Plasma Long-chain Polyunsaturated Fatty Acids Research Articles

Applying Statistical Methods to Identify Variables Associated With a Beneficial Physiological Response to Fish Oil Intervention

ObjectivesThe primary goal of this analysis was to use baseline and pre-intervention variables from a large dietary intervention study (the FINGEN study) to develop models to predict change in levels of plasma triglycerides (TG), and in the plasma long-chain polyunsaturated fatty acids eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA), after fish oil supplementation. A secondary goal was whether clustering of baseline and pre-intervention data could lead to identification of groups of participants who responded differentially.MethodsAll statistical analyses were undertaken in R, with outcomes of interest kept on a continuous scale. Multiple imputation was conducted which generated 5 complete datasets. Variable selection methods (forward stepwise selection, backward stepwise selection, LASSO and the Boruta algorithm) were applied across each imputed dataset to generate models. Validation methods were applied to minimise model overfitting. Validation set root mean squared errors (RMSEs) were averaged across the 5 imputed datasets, with final model chosen corresponding to the lowest RMSE and therefore most accurate predictions on data not included in model development.ResultsThe final model for predicting TG change contained the predictors pre-intervention TG and baseline fasting insulin and ApoB levels. For EPA + DHA change, these were pre-intervention EPA, DHA and baseline ApoE levels. Both models explained over 40% of variation in the outcome, generated using forward stepwise selection. Unsupervised analysis using baseline and pre-intervention data did not lead to significant differences in the outcomes between clusters.ConclusionsOur models successfully identified predictors of response for plasma triglyceride and EPA + DHA change upon intervention with fish oil. This analysis approach therefore offers opportunities as a tool for precision nutrition approaches, to determine those most likely to respond beneficially to dietary interventions.Funding SourcesBiotechnology and Biological Sciences Research Council (BBSRC) UK and Unilever Foods Innovation Centre, Wageningen, The Netherlands: Collaborative Training Partnership (CTP) PhD.

Maternal Fatty Acid Metabolism in Pregnancy and Its Consequences in the Feto-Placental Development.

During pregnancy, maternal plasma fatty acids are critically required for cell growth and development, cell signaling, and the development of critical structural and functional aspects of the feto-placental unit. In addition, the fatty acids modulate the early stages of placental development by regulating angiogenesis in the first-trimester human placenta. Preferential transport of maternal plasma long-chain polyunsaturated fatty acids during the third trimester is critical for optimal fetal brain development. Maternal status such as obesity, diabetes, and dietary intakes may affect the functional changes in lipid metabolic processes in maternal-fetal lipid transport and metabolism. Fatty acids traverse the placental membranes via several plasma membrane fatty acid transport/binding proteins (FAT, FATP, p-FABPpm, and FFARs) and cytoplasmic fatty acid-binding proteins (FABPs). This review discusses the maternal metabolism of fatty acids and their effects on early placentation, placental fatty acid transport and metabolism, and their roles in feto-placental growth and development. The review also highlights how maternal fat metabolism modulates lipid processing, including transportation, esterification, and oxidation of fatty acids.

FADS2 polymorphisms are associated with plasma arachidonic acid and estimated desaturase-5 activity in a cross-sectional study

Polymorphisms in FADS genes are associated with plasma long-chain polyunsaturated fatty acids (LC-PUFA) and modulate omega-6/omega-3 balance. We hypothesized that the FADS2 gene variants will be associated with lower product-to-precursor ratio in the fatty acid metabolic pathways. Thus, we explored FADS2 rs174593, rs174616, and rs174576 effects on plasma phospholipid fatty acid profile, markers of desaturase activities, and risk factors in a sample of apparently healthy Serbian adults. Food and nutrient intake data were compiled through 24 h recalls. Plasma phospholipid fatty acid content was assessed by gas-chromatography. Estimated desaturase activities were calculated as conversion rates towards LC-PUFA in omega-6 pathway. During the selection of FADS2 polymorphisms, we accounted for their positional and functional aspect. Genotyping was performed by Real-Time PCR. Multivariable-adjusted general linear and hierarchical regression models were applied. Study subjects (mean age = 40 ± 7 years, 70% who were overweight) had a median dietary omega-6/omega-3 ratio of 16.29. Alternative allele frequencies were 33%, 36%, and 51% for rs174593, rs174576, and rs174616, respectively. Addition of FADS2 alternative alleles was associated with lower plasma arachidonic acid (AA, C20:4 n-6, P < .001) and estimated desaturase-5 activity (P < .001), irrespective of gender, age, daily polyunsaturated/saturated fatty acid intake, and obesity. The rs174576 association with AA withstood multiple testing and additional adjustments for other variants (multivariable-adjusted β = −1.14 [95% CI: −2.25, −0.43]). None of the variants was associated with dietary intake, serum lipids, or obesity. We observed inverse associations between FADS2 variants and plasma AA but not omega-3 fatty acids in Serbian subjects, with rs174576 exhibiting the strongest relation.

