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Maize which has very high omega-6 fatty acid content has been used as a main feed grain for Hanwoo beef production to increase marbling, and thus omega-6 to omega-3 fatty acids ratio in Hanwoo beef is expected to be biased. To elucidate the current status of omega fatty acids ratio in Hanwoo beef, fatty acid profiles of neutral lipid and phospholipid fraction were analyzed separately using 55 Hanwoo steers' Show less

Gestational diabetes mellitus (GDM) is a carbohydrate intolerance that occurs in women during pregnancy. The aims of this study were to develop a model to predict the risk of GDM development using common clinical parameters and selected genetic polymorphisms and to analyse the performance of the model using receiver operator characteristic (ROC) curves. ROC analysis was used to examine whether the evaluation of genetic polymorphisms may enhance the accuracy of GDM prediction in comparison to using common clinical risk factors only. This study included 204 pregnant women with GDM and 207 pregnant women with normal glucose tolerance. The diagnosis of GDM was based on a 75 g oral glucose tolerance test at 24-28 weeks gestation. The difference between the AUC of ROC curves for the model 1 including only age and BMI and the model 2 also including 8 genetic polymorphisms was highly significant (p=0.0001) in favour of model 2 (0.090±0.023). Moreover, the additional use of 8 genetic polymorphisms may increase both the sensitivity and specificity of GDM prediction by 10%. The results of this study indicate that the use of 8 genetic polymorphisms associated with carbohydrate and lipid metabolism and type 2 diabetes [ Show less

Statins have been reported to increase the plasma concentration of arachidonic acid (AA), an omega-6 long chain polyunsaturated fatty acid (LCPUFA) in several clinical studies indicating that statins affect the endogenous synthesis of LCUFAs. In the present study, we investigated the roles of the intrinsic mevalonate cascade and Rho-dependent pathway in LCPUFA synthesis, especially focusing on fatty acid desaturases (Fads) 2, using the human hepatocellular carcinoma cell line HepG2. Cell number and the activity of caspase-3 and 7 (caspase-3/7) was measured using a commercial kit. Gene expression was analyzed by quantitative real-time PCR. Protein expression was detected by Western blot analysis. Atorvastatin decreased cell viability and increased caspase-3/7 activity in a dose-dependent manner. At lower concentrations, atorvastatin stimulated both mRNA and protein expression of Fads2, and increased mRNA expression of FADS1 and ELVOL5. Both mevalonate and geranylgeranyl-pyrophosphate (GGPP), but not cholesterol, fully reversed atorvastatin-induced upregulation of Fads2, and mevalonate-effected reversal was inhibited by treatment with the Rho-associated protein kinase inhibitor Y-27632. These data clearly demonstrated that in human HepG2 cells, statins affect the endogenous synthesis of LCPUFAs by regulation of not only Fads2, but also Fads1 and Elovl5, through the GGPP-dependent Rho kinase pathway. Show less

Arthrogryposis multiplex congenita (AMC) refers to an aetiologically heterogenous condition, which consists of joint contractures affecting two or more joints starting prenatally. The incidence is approximately one in 3000 live births; however, the prenatal incidence is higher, indicating a high intrauterine mortality. Over 320 genes have been implicated showing the genetic heterogeneity of the condition. AMC can be of extrinsic aetiology resulting from intrauterine crowding secondary to congenital structural uterine abnormalities (eg, bicornuate or septate uterus), uterine tumors (eg, fibroid), or multifetal pregnancy or intrinsic/primary/fetal aetiology, due to functional abnormalities in the brain, spinal cord, peripheral nerves, neuromuscular junction, muscles, bones, restrictive dermopathies, tendons and joints. Unlike many of the intrinsic/primary/fetal causes which are difficult to treat, secondary AMC can be treated by physiotherapy with good response. Primary cases may present prenatally with fetal akinesia associated with joint contractures and occasionally brain abnormalities, decreased muscle bulk, polyhydramnios, and nonvertex presentation while the secondary cases usually present with isolated contractures. Complete prenatal and postnatal investigations are needed to identify an underlying aetiology and provide information regarding its prognosis and inheritance, which is critical for the obstetrical care providers and families to optimize the pregnancy management and address future reproductive plans. Show less

Fetal akinesia deformation sequence (FADS) and lethal multiple pterygium syndrome (LMPS) are clinically overlapping syndromes manifesting with reduced or absent fetal movement, arthrogryposis, and several anomalies during fetal life. The etiology of these syndromes is heterogeneous, and in many cases it remains unknown. In order to determine the genetic etiology of FADS in two fetuses with fetal akinesia, arthrogryposis, edema, and partial cleft palate, we utilized exome sequencing. Our investigations revealed a homozygous nonsense variant [c.1116C>A, p.(Cys372Ter)] in the SLC18A3 gene, which encodes for the vesicular acetylcholine transporter (VAChT) responsible for active transport of acetylcholine in the neuromuscular junction. This is the first description of a nonsense variant in the SLC18A3 gene, as only missense variants and whole gene deletions have been previously identified in patients. The previously detected SLC18A3 defects have been associated with congenital myasthenic syndromes, and therefore our findings extend the clinical spectrum of SLC18A3 defects to severe prenatal phenotypes. Our findings suggest that nonsense variants in SLC18A3 cause a more severe phenotype than missense variants and are in line with previous studies showing a lethal phenotype in VAChT knockout mice. Our results underline the importance of including SLC18A3 sequencing in the differential diagnostics of fetuses with arthrogryposis, FADS, or LMPS of unknown etiology. Show less

