosclerosis lowers triglycerides and soluble E-selectin concentrations, but has limited broad impact on the plasma lipid profile or on inflammatory markers. This may be because the duration of intervention was too short or the dose of n-3 fatty acids was too low.
doi:10.3390/md11093569
PMCID: PMC3806474  PMID: 24065166
omega-3; fish oil; cytokine; adhesion molecule; cardiovascular disease
17.  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
18.  Maternal fat intake in rats alters 20:4n-6 and 22:6n-3 status and the epigenetic regulation of Fads2 in offspring liver☆☆☆★ 
Poor prenatal nutrition, acting through epigenetic processes, induces persistent changes in offspring phenotype. We investigated the effect of maternal fat intake on polyunsaturated fatty acid (PUFA) status and on the epigenetic regulation of Fads2, encoding Δ6 desaturase (rate limiting in PUFA synthesis), in the adult offspring. Rats (n=6 per dietary group) were fed either 3.5% (w/w), 7% (w/w) or 21% (w/w) butter or fish oil (FO) from 14 days preconception until weaning. Offspring (n=6 males and females per dietary group) were fed 4% (w/w) soybean oil until postnatal day 77. 20:4n-6 and 22:6n-3 levels were lower in liver phosphatidylcholine (PC) and phosphatidylethanolamine and plasma PC (all P<.0001) in offspring of dams fed 21% than 3.5% or 7% fat regardless of type. Hepatic Fads2 expression related inversely to maternal dietary fat. Fads2 messenger RNA expression correlated negatively with methylation of CpGs at −623, −394, −84 and −76 bases relative to the transcription start site (all P<.005). Methylation of these CpGs was higher in offspring of dams fed 21% than 3.5% or 7% fat; FO higher than butter. Feeding adult female rats 7% fat reduced 20:4n-6 status in liver PC and Fads2 expression and increased methylation of CpGs −623, −394, −84 and −76 that reversed in animals switched from 7% to 4% fat diets. These findings suggest that fat exposure during development induces persistent changes, while adults exhibit a transient response, in hepatic PUFA status in offspring through epigenetic regulation of Fads2. Thus, epigenetic regulation of Fads2 may contribute to short- and long-term regulation of PUFA synthesis.
doi:10.1016/j.jnutbio.2012.09.005
PMCID: PMC3698442  PMID: 23107313
Maternal dietary fat; Early life programming; Liver; Arachidonic acid; Docosahexaenoic acid; Δ6 desaturase
19.  Changes in plasma and erythrocyte omega-6 and omega-3 fatty acids in response to intravenous supply of omega-3 fatty acids in patients with hepatic colorectal metastases 
Background
Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are functionally the most important omega-3 polyunsaturated fatty acids (PUFAs). Oral supply of these fatty acids increases their levels in plasma and cell membranes, often at the expense of the omega-6 PUFAs arachidonic acid (ARA) and linoleic acid. This results in an altered pattern of lipid mediator production to one which is less pro-inflammatory. We investigated whether short term intravenous supply of omega-3 PUFAs could change the levels of EPA, DHA, ARA and linoleic acid in plasma and erythrocytes in patients with hepatic colorectal metastases.
Methods
Twenty patients were randomised to receive a 72 hour infusion of total parenteral nutrition with (treatment group) or without (control group) omega-3 PUFAs. EPA, DHA, ARA and linoleic acid were measured in plasma phosphatidylcholine (PC) and erythrocytes at several times points up to the end of infusion and 5 to 12 days (mean 9 days) after stopping the infusion.
Results
The treatment group showed increases in plasma PC EPA and DHA and erythrocyte EPA and decreases in plasma PC and erythrocyte linoleic acid, with effects most evident late in the infusion period. Plasma PC and erythrocyte EPA and linoleic acid all returned to baseline levels after the 5–12 day washout. Plasma PC DHA remained elevated above baseline after washout.
Conclusions
Intravenous supply of omega-3 PUFAs results in a rapid increase of EPA and DHA in plasma PC and of EPA in erythrocytes. These findings suggest that infusion of omega-3 PUFAs could be used to induce a rapid effect especially in targeting inflammation.
Trial registration
http://www.clinicaltrials.gov identifier NCT00942292
doi:10.1186/1476-511X-12-64
PMCID: PMC3659039  PMID: 23648075
Parenteral nutrition; Fish oil; Omega-3 fatty acids; Eicosapentaenoic acid; Docosahexaenoic acid; Arachidonic acid; Liver metastases
20.  Perioperative Immunonutrition in Well-Nourished Patients Undergoing Surgery for Head and Neck Cancer: Evaluation of Inflammatory and Immunologic Outcomes 
Nutrients  2013;5(4):1186-1199.