Maternal dietary deficiency of n-3 fatty acids affects metabolic and epigenetic phenotypes of the developing fetus

Polyunsaturated fatty acids (PUFAs) play multiple physiological roles. They regulate the structure and function of cell membranes and cell growth and proliferation, and apoptosis. In addition, PUFAs are involved in cellular signaling, gene expression and serve as precursors to second messengers such as eicosanoids, docosanoids etc. and regulate several physiological processes including placentation, inflammation, immunity, angiogenesis, platelet function, synaptic plasticity, neurogenesis, bone formation, energy homeostasis, pain sensitivity, stress, and cognitive functions. Linoleic acid, 18:2n-6 (LA) and alpha-linolenic acid, 18:3n-3 (ALA) are the two essential fatty acids obtained from the diets and subsequently their long-chain polyunsaturated fatty acids (LCPUFAs) are accumulated in the body. The maternal plasma LCPUFAs especially accumulated in larger amounts in the brain during the third trimester of pregnancy via the placenta and postnatally from mother's breast milk. Various studies, including ours, suggest PUFA's important role in placentation, as well as in growth and development of the offspring. However, intakes of maternal n-3 PUFAs during pregnancy and lactation are much lower in India compared with the Western population. In India, n-3 fatty acid status is further reduced by higher intake of n-6 PUFA rich oils and trans fats. More data on the impacts of long term maternal n-3 PUFA deficiency on placental structure and function, gene expression, epigenetic changes and resultant cognitive function of fetus & infants are emerging. This review summarizes the impacts of n-3 PUFA deficiency in utero on fetal growth and development, adiposity, energy metabolism, musculoskeletal development, and epigenetic changes in feto-placental axis from the recently available pre-clinical and clinical data.

FADS1 and ELOVL2 polymorphisms reveal associations for differences in lipid metabolism in a cross-sectional population-based survey of Brazilian men and women

Cardiometabolic risk involves environmental and genetic factors. We aimed to investigate the relationship between plasma fatty acids and single nucleotide polymorphisms (SNPs), located in elongase and desaturases genes, and cardiometabolic parameters in a cross-sectional population-based survey. A sample of 226 adults who participated in the Health Survey of Sao Paulo, Brazil, was selected. Clinical and anthropometric variables, plasma lipoprotein, and fatty acid were evaluated. We hypothesized that differences in SNPs could lead to changes in plasma long-chain polyunsaturated fatty acids. We analyzed the relationship between SNPs in FADS1 (rs174546) and ELOVL2 (rs953413) genes, plasma fatty acid profiles, and cardiometabolic-related phenotypes using multiple linear regression, which was adjusted for confounders. Plasma high-density lipoprotein cholesterol and low-density lipoprotein cholesterol levels were significantly lower in carriers of the T allele for the FADS1 SNP. Plasma oleic acid levels were statistically higher in individuals with CT/TT genotypes in the FADS1 and AG/GG genotypes in the ELOVL2 SNPs in comparison to the CC and AA genotypes, respectively. Higher levels of linoleic and linolenic acid were found for T-allele carriers of FADS1 SNP. The estimated activity of the stearoyl CoA desaturase enzyme (SDC_18) was higher in the CT/TT genotypes (FADS1). Delta-5 desaturase estimated activity was statistically lower in the presence of the minor FADS1 allele. The estimated activity of the enzyme delta-6 desaturase was statistically lower for FADS1 CT and TT genotypes. SNPs in FADS1 and ELOVL2 genes showed protective associations for lipid metabolism and could be markers of lower cardiometabolic risk.

