Selenium-dependent glutathione peroxidase 1 regulates transcription of elongase 3 in murine tissues.

We have previously shown dysregulated lipid metabolism in tissues of glutathione peroxidase 1 (GPX1) overexpressing (OE) or deficient (KO) mice. This study explored underlying mechanisms of GPX1 in regulating tissue fatty acid (FA) biosynthesis. GPX1 OE, KO, and wild-type (WT) mice (n = 5, male, 3-6 months old) were fed a Se-adequate diet (0.3 mg/kg) and assayed for liver and adipose tissue FA profiles and mRNA levels of key enzymes of FA biosynthesis and redox-responsive transcriptional factors (TFs). These three genotypes of mice (n = 5) were injected intraperitoneally with diquat, ebselen, and N-acetylcysteine (NAC) at 10, 50, and 50 mg/kg of body weight, respectively, and killed at 0 and 12 h after the injections to detect mRNA levels of FA elongases and desaturases and the TFs in the liver and adipose tissue. A luciferase reporter assay with targeted deletions of mouse Elovl3 promoter was performed to determine transcriptional regulations of the gene by GPX1 mimic ebselen in HEK293T cells. Compared with WT, GPX1 OE and KO mice had 9-42% lower (p < 0.05) and 36-161% higher (p < 0.05) concentrations of C20:0, C22:0, and C24:0 in these two tissues, respectively, along with reciprocal increases and decreases (p < 0.05) of Elovl3 transcripts. Ebselen and NAC decreased (p < 0.05), whereas diquat decreased (p < 0.05), Elovl3 transcripts in the two tissues. Overexpression and knockout of GPX1 decreased (p < 0.05) and increased (p < 0.05) ELOVL3 levels in the two tissues, respectively. Three TFs (GABP, SP1, and DBP) were identified to bind the Elovl3 promoter (-1164/+33 base pairs). Deletion of DBP (-98/-86 base pairs) binding domain in the promoter attenuated (13%, p < 0.05) inhibition of ebselen on Elovl3 promoter activation. In summary, GPX1 overexpression down-regulated very long-chain FA biosynthesis via transcriptional inhibition of the Elovl3 promoter activation.

ELOVL5-mediated fatty acid elongation promotes cellular proliferation and invasion in renal cell carcinoma.

Renal cell carcinoma (RCC) features altered lipid metabolism and accumulated polyunsaturated fatty acids (PUFAs). Elongation of very long-chain fatty acid (ELOVL) family enzymes catalyze fatty acid elongation, and ELOVL5 is indispensable for PUFAs elongation, but its role in RCC progression remains unclear. Here, we show that higher levels of ELOVL5 correlate with poor RCC clinical prognosis. Liquid chromatography/electrospray ionization-tandem mass spectrometry analysis showed decreases in ELOVL5 end products (arachidonic acid and eicosapentaenoic acid) under CRISPR/Cas9-mediated knockout of ELOVL5 while supplementation with these fatty acids partially reversed the cellular proliferation and invasion effects of ELOVL5 knockout. Regarding cellular proliferation and invasion, CRISPR/Cas9-mediated knockout of ELOVL5 suppressed the formation of lipid droplets and induced apoptosis via endoplasmic reticulum stress while suppressing renal cancer cell proliferation and in vivo tumor growth. Furthermore, CRISPR/Cas9-mediated knockout of ELOVL5 inhibited AKT Ser473 phosphorylation and suppressed renal cancer cell invasion through chemokine (C-C motif) ligand-2 downregulation by AKT-mTOR-STAT3 signaling. Collectively, these results suggest that ELOVL5-mediated fatty acid elongation promotes not only cellular proliferation but also invasion in RCC.

Branched-Chain Fatty Acids Alter the Expression of Genes Responsible for Lipid Synthesis and Inflammation in Human Adipose Cells.

Recently, we have demonstrated a decreased level of iso-branched-chain fatty acids (iso-BCFAs) in patients with excessive weight. However, it is still unclear whether BCFAs may influence lipid metabolism and inflammation in lipogenic tissues. To verify this, human visceral adipocytes were cultured with three different concentrations of selected iso-BCFA (14-methylpentadecanoic acid) and anteiso-BCFA (12-methyltetradecanoic acid), and then the expression of genes associated with lipid metabolism (FASN-fatty acid synthase; SREBP1-sterol regulatory element-binding protein 1; SCD1-stearoyl-CoA desaturase; ELOVL4-fatty acid elongase 4; ELOVL6-fatty acid elongase 6; FADS2-fatty acid desaturase 2; FADS1-fatty acid desaturase 1) and inflammation (COX-2-cyclooxygenase 2; ALOX-15-lipoxygenase 15; IL-6-interleukin 6) were determined. This study demonstrates for the first time that incubation with iso-BCFA decreases the expression of adipocyte genes that are associated with lipid metabolism (except FASN) and inflammation. These findings suggest that changes in the iso-BCFA profile in obese patients may contribute to adipose inflammation and dyslipidemia. Further studies should evaluate whether iso-BCFA supplementation in obese patients would be beneficial.