Limited work is available on the benefits of nutritional support enriched with arginine and n-3 fatty acids in surgical patients with head and neck cancer, particularly if well-nourished. We conducted a pilot study in these patients to examine effects on inflammatory markers and clinical outcome. Patients scheduled for radical resection of the oral cavity were randomised to 5 day preoperative and 5 day postoperative Impact® (IMN, n = 4), or no preoperative supplementary nutrition and Isosource® postoperatively (STD, n = 4). Plasma fatty acids, C-reactive protein (CRP), tumour necrosis factor (TNF)-α, interleukin (IL)-6 and IL-10 were measured at baseline, day of surgery and on postoperative days (POD) 2, 4 and 10. Postoperative complications were recorded. The (eicosapentaenoic acid plus docosahexaenoic acid) to arachidonic acid ratio was significantly higher in IMN patients on POD 2, 4 and 10 (P < 0.01). While not statistically significant, CRP, TNF-α, and IL-6 concentrations were higher in the STD group on POD2 while IL-10 was lower. Median length of stay was 10 (range 10–43) days in the IMN group and 21.5 (7–24) days in the STD group. Five complications were seen in the STD group and two in the IMN group. The results support the need for a larger trial focusing on clinical outcome.
doi:10.3390/nu5041186
PMCID: PMC3705342  PMID: 23571650
immunonutrition; arginine; omega-3 fatty acids; fish oil; surgery; head and neck cancer; inflammation; cytokines
21.  Maternal Plasma Phosphatidylcholine Fatty Acids and Atopy and Wheeze in the Offspring at Age of 6 Years 
Variation in exposure to polyunsaturated fatty acids (PUFAs) might influence the development of atopy, asthma, and wheeze. This study aimed to determine whether differences in PUFA concentrations in maternal plasma phosphatidylcholine are associated with the risk of childhood wheeze or atopy. For 865 term-born children, we measured phosphatidylcholine fatty acid composition in maternal plasma collected at 34 weeks' gestation. Wheezing was classified using questionnaires at 6, 12, 24, and 36 months and 6 years. At age of 6 years, the children underwent skin prick testing, fractional exhaled nitric oxide (FENO) measurement, and spirometry. Maternal n-6 fatty acids and the ratio of n-3 to n-6 fatty acids were not associated with childhood wheeze. However, higher maternal eicosapentaenoic acid, docosahexaenoic acid, and total n-3 fatty acids were associated with reduced risk of non-atopic persistent/late wheeze (RR 0.57, 0.67 and 0.69, resp. P = 0.01, 0.015, and 0.021, resp.). Maternal arachidonic acid was positively associated with FENO (P = 0.024). A higher ratio of linoleic acid to its unsaturated metabolic products was associated with reduced risk of skin sensitisation (RR 0.82, P = 0.013). These associations provide some support for the hypothesis that variation in exposure to n-6 and n-3 fatty acids during pregnancy influences the risk of childhood wheeze and atopy.
doi:10.1155/2012/474613
PMCID: PMC3463812  PMID: 23049600
22.  Incorporation of eicosapentaenoic and docosahexaenoic acids into lipid pools when given as supplements providing doses equivalent to typical intakes of oily fish1234 
Background: Estimation of the intake of oily fish at a population level is difficult. The measurement of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in biological samples may provide a useful biomarker of intake.
Objective: We identified the most appropriate biomarkers for the assessment of habitual oily fish intake and changes in intake by elucidating the dose- and time-dependent response of EPA and DHA incorporation into various biological samples that represent roles in fatty acid transport, function, and storage.
Design: This was a double-blind, randomized, controlled intervention trial in 204 men and women that lasted 12 mo. EPA and DHA capsules were provided in a manner to reflect sporadic consumption of oily fish (ie, 1, 2, or 4 times/wk). EPA and DHA were assessed at 9 time points over 12 mo in 9 sample types (red blood cells, mononuclear cells, platelets, buccal cells, adipose tissue, plasma phosphatidylcholine, triglycerides, cholesteryl esters, and nonesterified fatty acids).
Results: A dose response (P < 0.05) was observed for EPA and DHA in all pools except for red blood cell EPA (P = 0.057). EPA and DHA measures in plasma phosphatidylcholine and platelets were best for the discrimination between different intakes (P < 0.0001). The rate of incorporation varied between sample types, with the time to maximal incorporation ranging from days (plasma phosphatidylcholine) to months (mononuclear cells) to >12 mo (adipose tissue).
Conclusions: Plasma phosphatidylcholine EPA plus DHA was identified as the most suitable biomarker of acute changes in EPA and DHA intake, and platelet and mononuclear cell EPA plus DHA were the most suitable biomarkers of habitual intake. This trial was registered at Current Controlled Trials (www.controlled-trials.com) as ISRCTN48398526.
doi:10.3945/ajcn.112.041343
PMCID: PMC3441107  PMID: 22932281
23.  Workshop Report UK Food Standards Agency Workshop Report: carbohydrate and cardiovascular risk 
The British journal of nutrition  2010;103(11):1688-1694.