Identification of Genetic Loci Associated with Plasma Long-chain Polyunsaturated Fatty Acids in Hispanic Children (P08-129-19)

Abstract Objectives Long-chain polyunsaturated fatty acids (LC-PUFAs) are critical to the functioning of cell membranes as important constituents of phospholipids. They also serve as precursors for prostaglandins, leukotrienes and thromboxanes which affect metabolic processes such as vasodilation, inflammation and cell proliferation. The objective of this study was to identify genes that influence the plasma levels of LC-PUFAs in Hispanic children of the Viva La Familia study. Methods Plasma levels of LC-PUFAs, including eicosapentanoic acid (EPA, 20:5, n-3), docosahexanoic acid (DHA, 22:6, n-3), docosapentanoic acid (DPA, 22:5, n-3), arachidonic acid (20: 4 n-6) and docosapentanoic acid (DPA, 22:5 n-6), were measured as part of metabolomics profiling. Genome-wide single nucleotide polymorphisms (SNP) (array and exome sequence) association analysis (GWAS) were conducted using additive genetic models adjusting for kinships. Results GWAS identified several loci on chromosome 11 with significant evidence of association with LC-PUFAs. These include association of EPA and arachidonic acid with rs174548, rs174545, rs174546, rs174550, 1rs74538 of fatty acid desaturase 1 (FADS1), rs1535, rs174577, rs174568, 174570, 2072114, 2727270 of FADS2, rs174538 of flap structure-specific endonuclease 1 (FEN1), rs174535, rs174528, rs198462, rs174532, rs149803 and rs198464 of myelin regulatory factor (MYRF) and rs102275 and rs102274 of transmembrane protein 258 (TMEM258) (P &lt; 10−12, MAF 5–45%). Other LC-PUFAs showed suggestive evidence of association with the same SNPs. Except for FADS2 SNPs, carriers of minor alleles of all other identified SNPs had lower levels of EPA and arachidonic acid with effect sizes ranging from 5–10%. The analysis of exome variants revealed significant association of EPA with two novel SNPs in syphingomyelin synthase 2 (SGMS2) (P = 1.6 × 10−8) and synaptotagmin 7 (SYT7) (&lt;3 × 10−15, MAF 1.5–33%). The same two loci were associated with arachidonic acid (&lt;6 × 10−9). No significant or suggestive associations were found for other LC-PUFAs. Conclusions In summary, our genome-wide and exome sequencing results replicated the association of EPA and arachidonic acid with FADS and TMEM258 genes and identified novel loci related to neuronal signaling mainly in MYRF, SGMS2 and SYT7. Funding Sources National Institutes of Health (NIH) [DK080457], and the USDA/ARS [Cooperative Agreement 6250-51000-053].

The association of fatty acid desaturase gene polymorphisms on long-chain polyunsaturated fatty acid composition in Indonesian infants

ABSTRACTBackgroundAdequate availability of long-chain polyunsaturated fatty acids (LC-PUFAs) is important for human health from pregnancy to adulthood. Previous studies on fatty acid desaturase (FADS) gene single-nucleotide polymorphisms (SNPs) have been performed predominantly in Western populations and showed that FADS SNPs had a marked impact on LC-PUFA composition in blood and tissues.ObjectivesWe aimed to investigate the influence of fetal FADS genotypes on LC-PUFA composition in umbilical artery plasma lipids in Indonesian infants.DesignWe performed a cross-sectional study to assess for these associations.ResultsA total of 12 cord plasma n–6 (ω-6) and n–3 (ω-3) fatty acids were analyzed for associations with 18 FADS gene cluster SNPs from 390 women with single parturition from the Indonesian Prospective Study of Atopic Dermatitis in Infants (ISADI). Fetal FADS genotypes influenced cord plasma LC-PUFA composition, but, in contrast to previous studies from Western populations, the quantitatively predominant SNPs were associated with lower LC-PUFA content.ConclusionTo our knowledge, this study was the first in South East Asia on FADS genotypes and arterial cord blood fatty acids to show an association between fetal LC-PUFA composition and fetal FADS SNPs. The FADS genotype distribution differs markedly between different geographical populations. This trial was registered at clinicaltrials.gov as NCT02401178.