Hepatic fatty acid oxidation of yolk lipoproteins provides the main energy source for chick embryos. Post-hatching these yolk lipids are rapidly exhausted and metabolism switches to a carbohydrate-based energy source. We recently demonstrated that many microRNAs (miRNAs) are key regulators of hepatic metabolic pathways during this metabolic switching. MiRNAs are small non-coding RNAs that post-transcriptionally regulate gene expression in most eukaryotes. To further elucidate the roles of miRNAs in the metabolic switch, we used delayed feeding for 48 h to impede the hepatic metabolic switch. We found that hepatic expression of several miRNAs including Show less

Recombinant human relaxin-2, serelaxin, is being proved as a novel drug with therapeutic efficacy in some cardiovascular diseases, especially heart failure, a disease whose physiopathology and course are firmly correlated with important alterations in cardiac metabolism. The aim of our present work was to investigate changes in the cardiac metabolome following relaxin-2 treatment. Sprague-Dawley rats were treated with human recombinant relaxin-2 using osmotic minipumps at a dose of 0.4 mg/kg/day for 2 weeks. Body composition was measured with a nuclear magnetic resonance imaging system seven days after surgery and on the final day of the experiment. The last two days of treatment, respiratory quotient, locomotor activity and energy expenditure were measured with a calorimetric system. The plasma levels of relaxin-2, total cholesterol, high- and low- density lipoproteins (HDL, LDL), triglycerides and the hepatic enzymes glutamic-pyruvic transaminase (GTP) and gamma-glutamyltransferase (GGT) levels were analyzed. The metabolic profiling of both atria from relaxin-2-treated and control rats was carried out using two separate ultra-high performance liquid chromatography (UHPLC)-Time of Flight-MS based platforms analyzing methanol and chloroform/methanol extracts combined with a UHPLC-single quadrupole-MS based platform used to analyze aminoacids and with a methanol/water extract platform that covered polar metabolites. Identified ion features in the methanol extract platform included fatty acids, acyl carnitines, bile acids, monoacylglycerophospholipids, monoetherglycerophospholipids, free sphingoid bases, and oxidized fatty acids. The chloroform / methanol extract platform provided coverage over glycerolipids, cholesterol esters, sphingolipids, diacylglycerophospholipids, and acyl-ether-glycerophospholipids. Gene expression levels of the adipokines adiponectin, leptin and nesfatin-1 in visceral adipose tissue and cardiac gene expression levels of key enzymes of desaturation and elongation of n-6 and n-3 PUFAs were assessed by Real Time-PCR. Twenty-eight metabolites out of three hundred sixty-two were significantly altered by human relaxin-2. These included fifteen glycerophospholipids: three phosphatidylethanolamines (PE) and twelve phosphatidylcholines (PC); eight sphingolipids: three ceramides (Cer) and five sphingomyelins (SM); and also five aminoacids and one carboxylic acid. Interestingly, the majority of changes correspond to lipid classes, twelve of them polyunsaturated diacylglycerophosphatidylcholines with long acyl chains, containing mainly docosahexaenoic acid (22:6) and arachidonic acid (20:4). Atrial levels of Elovl5 (Elongation of very long chain fatty acids protein 5), Fads1 (Δ5-fatty acid desaturase) and Fads2 (Δ6-fatty acid desaturase), key enzymes of elongation and desaturation of n-6 and n-3 PUFAs like arachidonic acid and DHA, respectively, were significantly increased by relaxin-2 treatment. Atrial tissues from rats treated with relaxin-2 showed a significant increase in the mRNA levels of Srebf1, a transcription factor that activates the gene expression of Elovl5, Fads1 and Fads2. The treatment with relaxin-2 significantly decreased the visceral fat mRNA expression levels of adiponectin, leptin and nesfatin-1, adipokines known to exert an important influence on the regulation of cardiovascular function. Serelaxin (human recombinant relaxin-2) treatment induces significant changes in cardiac major components of the membrane lipid bilayer such as glycerophospholipids and sphingolipids, known to have structural roles but also very relevant regulatory effects in cardiac function. Serelaxin induced also modifications in several aminoacids of high influence in cardiac energy metabolism regulation. Our results highlight the need to further understand the role of relaxin-2 in the regulation of cardiac energy metabolism, in the context of the therapeutic strategies for the treatment of cardiometabolic pathologies as heart failure. Show less