Influence of Dietary Lipids and Environmental Salinity on the n-3 Long-Chain Polyunsaturated Fatty Acids Biosynthesis Capacity of the Marine Teleost Solea senegalensis.

Fish vary in their ability to biosynthesise long-chain polyunsaturated fatty acids (LC-PUFA) depending upon the complement and function of key enzymes commonly known as fatty acyl desaturases and elongases. It has been reported in Solea senegalensis the existence of a Δ4 desaturase, enabling the biosynthesis of docosahexaenoic acid (DHA) from eicosapentaenoic acid (EPA), which can be modulated by the diet. The present study aims to evaluate the combined effects of the partial replacement of fish oil (FO) with vegetable oils and reduced environmental salinity in the fatty acid composition of relevant body compartments (muscle, hepatocytes and enterocytes), the enzymatic activity over α-linolenic acid (ALA) to form n-3 LC-PUFA through the incubation of isolated hepatocytes and enterocytes with [1-14C] 18:3 n-3, and the regulation of the S. senegalensis fads2 and elovl5 in the liver and intestine. The presence of radiolabelled products, including 18:4n-3, 20:4n-3 and EPA, provided compelling evidence that a complete pathway enabling the biosynthesis of EPA from ALA, establishing S. senegalensis, has at least one Fads2 with ∆6 activity. Dietary composition prevailed over salinity in regulating the expression of fads2, while salinity did so over dietary composition for elovl5. FO replacement enhanced the proportion of DHA in S. senegalensis muscle and the combination with 20 ppt salinity increased the amount of n-3 LC-PUFA in hepatocytes.

Dietary supplementation with myo-inositol reduces high-fructose diet-induced hepatic ChREBP binding and acetylation of histones H3 and H4 on the Elovl6 gene in rats.

ELOVL fatty acid elongase 6 (ELOVL6) is a long-chain fatty acid elongase, and the hepatic expression of the Elovl6 gene and accumulation of triglycerides (TG) are enhanced by long-term high-fructose intake. Fatty acid synthesis genes, including Elovl6, are regulated by lipogenic transcription factors, sterol regulatory element-binding protein 1c (SREBP-1c) and carbohydrate-responsive element-binding protein (ChREBP). In addition, carbohydrate signals induce the expression of fatty acid synthase not only via these transcription factors but also via histone acetylation. Since a major lipotrope, myo-inositol (MI), can repress short-term high-fructose-induced fatty liver and the expression of fatty acid synthesis genes, we hypothesized that MI might influence SREBP-1c, ChREBP, and histone acetylation of Elovl6 in fatty liver induced by even short-term high-fructose intake. This study aimed to investigate whether dietary supplementation with MI affects Elovl6 expression, SREBP-1 and ChREBP binding, and acetylation of histones H3 and H4 at the Elovl6 promoter in short-term high-fructose diet-induced fatty liver in rats. Rats were fed a control diet, high-fructose diet, or high-fructose diet supplemented with 0.5% MI for 10 days. This study showed that MI supplementation reduced short-term high-fructose diet-induced hepatic expression of the Elovl6 gene, ChREBP binding, but not SREBP-1 binding, and acetylation of histones H3 and H4 at the Elovl6 promoter.

Higher Increase in Plasma DHA in Females Compared to Males Following EPA Supplementation May Be Influenced by a Polymorphism in ELOVL2: An Exploratory Study.

Young adult females have higher blood docosahexaenoic acid (DHA), 22:6n-3 levels than males, and this is believed to be due to higher DHA synthesis rates, although DHA may also accumulate due to a longer half-life or a combination of both. However, sex differences in blood fatty acid responses to eicosapentaenoic acid (EPA), 20:5n-3 or DHA supplementation have not been fully investigated. In this exploratory analysis, females and males (n = 14-15 per group) were supplemented with 3 g/day EPA, 3 g/day DHA, or olive oil control for 12 weeks. Plasma was analyzed for sex effects at baseline and changes following 12 weeks' supplementation for fatty acid levels and carbon-13 signature (δ13 C). Following EPA supplementation, the increase in plasma DHA in females (+23.8 ± 11.8, nmol/mL ± SEM) was higher than males (-13.8 ± 9.2, p < 0.01). The increase in plasma δ13 C-DHA of females (+2.79 ± 0.31, milliUrey (mUr ± SEM) compared with males (+1.88 ± 0.44) did not reach statistical significance (p = 0.10). The sex effect appears driven largely by increased plasma DHA in the AA genotype of females (+58.8 ± 11.5, nmol/mL ± SEM, n = 5) compared to GA + GG in females (+4.34 ± 13.5, n = 9) and AA in males (-29.1 ± 17.2, n = 6) for rs953413 in the ELOVL2 gene (p < 0.001). In conclusion, EPA supplementation increases plasma DHA levels in females compared to males, which may be dependent on the AA genotype for rs953413 in ELOVL2.