Variable Methylation Potential in Preterm Placenta: Implication for Epigenetic Programming of the Offspring

Children born preterm are reported to be at increased risk of developing noncommunicable diseases in later life. Altered placental DNA methylation patterns are implicated in fetal programming of adult diseases. Our earlier animal studies focus on micronutrients (folic acid, vitamin B12) and long-chain polyunsaturated fatty acids (LCPUFAs) that interact in the 1 carbon cycle, thereby influencing methylation reactions. Our previous studies in women delivering preterm show altered plasma levels of micronutrients and lower plasma LCPUFA levels. We postulate that alterations in the micronutrient metabolism may affect the regulation of enzymes, methionine adenosyltransferase ( MAT2A), and SAH-hydrolase ( AHCY), involved in the production of methyl donor S-adenosylmethionine (SAM), thereby influencing the methylation potential (MP) in the placenta of women delivering preterm. The present study, therefore, examines the mRNA, protein levels of enzymes ( MAT2A and AHCY), SAM, S-adenosylhomocysteine (SAH) levels, and global DNA methylation levels from preterm (n = 73) and term (n = 73) placentae. The enzyme messenger RNA (mRNA) levels were analyzed by real-time quantitative polymerase chain reaction, protein levels by enzyme-linked immunosorbent assay, and SAM-SAH levels by high-performance liquid chromatography. The mRNA levels for MAT2A and AHCY are higher ( P < .05 for both) in the preterm group as compared to the term group. S-Adenosylmethionine and SAH levels were similar in both groups, although SAM:SAH ratio was lower ( P < .05) in the preterm group as compared to the term group. The global DNA methylation levels were higher ( P < .05) in women delivering small for gestation age infants as compared to women delivering appropriate for gestation age infants at term. Our data showing lower MP in the preterm placenta may have implications for the epigenetic programming of the developing fetus.

Enhanced absorption of long-chain polyunsaturated fatty acids following consumption of functional milk formula, pre-digested with immobilized lipase ex vivo, in an exocrine pancreatic insufficient (EPI) pig model

An exocrine pancreatic insufficient (EPI) pig model was used in the study. The effects of milk formula pre-digestion with immobilized microbial lipase, on the absorption and tissue accretion of long chain polyunsaturated fatty acids (LCPUFA) were assessed. Thirteen male EPI pigs, 10weeks of age, were used in the study. Six healthy pigs, 6weeks of age, were used as controls. The pigs were fed either a regular or a pre-digested milk formula. The formula pre-digestion resulted in the decreased faecal total fat and LCPUFA excretion (by 43% and 38% respectively), increased plasma and tissue LCPUFA content (up to 38%). In conclusion, we postulate that feeding a pre-digested milk formula, is an efficient method to develop a functional milk formula, the consumption of which will ensure an increase in total fat absorption (in particular LCPUFA) in human infants as was indicated in the present study in the EPI pig model.

Neonatal fatty acid profiles are correlated with infant growth measures at 6 months.

Rapid weight gain in infancy and low levels of n-3 long chain polyunsaturated fatty acids (LCPUFA) at birth are associated with increased adiposity later in life. The association between placental LCPUFA delivery and weight gain in infancy is poorly understood. We sought to determine the relationships between maternal phenotype, placental fatty acid transporter expression and offspring growth patterns over the first 6 months. Placental tissue and cord blood were collected at term delivery from women with uncomplicated pregnancies. Offspring body composition measurements were recorded 1 day and 6 months after birth. Body mass index (BMI) z-scores were determined using World Health Organization 2006 reference data. Body phenotype patterns were compared among offspring who had an increase in BMI z-score and those who had a decrease. High skinfold thickness at birth and positive change in BMI z-scores during infancy were associated with low neonatal n-3 LCPUFA plasma levels (r=-0.46, P=0.046) and high saturated fatty acids levels (r=0.49, P=0.034). Growth of skinfolds over 6 months of age was associated with placental fatty acid transporter gene expression. Change in BMI z-score in the first 6 months of life correlated with arm muscle area growth, a measure of lean mass (r=0.62, P=0.003), but not with growth in skinfold thickness. Early infancy weight gain was associated with poor plasma LCPUFA status at birth, and fat deposition in infancy was related to changes in placental lipid handling. Thus, neonatal fatty acid profiles may influence the trajectory of infant growth and fat and lean mass deposition.