Disturbed calcium homeostasis has detrimental effects on brain development and function, particularly in early life because of epigenetic determination of early nutrition on later health. We hypothesized that the imbalance of calcium status in early life might have long-lasting effects on brain DHA accretion though epigenetic modification on fatty acid desaturases (Fads). Three to four week old C57BL/6J female mice were fed 3 reproductive diets with different calcium concentrations - low (LC, 0.25%), normal (NC, 0.70%) and high-calcium (HC, 1.20%) respectively throughout pregnancy and lactation. Maternal LC diet reduced tissue (brain and hepatic) DHA concentrations in both male and female offsprings at postnatal 21 day, with reductions in male instead of female offsprings in adulthood. Maternal HC diet only reduced hepatic DHA concentration in adult male offsprings. Furthermore, maternal LC diet reduced hepatic but increased brain expressions of Fads1 or Fads2 in 21-days old offsprings, with similar changes in adult male instead of female offsprings. Maternal HC diet reduced hepatic or brain expressions of Fads1 or Fads2 in 21-days old offsprings, and only reduced Fads2 in the liver with adult male offsprings. Determination of DNA methylation (CpG4, CpG5, CpG7,8, CpG14-17 and CpG19) showed that maternal LC diet caused hypermethylation of Fads2 promoter in the liver and hypomethylation in the brain in 21-days old offsprings, as well as in adult male offsprings. These data demonstrate that the imbalance of calcium intake in early life might have long-term gender-specific effects on brain accretion of DHA mediated by altered DNA methylation and associated expressions of Fads. Show less

Metabolic rewiring has been recognized as an important feature to the progression of cancer. However, the essential components and functions of lipid metabolic networks in breast cancer progression are not fully understood. In this study, we investigated the roles of altered lipid metabolism in the malignant phenotype of breast cancer. Using a spheroid-induced epithelial-mesenchymal transition (EMT) model, we conducted multi-layered lipidomic and transcriptomic analysis to comprehensively describe the rewiring of the breast cancer lipidome during the malignant transformation. A tremendous homeostatic disturbance of various complex lipid species including ceramide, sphingomyelin, ether-linked phosphatidylcholines, and ether-linked phosphatidylethanolamine was found in the mesenchymal state of cancer cells. Noticeably, polyunsaturated fatty acids composition in spheroid cells was significantly decreased, accordingly with the gene expression patterns observed in the transcriptomic analysis of associated regulators. For instance, the up-regulation of Show less

Studies have shown that the reduction in serum TAG concentrations with long-chain n-3 fatty acid supplementation is highly variable among individuals. The objectives of the present study were to compare the proportions of individuals whose TAG concentrations lowered after high-dose DHA and EPA, and to identify the predictors of response to both modalities. In a double-blind, controlled, crossover study, 154 men and women were randomised to three supplemented phases of 10 weeks each: (1) 2·7 g/d of DHA, (2) 2·7 g/d of EPA and (3) 3 g/d of maize oil, separated by 9-week washouts. As secondary analyses, the mean intra-individual variation in TAG was calculated using the standard deviation from the mean of four off-treatment samples. The response remained within the intra-individual variation (±0·25 mmol/l) in 47 and 57 % of participants after DHA and EPA, respectively. Although there was a greater proportion of participants with a reduction >0·25 mmol/l after DHA than after EPA (45 υ. 32 %; P 0·25 mmol/l after both DHA and EPA had higher non-HDL-cholesterol, TAG and insulin concentrations compared with other responders at baseline (all P < 0·05). In conclusion, supplementation with 2·7 g/d DHA or EPA had no meaningful effect on TAG concentrations in a large proportion of individuals with normal mean TAG concentrations at baseline. Although DHA lowered TAG in a greater proportion of individuals compared with EPA, the magnitude of TAG lowering among them was similar. Show less

Fatty acyl composition of cell membrane lipids, particularly the abundance of highly unsaturated docosahexaenoic fatty acid (22:6n-3, DHA), is likely to be an important predictor of basal metabolic rate (BMR). Our study was performed using two lines of laboratory mice divergently selected for either high or low BMR. We describe a novel single nucleotide polymorphism in the Fads2 gene encoding Δ6-desaturase, a key enzyme in the metabolic pathways of polyunsaturated fatty acids (PUFAs). The allele frequencies of Fads2 were significantly different in both lines of mice. The analysis of genetic distances revealed that the genetic differentiation between the two studied lines developed significantly faster at the Fads2 locus than it did at neutral loci. Such a pattern suggests that the Fads2 polymorphism is related to the variation in BMR, i.e. the direct target of selection. The Fads2 polymorphism significantly affected abundance of several PUFAs; however, the differences in PUFA composition between lines were compatible with the difference in frequency of Fads2 alleles only for DHA. We hypothesize that the polymorphism in the Fads2 gene affects the BMR through modification of DHA abundance in cell membranes. This may be the first example of a significant link between a polymorphism in a gene responsible for fatty acyl composition and variation in BMR. Show less