This report summarises a workshop convened by the UK Food Standards Agency (FSA) on 14 October 2008 to discuss current FSA-funded research on carbohydrates and cardiovascular health. The objective of this workshop was to discuss the results of recent research and to identify any areas which could inform future FSA research calls. This workshop highlighted that the FSA is currently funding some of the largest, well-powered intervention trials investigating the type of fat and carbohydrate, whole grains and fruit and vegetables, on various CVD risk factors. Results of these trials will make a substantive contribution to the evidence on diet and cardiovascular risk.
doi:10.1017/S0007114510000735
PMCID: PMC3359681  PMID: 20236556
24.  Vascular Dysfunction Induced in Offspring by Maternal Dietary Fat Involves Altered Arterial Polyunsaturated Fatty Acid Biosynthesis 
PLoS ONE  2012;7(4):e34492.
Nutrition during development affects risk of future cardiovascular disease. Relatively little is known about whether the amount and type of fat in the maternal diet affect vascular function in the offspring. To investigate this, pregnant and lactating rats were fed either 7%(w/w) or 21%(w/w) fat enriched in either18:2n-6, trans fatty acids, saturated fatty acids, or fish oil. Their offspring were fed 4%(w/w) soybean oil from weaning until day 77. Type and amount of maternal dietary fat altered acetylcholine (ACh)-mediated vaso-relaxation in offspring aortae and mesenteric arteries, contingent on sex. Amount, but not type, of maternal dietary fat altered phenylephrine (Pe)-induced vasoconstriction in these arteries. Maternal 21% fat diet decreased 20:4n-6 concentration in offspring aortae. We investigated the role of Δ6 and Δ5 desaturases, showing that their inhibition in aortae and mesenteric arteries reduced vasoconstriction, but not vaso-relaxation, and the synthesis of specific pro-constriction eicosanoids. Removal of the aortic endothelium did not alter the effect of inhibition of Δ6 and Δ5 desaturases on Pe-mediated vasoconstriction. Thus arterial smooth muscle 20:4n-6 biosynthesis de novo appears to be important for Pe-mediated vasoconstriction. Next we studied genes encoding these desaturases, finding that maternal 21% fat reduced Fads2 mRNA expression and increased Fads1 in offspring aortae, indicating dysregulation of 20:4n-6 biosynthesis. Methylation at CpG −394 bp 5′ to the Fads2 transcription start site predicted its expression. This locus was hypermethylated in offspring of dams fed 21% fat. Pe treatment of aortae for 10 minutes increased Fads2, but not Fads1, mRNA expression (76%; P<0.05). This suggests that Fads2 may be an immediate early gene in the response of aortae to Pe. Thus both amount and type of maternal dietary fat induce altered regulation of vascular tone in offspring though differential effects on vaso-relaxation, and persistent changes in vasoconstriction via epigenetic processes controlling arterial polyunsaturated fatty acid biosynthesis.
doi:10.1371/journal.pone.0034492
PMCID: PMC3317992  PMID: 22509311
25.  Nutrition issues in Codex: health claims, nutrient reference values and WTO agreements: a conference report 
European Journal of Nutrition  2012;51(Suppl 1):1-7.
Background
Codex documents may be used as educational and consensus materials for member governments. Also, the WTO SPS Agreement recognizes Codex as the presumptive international authority on food issues. Nutrient bioavailability is a critical factor in determining the ability of nutrients to provide beneficial effects. Bioavailability also influences the quantitative dietary requirements that are the basis of nutrient intake recommendations and NRVs.
Health claims
Codex, EFSA and some national regulatory authorities have established guidelines or regulations that will permit several types of health claims. The scientific basis for claims has been established by the US FDA and EFSA, but not yet by Codex. Evidence-based nutrition differs from evidence-based medicine, but the differences are only recently gaining recognition. Health claims on foods may provide useful information to consumers, but many will interpret the information to mean that they can rely upon the food or nutrient to eliminate a disease risk.
Nutrient reference values
NRVs are designed to provide a quantitative basis for comparing the nutritive values of foods, helping to illustrate how specific foods fit into the overall diet. The INL-98 and the mean of adult male and female values provide NRVs that are sufficient when used as targets for individual intakes by most adults.
World Trade Organization agreements
WTO recognizes Codex as the primary international authority on food issues. Current regulatory schemes based on recommended dietary allowances are trade restrictive. A substantial number of decisions by the EFSA could lead to violation of WTO agreements.
doi:10.1007/s00394-012-0306-8
PMCID: PMC3319875  PMID: 22350923
Codex Alimentarius; Bioavailability; Health claims; Nutrient reference values; World Trade Organization; WTO agreements

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