Genetic variants of FADS gene cluster, plasma LC-PUFA levels and the association with cognitive function of under-two-year-old Sasaknese Indonesian children.

Long-chain polyunsaturated fatty acids (LC-PUFA) are regarded as essential for child cognition. Genetic variation in fatty acid (FA) desaturase enzyme (FADS) has been recognized as an important effect modifier in the relation between LC-PUFA and child cognitive function. This study aimed to identify the distribution of genetic variant (genotype) SNP rs174468 and to assess plasma FA and developmental outcome by the genotype among under-2 year old Sasaknese Indonesian children. Data was collected at baseline of a randomized trial (NUPICO, clinicaltrials.gov NCT01504633) in East Lombok district, Indonesia. Breastfed, 12- 17 month old children were recruited and 240 subjects were included in the study. Child cognition was assessed as Bayley Mental Developmental Index (MDI). From 206 subjects whose blood samples can be collected, only two genotypes were found (90.3% GG homozygotes, 9.7% AG heterozygotes), and minor allele AG was significantly associated with higher level of arachidonic acid (20:4 n-6), n-6 LC-PUFA and FADS1 index. MDI score was associated with a FADS2 index (DHA:EPA ratio) but not genotype (Adjusted R-square= 0.043). FADS2 index was associated with cognitive function. No difference was found between children with GG and AG genotypes who were all breastfed and not low birth weight.

Omega-3 fatty acids are inversely related to callous and unemotional traits in adolescent boys with attention deficit hyperactivity disorder

A number of research studies have reported abnormal plasma fatty acid profiles in children with ADHD along with some benefit of n−3 to symptoms of ADHD. However, it is currently unclear whether (lower) long chain-polyunsaturated fatty acids (LC-PUFAs) are related to ADHD pathology or to associated behaviours. The aim of this study was to test whether (1) ADHD children have abnormal plasma LC-PUFA levels and (2) ADHD symptoms and associated behaviours are correlated with LC-PUFA levels. Seventy-two, male children with (n=29) and without a clinical diagnosis of ADHD (n=43) were compared in their plasma levels of LC-PUFA. Plasma DHA was higher in the control group prior to statistical correction. Callous–unemotional (CU) traits were found to be significantly negatively related to both eicosapentaenoic acid (EPA), and total omega-3 in the ADHD group. The findings unveil for the first time that CU and anti-social traits in ADHD are associated with lower omega-3 levels.

Fatty-acid composition of maternal and umbilical cord plasma and early childhood atopic eczema in a Spanish cohort

Fatty-acid status during in-utero development might influence the risk of atopic diseases in early childhood. The aim of this work was to identify the relationship between maternal plasma and cord blood fatty acid (FA) composition and the risk of atopic eczema in the offspring at 14 months of age. Two hundred and eleven non-atopic mothers and their children were studied. Mothers were recruited in their first trimester of gestation and children were monitored until 14 months of age. Samples of maternal plasma and cord blood plasma were analyzed to determine the FA profile of total lipids. Presence of atopic eczema in the infants was documented through questionnaires at 6 and 14 months of age. Higher concentrations of total long-chain polyunsaturated FA (LC-PUFA) were found in maternal plasma of non-atopic children in relation to atopic group. Moreover, this maternal plasma LC-PUFA content was negatively correlated with the atopic eczema (odds ratios (OR)=0.83, P=0.04) in infants. Regarding cord blood samples, docosahexaenoic acid (DHA C22:6n3) and the sum of total n-3 and of LC-PUFA n-3 showed a negative correlation with the prevalence of the disease (OR=0.50, 0.49 and 0.49, respectively). Our results show that the fatty-acid status of the fetus during pregnancy has an important role in the development of atopic eczema in early childhood. The prevalence of this atopic disorder is related to lower cord blood plasma levels of FA belonging to n-3 series, especially DHA.