As cardiovascular events are one of the main causes of death in developed countries, each factor potentially increasing the risk of cardiovascular disease deserves special attention. One such factor is the potentially atherogenic effect of lead (Pb) on lipid metabolism, and is significant in view of the still considerable Pb environmental pollution and the non-degradability of Pb compounds. Analysis of saturated fatty acids (SFA) (caprylic acid (C8:0), decanoic acid (C10:0), lauric acid (C12:0), tridecanoic acid (C13:0), myristic acid (C14:0), pentadecanoic acid (C15:0), palmitic acid (C16:0), heptadecanoic acid (C17:0), stearic acid (C18:0), and behenic acid (C22:0)), monounsaturated fatty acid (MUFA) (palmitoleic acid (C16:1), oleic acid (18:1w9), trans-vaccenic acid (C18:1 trans11)), and polyunsaturated fatty acid (PUFA) (linoleic acid (C18:2n6), gamma-linolenic acid (C18:3n6), arachidonic acid (C20:4n6)), was conducted by gas chromatography. Analysis of stearoyl-CoA desaturase (SCD), fatty acid desaturase 1 (FADS1) and fatty acid desaturase 2 (FADS2) expression was performed using qRT-PCR. Oxidative stress intensity (malondialdehyde - MDA concentration) was measured using spectrophotometric method. Intracellular generation of reactive oxygen species (ROS) in macrophages was visualized by fluorescence microscopy and quantitatively measured by plate reader. Pb caused quantitative alterations in FAs profile in macrophages; the effect was Pb-concentration dependent and selective (i.e. concerned only selected FAs). In general, the effect of Pb was biphasic, with Pb levels of 1.25 μg/dL and 2.5 μg/dL being stimulatory, and 10 μg/dL being inhibitory on concentrations of selected FAs. The most potent Pb concentration, resulting in increase in levels of 9 FAs, was 2.5 μg/dL, the Pb-level corresponding to the mean blood Pb concentrations of people living in urban areas not contaminated by Pb. Pb was found to exert similar, biphasic effect on the expression of FADS1. However, Pb decreased, in a concentration-dependent manner, the expression of SCD and FADS2. Pb significantly increased MDA and ROS concentration in macrophages. Environmental Pb exposure might be a risk factor resulting in alterations in FAs levels, oxidative stress and increased MDA concentration in macrophages, which might lead to the formation of foam cells and to inflammatory reactions. Show less

Non-alcoholic fatty liver disease has been associated with increased mRNA expression of FADS2 in the liver and estimated activity of delta-6 desaturase in serum, encoded by the FADS2 gene. Since DNA methylation in the FADS1/2/3 gene cluster has been previously linked with genetic variants and desaturase activities, we now aimed to discover factors regulating DNA methylation of the CpG sites annotated to FADS1/2 genes. DNA methylation levels in the CpG sites annotated to FADS2 and FADS1 were analyzed from liver samples of 95 obese participants of the Kuopio Obesity Surgery Study (34 men and 61 women, age 49.5 ± 7.7 years, BMI 43.0 ± 5.7 kg/m We found a negative correlation between DNA methylation levels of cg06781209 and cg07999042 and hepatic FADS2 mRNA expression (both p < 0.05), and with estimated delta-6 desaturase activity based on both liver and serum fatty acids (all p < 0.05). Interestingly, the methylation level of cg07999042 (p = 0.001) but not of cg06781209 (p = 0.874) was associated with FADS2 variant rs174616. Genetic variants of FADS2 may contribute to the pathogenesis of non-alcoholic fatty liver disease by modifying DNA methylation. Show less

Fish oil supplementation may represent a potential chemopreventive agent for reducing colorectal cancer risk. The mechanism of action of fish oil is unknown but presumed to be related to eicosanoid modification. The purpose of this study was to evaluate the effects of fish oil supplementation on the levels of urinary and rectal eicosanoids. We conducted a randomized, double-blind, controlled trial of 2.5 g of fish oil per day compared with olive oil supplementation over a 6-month period. Study participants had a history of colorectal adenomas. Randomization was stratified based on the gene variant rs174535 in the fatty acid desaturase 1 enzyme (FADS1), which affects tissue levels of arachidonic acid. A total of 141 participants were randomized. Urinary prostaglandin E2 metabolite (PGE-M) was measured at baseline, 3, and 6 months and rectal prostaglandin E2 (PGE2) at baseline and 6 months. Repeated-measures linear regression was used to determine the effect of the intervention on each outcome measure. Overall, fish oil supplementation was found to reduce urinary PGE-M production compared with olive oil (P=0.03). Fish oil did not reduce rectal PGE2 overall; however, it did significantly reduce PGE2 in the subgroup of participants not using aspirin or NSAIDs (P=0.04). FADS1 genotype did not seem to modify effects of fish oil on PGE2 production. We conclude that fish oil supplementation has a modest but beneficial effect on eicosanoids associated with colorectal carcinogenesis, particularly in those not taking aspirin or NSAIDs. Show less

The health benefits of substituting dietary polyunsaturated fatty acids (PUFAs) for saturated fatty acids are well known. However, limited information exists on how the response to dietary intake of linoleic acid (LA; 18:2n-6) is modified by polymorphisms in the fatty acid desaturase (FADS) gene cluster. The aim of the current study was to test the hypothesis that the FADS1 rs174550 genotype modifies the effect of dietary LA intake on the fatty acid composition of plasma lipids, fasting glucose, and high-sensitivity C-reactive protein (hsCRP). Associations were investigated between genotype, plasma PUFAs, fasting glucose, and hsCRP concentrations in the cross-sectional, population-based Metabolic Syndrome in Men cohort (n = 1337). In addition, 62 healthy men from the cohort who were homozygotes for the TT or CC genotype of the FADS1 rs174550 were recruited to a 4-wk intervention (FADSDIET) with an LA-enriched diet. The fatty acid composition of plasma PUFAs and concentrations of plasma fasting glucose, serum hsCRP, and plasma lipid mediators (eicosanoids and related analogs) were measured at the beginning and end of the 4-wk intervention period. In the FADSDIET trial, the plasma LA proportion increased in both genotype groups in response to an LA-enriched diet. Responses in concentrations of serum hsCRP and plasma fasting glucose and the proportion of arachidonic acid (20:4n-6) in plasma phospholipids and cholesteryl esters differed between genotype groups (interaction of diet × genotype, P < 0.05). In TT homozygous subjects, plasma eicosanoid concentrations correlated with the arachidonic acid proportion in plasma and with hsCRP (r = 0.4-0.7, P < 0.05), whereas in the CC genotype there were no correlations. Our findings show that the FADS1 genotype modifies metabolic responses to dietary LA. The emerging concept that personalized dietary counseling should be modified by the FADS1 genotype needs to be tested in larger randomized trials. The study was registered at clinicaltrials.gov as NCT02543216. Show less

In mammalian species, the Fatty Acid Desaturase (FADS) gene cluster includes FADS1 (∆5-desaturase), FADS2 (∆6-desaturase), and a third gene member, named FADS3. According to its high degree of nucleotide sequence homology with both FADS1and FADS2, FADS3 was promptly suspected by researchers in the field to code for a new mammalian membrane-bound fatty acid desaturase. However, no catalytic activity was attributed to the FADS3 protein for a decade, until the rat FADS3 protein was shown in vitro to be able to catalyze the unexpected ∆13-desaturation of trans-vaccenic acid, producing the trans11,cis13-conjugated linoleic acid isomer. This review summarizes the recent investigations establishing the FADS3 enzyme as a reliable mammalian trans-vaccenate ∆13-desaturase in vivo and tries to identify further unresolved issues that need to be addressed. Show less

The diagnosis of fetal akinesia deformation sequence (FADS) is a challenge. Motor assessment is of additional value to advanced ultrasound examinations (AUE) for in utero FADS diagnosis before 24 weeks of gestation. All consecutive fetuses with greater than or equal to two contractures on the 20 week structural anomaly scan (2007-2016) were included. Findings at AUE, including motor assessment were analysed and related to outcome. Sixty-six fetuses fulfilled the inclusion criteria. On the basis of the first AUE, FADS was suspected in 13 of 66, arthrogryposis multiplex congenita (AMC) in 12 of 66, bilateral pes equinovares (BPEV) in 40 of 66, and Holt-Oram syndrome in one of 66. On the basis of the first motor assessment, the suspected diagnosis changed in 19 of 66, in 13 of 66 worsening to FADS, six of 66 amelioration from FADS, and confirmed FADS in seven of 13. The result was 20 FADS, seven AMC, and 38 BPEV. Second AUE in 44 fetuses showed additional contractures in two of eight FADS, and one intrauterine fetal death (IUFD). The second motor assessment changed the diagnosis in three of 43, one worsening from BPEV into FADS, two ameliorations from FADS, and confirmed FADS in seven by deterioration of motility. The result was nine FADS, six AMC, and 29 BPEV. The results suggest that motor assessment has additional value to distinguish between FADS, AMC, and BPEV. Show less

Conversion of α-linolenic acid (ALA) into the longer chain n-3 PUFA has been suggested to be affected by the dietary intake of linoleic acid (LA), but the mechanism is not well known. Therefore, the purpose of this study was to evaluate the effect of a low-LA diet with and without oestrogen on the fatty acid conversion enzymes and transcription factors. Rats were fed a modified American Institute of Nutrition-93G diet with 0% n-3 PUFA or ALA, containing low or high amounts of LA for 12 weeks. At 8 weeks, the rats were injected with maize oil with or without 17β-oestradiol-3-benzoate (E) at constant intervals for the remaining 3 weeks. Both the low-LA diet and E significantly increased the hepatic expressions of PPAR-α, fatty acid desaturase (FADS) 2, elongase of very long chain fatty acids 2 (ELOVL2) and ELOVL5 but decreased sterol regulatory element binding protein 1. The low-LA diet, but not E, increased the hepatic expression of FADS1, and E increased the hepatic expression of oestrogen receptor-α and β. The low-LA diet and E had synergic effects on serum and liver levels of DHA and on the hepatic expression of PPAR-α. In conclusion, the low-LA diet and oestrogen increased the conversion of ALA into DHA by upregulating the elongases and desaturases of fatty acids through regulating the expression of transcription factors. The low-LA diet and E had a synergic effect on serum and liver levels of DHA through increasing the expression of PPAR-α. Show less