Ethnicity, plasma phospholipid fatty acid composition and inflammatory/endothelial activation biomarkers in the Multi-Ethnic Study of Atherosclerosis (MESA)

It has been recognized that certain long-chain polyunsaturated fatty acids (LC-PUFAs) are involved in inflammation and its resolution. It has also been shown that ethnicity may be a factor in affecting systemic inflammation, and limited evidence suggests it may influence plasma LC-PUFA composition. Given the links among these three factors, we aim to determine ethnicity-based differences in plasma LC-PUFA composition among White, Black, Hispanic and Chinese participants, and whether such differences contribute to variations in markers of inflammation and endothelial activation in a sub-cohort of the Multi-Ethnic Study of Atherosclerosis (MESA). Plasma phospholipid LC-PUFAs levels (%) were determined in 2848 MESA participants using gas chromatography-flame ionization detection. Enzyme immunoassays determined inflammatory markers levels for high-sensitivity C-reactive protein (n=2848), interleukin-6 (n=2796), soluble tumor necrosis factor-α receptor type 1 (n=998), and endothelial activation markers soluble intercellular adhesion molecule-1 (n=1192) and soluble E-selectin (n=998). The modifying influence of ethnicity was tested by linear regression analysis. Chinese adults were found to have the highest mean levels of plasma eicosapentaenoic acid (EPA, 1.24%) and docosahexaenoic acid (DHA, 4.95%), and the lowest mean levels of γ-linolenic (0.10%), dihomo-γ-linolenic (DGLA, 2.96%) and arachidonic (10.72%) acids compared with the other ethnicities (all P ≤ 0.01). In contrast, Hispanics had the lowest mean levels of plasma EPA (0.70%) and DHA (3.49%), and the highest levels of DGLA (3.59%; all P ≤ 0.01). Significant differences in EPA and DHA among ethnicities were attenuated following adjustment for dietary non-fried fish and fish oil supplementation. Ethnicity did not modify the associations of LC-PUFAs with markers of inflammation or endothelial activation (all P (interaction)>0.05). The absence of a modifying effect of ethnicity indicates that the putative benefits of LC-PUFAs with respect to inflammation are pan-ethnic. Future longitudinal studies may elucidate the origin(s) of ethnicity-based differences in LC-PUFA composition and whether certain patterns, that is, high plasma levels of DGLA and low levels of EPA/DHA, contribute to inflammation-associated health outcomes.

Plasma long-chain fatty acids profile and metabolic outcomes in normolipidaemic obese children after one-year nutritional intervention

To assess the association between changes in plasma long-chain polyunsaturated fatty acids (LCPUFAs) profile and metabolic outcomes after 1-year nutritional intervention in normolipidaemic obese children. Fifty-seven normolipidaemic obese children, aged 8-13 years, were recruited in the study. Body mass index (BMI) z-scores were calculated. Fasting blood samples were analysed for insulin, glucose, lipid profile and fatty acid (FA) levels at baseline and after an 1-year nutritional-behaviour intervention. Insulin resistance was estimated by homeostatic model assessment (HOMA). Fifty-one obese children completed the study. At the end of the intervention, the children showed decreased BMI z-score (mean reduction 0.25; 95% confidence interval [CI], 0.18-0.31), HOMA index (1.6; 0.6-2.5), plasma-saturated FA (1.49; 0.67-2.31 mg/dL), C20:3n-9 (0.05; 0.02-0.07 mg/dL) and increased plasma levels of monounsaturated FA (mean increase 1.35; 0.63-2.07 mg/dL), n-6 PUFA (1.02; 0.08-1.97 mg/dL), n-3 PUFA (0.24; 0.07-0.40 mg/dL), C20:4n-6 (0.37; 0.11-0.63 mg/dL), C18:3n-3 (0.04; 0.01-0.07 mg/dL), C22:6n-3 (0.30; 0.17-0.42 mg/dL) and the C22:6n-3/C20:4n-6 ratio (0.02; 0.01-0.03 mg/dL) ratio. Nutritional interventions may improve plasma LCPUFA profile and metabolic outcomes of normolipidaemic obese children.

Long-chain polyunsaturated fatty acid concentration in patients with inborn errors of metabolism

Long-chain polyunsaturated fatty acid (LCPUFA) can be provided by diet (fatty fish, eggs, viscera and human milk) or synthetised from essential fatty acids linoleic and α-linolenic acids through the microsomal pathway. However, endogenous LCPUFA synthesis is rather low, especially for docosahexaenoic (DHA), and seems insufficient to achieve normal DHA values in individuals devoid of preformed dietary supply. Inborn errors of metabolism (IEMs) are therefore diseases with a special risk for LCPUFA deficient status. Our aim was to evaluate LCPUFA status in 132 patients with different IEMs. We performed a cross-sectional study of plasma and erythrocyte LCPUFA composition of 63 patients with IEMs treated with protein-restricted diets compared with data from 69 patients with IEMs on protein-unrestricted diets, and 43 own reference values. Erythrocyte and plasma DHA and arachidonic acid concentrations were significantly decreased in patients treated with protein-restriction compared with those on protein-unrestricted diets and with our reference values (p < 0.0001). In the protein-restricted group, 45% of patients showed decreased erythrocyte and plasma DHA values (only 7% and 10%, respectively in the protein-unrestricted group) (p < 0.0001). Erythrocyte and plasma DHA values correlated with the natural protein intake in patients on protein-restriction (r = 0.257; p = 0.045; r = 0.313; p = 0.014, respectively). Plasma and erythrocyte DHA concentrations are decreased in patients with IEMs treated with protein restriction. DHA concentration correlates with the patients' protein intake. Supplementation of patients with LCPUFA would have a beneficial influence on their nutritional status.

Omega-3 long chain fatty acid synthesis is regulated more by substrate levels than gene expression

The conversion of linoleic acid (LA) and alpha-linolenic acid (ALA) to long chain polyunsaturated fatty acids (LCPUFA) is known to involve desaturation and elongation steps. Although there is evidence that genes for these steps can be regulated by extremes of dietary PUFA, the degree to which there is meaningful regulation of LCPUFA levels in tissues by diet as a result of changes in expression of desaturase and elongase genes is unclear. In this study, we tested the effect of increasing ALA levels in diets of rats from 0.2% to 2.9% energy (en) against a constant LA level (1%en) on plasma and liver phospholipid LCPUFA content together with the expression of hepatic genes involved in PUFA metabolism, the desaturases FADS1 and FADS2, the elongases ELOV2 and ELOV5, and the transcription factors sterol regulatory element-binding protein-1c (SREBP-1c) and peroxisome proliferator-activated receptor alpha (PPARα). The levels of plasma and liver eicosapentaenoic acid (EPA) and docosapentaenoic acid (DPA) increased in proportion to dietary ALA whereas docosahexaenoic acid (DHA) increased only up to 1%en ALA. A low PUFA (0.4%en) reference diet stimulated the expression of delta 6 desaturase (FADS2) and elongase 2 (ELOVL2) when compared to higher PUFA diets. There was, however, no difference in the expression of any of the genes in rats, which were fed diets containing between 0.2%en and 2.9%en ALA and mRNA expression was unrelated to tissue/plasma LCPUFA content. These data suggest that the endogenous synthesis of n−3 LCPUFA from the precursor ALA is regulated independently of changes in the expression of the synthetic enzymes or regulatory transcription factor, and provides evidence that n−3 LCPUFA synthesis is regulated more by substrate competition for existing enzymes than by an increase in their mRNA expression.

Dietary intake and plasma concentrations of PUFA and LC-PUFA in breastfed and formula fed infants under real-life conditions