The aim of this study was to determine if the dietary pattern of pregnant women has any compensatory effect on the fatty acid desaturase (FADS) gene expression, thus enhancing the conversion of precursors to long chain polyunsaturated fatty acids (LCPUFA) to spare the overall LCPUFA levels. The dietary intake of plant-based precursor polyunsaturated fatty acids (PUFA) influences circulating levels of LCPUFA. We hypothesized that low LCPUFA diets during pregnancy would compensate by higher expression of FADS genes to enhance the conversion of precursors to LCPUFA to spare the overall LCPUFA levels. Seventy-five pregnant women were enrolled during the last trimester of pregnancy based on the eligibility and exclusion criteria. Maternal LCPUFA in plasma, expression of FADS1 and FADS2 genes, FADS2 Indel genotype status and neonate birth weight were studied.In the vegetarian group (n = 25), plasma α-linolenic acid (ALA) but not linoleic acid (LA) was significantly lower (p < 0.05) than the non-vegetarian group (n = 50). No significant differences were found for arachidonic acid (AA) or docosahexaenoic acid (DHA) levels. FADS1 expression was significantly higher in the vegetarian group compared to the non-vegetarian group. There was no significant difference in the birth weight of the neonates between two groups. No significant correlation was observed between FADS2 Indel genotype and birth weight. Our small sample size study demonstrated an increase FADS1expression during pregnancy in vegetarian pregnant women that may have contributed to the maintenance of AA, eicosapentaenoic acid and DHA levels thereby ensuring that the overall LCPUFA levels of the neonate is not compromised. Show less

Roux-en-Y gastric bypass (RYGB) limits food ingestion and may alter the intestinal expression of genes involved in the endogenous synthesis of polyunsaturated fatty acids (PUFAs). These changes may decrease the systemic availability of bioactive PUFAs after RYGB. To study the impact of RYGB on the dietary ingestion and plasma concentration of PUFAs and on the intestinal expression of genes involved in their endogenous biosynthesis in severely obese women with type 2 diabetes. Before, and 3 and 12 months after RYGB, obese women (n = 20) self-reported a seven-day dietary record, answered a food frequency query and provided plasma samples for alpha-linolenic (ALA), eicosapentaenoic (EPA), docosahexaenoic (DHA) and arachidonic (ARA) acid assessment by gas chromatography. Intestinal biopsies (duodenum, jejunum and ileum) were collected through double-balloon endoscopy before and 3 months after RYGB for gene expression analysis by microarray (Human GeneChip 1.0 ST array) and RT-qPCR validation. Compared to the preoperative period, patients had decreased intakes of PUFAs, fish and soybean oil (p < 0.05) and lower plasma concentrations of ALA and EPA (p < 0.001) 3 and 12 months after RYGB. FADS1 gene expression was lower in duodenum (RT-qPCR fold change = -1.620, p < 0.05) and jejunum (RT-qPCR fold change = -1.549, p < 0.05) 3 months following RYGB, compared to before surgery. RYGB decreased PUFA ingestion, plasma ALA and EPA levels, and intestinal expression of FADS1 gene. The latter encodes a key enzyme involved in endogenous biosynthesis of PUFAs. These data suggest that supplementation of omega-3 PUFAs may be required for obese patients undergoing RYGB. Clinical Trial Registry number and website: www.clinicaltrials.gov - NCT01251016; Plataforma Brasil - 19339913.0.0000.0068. Show less

Glycogen storage disease IV (GSD IV), caused by a defect in GBE1, is a clinically heterogeneous disorder. A classical hepatic form and a neuromuscular form have been described. The severe neuromuscular form presents as a fetal akinesia deformation sequence or a congenital subtype. We ascertained three unrelated families with fetuses/neonates who presented with fetal akinesia deformation sequence to our clinic for genetic counseling. We performed a detailed clinical evaluation, exome sequencing, and histopathology examination of two fetuses and two neonates from three unrelated families presenting with these perinatally lethal neuromuscular forms of GSD IV. Exome sequencing in the affected fetuses/neonates identified four novel pathogenic variants (c.1459G>T, c.144-1G>A, c.1680C>G, and c.1843G>C) in GBE1 (NM₀₀₀₁₅₈₎. Histopathology examination of tissues from the affected fetuses/neonate was consistent with the diagnosis. Here, we add three more families with the severe perinatally lethal neuromuscular forms of GSD IV to the GBE1 mutation spectrum. Show less

Ascorbic acid (AC) used as antioxidant in embryo culture is very sensitive and degrades unavoidably in aqueous solution. Methyl-β-cyclodextrin (CD) improved the stability of AC in solution to elevated temperature, light, humidity and oxidation. The aim of this study was to evaluate the effect of the complex AC-CD during in vitro maturation (IVM) or in vitro culture (IVC) on oocyte developmental competence and subsequent embryo development and quality. AC-CD (100 µM) was added to IVM media, and maturation level and embryo development were examined. Matured oocytes, their cumulus cells and produced blastocysts were snap-frozen for gene expression analysis by RT-qPCR. Besides, in vitro-produced zygotes were cultured with 100 µM of AC-CD and blastocysts were as well snap-frozen for gene expression analysis. A group without AC-CD (control Show less

Single nucleotide polymorphisms (SNPs) in FADS1/FADS2 genes are associated with changes in serum and tissue polyunsaturated fatty acid (PUFA) content. PUFA regulate inflammatory signaling pathways in adipose tissue; however, the effect of SNPs in FADS1/FADS2 on adipose tissue inflammation is equivocal. The present study examined if SNPs in FADS1/FADS2 modify human subcutaneous adipose tissue (SAT) fatty acid profiles and the expression of genes associated with inflammation/immune function, lipid metabolism, and cellular differentiation. SAT fatty acids and the expression of 117 genes were measured in 174 men and women from the DiOGenes Study using gas chromatography and qRT-PCR, respectively. Associations between fatty acids, gene expression, and SNPs in FADS1/FADS2 were investigated by linear regression and multivariate analysis. Four SNPs (rs174537, rs174546, rs174556, rs174601) in FADS1/FADS2 were significantly associated with SAT fatty acids. All SNPs were in high linkage disequilibrium with the commonly reported rs174537 SNP in FADS1. Minor allele carriers for rs174537 (GT+TT) had reduced 20:4n-6 (p = 1.74E-5), lower delta-5 desaturase enzyme activity (p = 2.09E-9), and lower FADS1 gene expression (p = 0.03) compared to major GG carriers. Multivariate analysis revealed that 20:4n-6 and 20:3n-6 explained ~19% of the variance between rs174537 genotypes, while gene expression explained <7%. Receiver operating characteristic (ROC) curves indicated that rs174537 genotype can be distinguished with SAT fatty acids (AUC = 0.842), but not gene expression (AUC = 0.627). No differences in SAT inflammatory gene expression were observed between rs174537 genotypes. SAT 20:3n-6 levels were positively correlated with the expression of several inflammatory genes, and inversely correlated with FADS1 expression. This study showed that FADS1 genotype is distinguished by SAT fatty acid profiles, but not inflammatory gene expression. Show less

Recent analyses in Greenlandic Inuit identified six genetic polymorphisms (rs74771917, rs3168072, rs12577276, rs7115739, rs174602 and rs174570) in the fatty acid desaturase gene cluster (FADS1-FADS2-FADS3) that are associated with multiple metabolic and anthropometric traits. Our objectives were to systematically assess whether dietary polyunsaturated fatty acid (PUFA) intake modifies the associations between genetic variants in the FADS gene cluster and cardiometabolic traits, and to functionally annotate top-ranking candidates to estimate their regulatory potential. Data analyses consisted of the following: interaction analyses between the 6 candidate genetic variants and dietary PUFA intake; gene-centric joint analyses to detect interaction signals in the FADS region; haplotype-centric joint tests across 30 haplotype blocks in the FADS region to refine interaction signals; and functional annotation of top-ranking loci from the previous steps. These analyses were undertaken in Swedish adults from the GLACIER Study (N = 5,160); data on genetic variation and eight cardiometabolic traits were used. Interactions were observed between rs174570 and n-6 PUFA intake on fasting glucose (P The association between FADS variants and triglycerides may be modified by PUFA intake. The intronic FADS2 rs5792235 variant is a potential causal variant in the region, having the highest regulatory potential. However, our results suggest that multiple haplotypes may harbour functional variants in a region, rather than a single causal variant. Show less