The breastfed infant is usually used as standard for formula feeding, also regarding long-chain polyunsaturated fatty acids (LC-PUFA). Here, plasma fatty acid concentrations in formula fed infants and the effects of LC-PUFA supplementation were investigated under real-life conditions. Term healthy infants being fully milk fed until the age of 4 months were categorized as breast milk "BM" (n = 73) if consuming >95% of energy from breast milk or formula (F) if consuming >95% of energy from formula subdivided into formula without (F-) (n = 15) and with LC-PUFA supplementation (F+) (n = 15). Formula as marketed was chosen by the parents. Dietary fatty acids (FA) intake was calculated from continuous dietary records from 2 months of age onwards. Total plasma FA were analyzed at the age of 4 months with docosahexaenoic acid (DHA) as primary outcome. Dietary ratios of the polyunsaturated fatty acids (PUFA; linoleic acid/alpha-linolenic acid) were smaller in both F groups than in the BM group. Plasma DHA as % of total FA was similar in BM and F(+) but higher in BM in absolute amounts (mg/L). Plasma DHA as % of total FA in F(-) was higher than what might be supposed on the basis of dietary intake. Infants consuming present-day LC-PUFA-supplemented formula achieved plasma LC-PUFA concentrations similar to breastfed infants. In infants consuming non-LC-PUFA-supplemented formula, the favorable PUFA pattern of the formula may have supported n-3 LC-PUFA biosynthesis.

The Relationship of Insulin Resistance With SNP 276G&gt;T at Adiponectin Gene and Plasma Long-Chain Polyunsaturated Fatty Acids in Obese Children

This study examined the association of insulin resistance with single-nucleotide polymorphism (SNP) 276G>T at adiponectin gene and the plasma long-chain polyunsaturated fatty acids (LCPUFAs) profile in obese children. One hundred thirty-one normolipidaemic obese children aged 8-13 y (53 girls and 68 boys) entered the study. The prevalence of T allele carriers at SNP276 was 48.8%. Mean [SD] values of fasting insulin and homeostasis model assessment-insulin resistance (HOMA-IR) index in noncarriers versus carriers of T allele were 12.4 [6.4] versus 20.6 [6.3] muU/mL (p = 0.039) and 2.6 [1.4] versus 4.5 [1.7] (p = 0.032). Mean [SD] values of plasma C18:3n - 3, C20:5n - 3/C20:4n - 6, and n - 6/n - 3 LCPUFA in phospholipids in noncarriers versus carriers of T allele were 0.10 [0.04] versus 0.08 [0.03] % (p = 0.013), 0.04 [0.01] versus 0.03 [0.01] % (p = 0.045), and 4.4 [0.7] versus 4.9 [0.9] % (p = 0.005), respectively. Insulin resistance was independently associated with SNP 276G>T (p = 0.002) and n - 6/n - 3 LCPUFA (p = 0.042) in plasma phospholipids, and interaction was found between SNP 276G>T and n - 6/n - 3 LCPUFA (p = 0.046). These findings suggest that obese children carriers of the SNP 276G>T may be at increased risk of metabolic complications compared with noncarriers, possibly due in part to a different plasma phospholipids profile.

Characteristics of obese children with low content of arachidonic acid in plasma lipids

Although there have been many studies on the relationship between obesity and long-chain polyunsaturated fatty acid (LCPUFA), the results and their interpretation are controversial, especially in children. Arachidonic acid (AA), the product of n-6 LCPUFA, is reported to be related to insulin resistance. The purpose of the present paper was to investigate the LCPUFA profile in obese children and mechanisms that contribute to reduced AA content. An age- and sex-matched control study was performed. The study subjects were 59 obese children (mean age, 11.8 years) and 53 healthy non-obese children (mean age, 12.5 years). The study parameters included anthropometric measurements, serum lipids, leptin and fatty acid composition in plasma. Plasma fatty acids in obese children had lower linoleic acid (P < 0.0001) and higher dihomo-gamma-linolenic acid (P = 0.0004) than those in non-obese children. In all subjects combined, delta-6 desaturase (D6D) index (ratios of [C 18:3n-6+C 20:2n-6]/C 20:4n-6 or C 20:4n-6/C 18: 2n-6) correlated with leptin (P < 0.0001). There was no significant difference in AA content between obese and non-obese. However, the AA content was low (<mean - 1SD in controls) in 27.1% of obese children, in whom D6D index was not elevated in spite of high insulin concentration. Obese children had changes in plasma LCPUFA profile that indicate upregulation of n-6 LCPUFA metabolism, probably caused by activated D6D activity to compensate AA demand. Heterogeneity of AA content in obese children depends on D6D and delta-5-desaturase activity, which may reflect insulin sensitivity.