Delta-5-desaturase (fatty acid desaturase-1, FADS1) and delta-6 desaturase (fatty acid desaturase-2, FADS2), rate-limiting enzymes in the biosynthesis of long-chain polyunsaturated fatty acids, may be associated with the risk of metabolic syndrome (MetS). We investigated how FADS1 rs174547 and FADS2 rs2845573 variants modify the prevalence of MetS and whether the risk is modulated by interactions with dietary fat. Genetic, anthropometric, biochemical, and dietary data were collected from the Ansan/Ansung (8842 adults) and City-Rural (5512 adults) cohorts in Korea. The association between FADS1 rs174547(C/T) and FADS2 rs2845573(C/T) variants and MetS was analyzed, as was the interaction of genotypes and fatty acid intake and the risk of MetS after adjusting for MetS-related confounders. Carriers of FADS1 rs174547 and FADS2 rs2845573 minor alleles had lower serum HDL-cholesterol and glucose levels and higher triglyceride levels than those with major alleles. Ansan/Ansung cohort individuals with FADS1 minor alleles or haplotypes of FADS1 and FADS2 minor alleles had increased risk of MetS, including lower serum HDL-cholesterol and triglyceride levels and blood pressure after adjusting for MetS-related confounders. The City-Rural cohort showed similar results. Total fat intake showed interactions with FADS1 and haplotype variants on MetS risk: MetS frequency was reduced in people consuming moderate fat diets as compared to low fat diets in FADS1 and haplotype of FADS1 and FADS2 major alleles. Korean carriers of the FADS1 rs174547 and FADS2 rs2845573 minor alleles have a greater susceptibility to MetS and moderate fat intake protected against the risk of MetS in carriers of the FADS1 major alleles. Show less

Breast milk is the sole nutrition source during exclusive breastfeeding, and polyunsaturated fatty acids (FAs) are critical micronutrients in infant physical and cognitive development. There has been no prior genomewide association study of breast milk, hence our objective was to test for genetic association with breast milk FA composition. We measured the fractional composition of 26 individual FAs in breast milk samples from three cohorts totalling 1142 Bangladeshi mothers whose infants were genotyped on the Illumina MEGA chip and replicated on a custom Affymetrix 30K SNP array (n=616). Maternal genotypes were imputed using IMPUTE. After running 33 separate FA fraction phenotypes, we found that SNPs known to be associated with serum FAs in the AA is the primary FA in breast milk influenced by genetic variation at the Show less

n-3 polyunsaturated fatty acids (PUFAs) and n-6 PUFAs are reported to have immunomodulatory effects, but few studies have examined these functions. Thus, we examined whether dietary n-3 and n-6 PUFAs are associated with the risk of gastric cancer and further investigated whether fatty acid desaturases 1 and 2 (FADS1 and FADS2) modify this association. In a case-control study, 1,464 participants (402 cases and 1,062 controls) were enrolled. A semi-quantitative food frequency questionnaire was utilized to measure dietary PUFA intake. Genotyping was performed using the Axiom® Exome 319 Array. Multivariable logistic models were established after adjusting for confounding variables. The risk of gastric cancer was significantly decreased among participants who had the highest tertile intake of docosahexaenoic acid (DHA), an n-3 PUFA, even after adjusting for covariates [odds ratios (OR) = 0.72, 95% confidence intervals (95% CIs) = 0.53-0.99]. However, no significant interaction according to FADS1 rs174546 or FADS2 rs174583 was observed. In conclusion, we observed a significant inverse association between dietary DHA and the risk of gastric cancer but found that FADS1 rs174546 and FADS2 rs174583 did not modify the association between dietary n-3 or n-6 PUFAs and gastric cancer risk. Show less

Increased production of long-chain unsaturated fatty acids (LCUFA) can have a positive effect on the nutritional value of ruminant milk for human consumption. In nonruminant species, fatty acid elongase 5 (ELOVL5) is a key enzyme for endogenous synthesis of long-chain unsaturated fatty acids. However, whether ELOVL5 protein plays a role (if any) in ruminant mammary tissue remains unclear. In the present study, we assessed the mRNA abundance of ELOVL5 at 3 stages of lactation in goat mammary tissue. Results revealed that ELOVL5 had the lowest expression at peak lactation compared with the nonlactating and late-lactating periods. The ELOVL5 was overexpressed or knocked down to assess its role in goat mammary epithelial cells. Results revealed that ELOVL5 overexpression increased the expression of perilipin2 (PLIN2) and decreased diacylglycerolacyltransferase 2 (DGAT2) and fatty acid desaturase 2 (FADS2) mRNA, but had no effect on the expression of DGAT1, FADS1, and stearoyl-CoA desaturase 1 (SCD1). Overexpression of ELOVL5 decreased the concentration of C16:1n-7, whereas no significant change in C18:1n-7 and C18:1n-9 was observed. Knockdown of ELOVL5 decreased the expression of PLIN2 but had no effect on DGAT1, DGAT2, FADS1, FADS2, and SCD1 mRNA expression. Knockdown of ELOVL5 increased the concentration of C16:1n-7 and decreased that of C18:1n-7. The alterations of expression of genes related to lipid metabolism after overexpression or knockdown of ELOVL5 suggested a negative feedback regulation by the products of ELOVL5 activation. However, the content of triacylglycerol was not altered by knockdown or overexpression of ELOVL5 in goat mammary epithelial cells, which might have been due to the insufficient availability of substrate in vitro. Collectively, these are the first in vitro results highlighting an important role of ELOVL5 in the elongation of 16-carbon to 18-carbon unsaturated fatty acids in ruminant mammary cells. Show less