Polyunsaturated fatty acid biosynthesis pathway determines ferroptosis sensitivity in gastric cancer.

Ferroptosis is an iron-dependent regulated necrosis mediated by lipid peroxidation. Cancer cells survive under metabolic stress conditions by altering lipid metabolism, which may alter their sensitivity to ferroptosis. However, the association between lipid metabolism and ferroptosis is not completely understood. In this study, we found that the expression of elongation of very long-chain fatty acid protein 5 (ELOVL5) and fatty acid desaturase 1 (FADS1) is up-regulated in mesenchymal-type gastric cancer cells (GCs), leading to ferroptosis sensitization. In contrast, these enzymes are silenced by DNA methylation in intestinal-type GCs, rendering cells resistant to ferroptosis. Lipid profiling and isotope tracing analyses revealed that intestinal-type GCs are unable to generate arachidonic acid (AA) and adrenic acid (AdA) from linoleic acid. AA supplementation of intestinal-type GCs restores their sensitivity to ferroptosis. Based on these data, the polyunsaturated fatty acid (PUFA) biosynthesis pathway plays an essential role in ferroptosis; thus, this pathway potentially represents a marker for predicting the efficacy of ferroptosis-mediated cancer therapy.

Functional analysis of ß-ketoacyl-CoA synthase from biofuel feedstock Thlaspi arvense reveals differences in the triacylglycerol biosynthetic pathway among Brassicaceae.

KEY MESSAGE: Differences in FAE1 enzyme affinity for the acyl-CoA substrates, as well as the balance between the different pathways involved in their incorporation to triacylglycerol might be determinant of the different composition of the seed oil in Brassicaceae. Brassicaceae present a great heterogeneity of seed oil and fatty acid composition, accumulating Very Long Chain Fatty Acids with industrial applications. However, the molecular determinants of these differences remain elusive. We have studied the ß-ketoacyl-CoA synthase from the high erucic feedstock Thlaspi arvense (Pennycress). Functional characterization of the Pennycress FAE1 enzyme was performed in two Arabidopsis backgrounds; Col-0, with less than 2.5% of erucic acid in its seed oil and the fae1-1 mutant, deficient in FAE1 activity, that did not accumulate erucic acid. Seed-specific expression of the Pennycress FAE1 gene in Col-0 resulted in a 3 to fourfold increase of erucic acid content in the seed oil. This increase was concomitant with a decrease of eicosenoic acid levels without changes in oleic ones. Interestingly, only small changes in eicosenoic and erucic acid levels occurred when the Pennycress FAE1 gene was expressed in the fae1-1 mutant, with high levels of oleic acid available for elongation, suggesting that the Pennycress FAE1 enzyme showed higher affinity for eicosenoic acid substrates, than for oleic ones in Arabidopsis. Erucic acid was incorporated to triacylglycerol in the transgenic lines without significant changes in their levels in the diacylglycerol fraction, suggesting that erucic acid was preferentially incorporated to triacylglycerol via DGAT1. Expression analysis of FAE1, AtDGAT1, AtLPCAT1 and AtPDAT1 genes in the transgenic lines further supported this conclusion. Differences in FAE1 affinity for the oleic and eicosenoic substrates among Brassicaceae, as well as their incorporation to triacylglycerol might explain the differences in composition of their seed oil.

The Immunogenicity of a Novel Chimeric Hemagglutinin-Neuraminidase-Fusion Antigen from Newcastle Disease Virus by Oral Delivery of Transgenic Canola Seeds to Chickens.

Newcastle disease (ND) is considered as one of the most devastating infectious diseases targeting domestic birds and has considerable threat to the commercial poultry production. Two surface glycoproteins, hemagglutinin-neuraminidase (HN) and fusion (F), act as antigens in the virus structure and also play important roles in infecting host cells. In the current study, the expression of the chimeric HN-F protein in canola seeds and its immunogenicity in chickens were investigated. The HN-F gene was cloned downstream of the fatty acid elongase 1 (FAE1) promoter in the binary expression vector, pBI1400-HN-F, and introduced into rapeseed (Brassica napus L.) using Agrobacterium-mediated transformation. The amount of the HN-F glycoprotein was estimated up to 0.18% and 0.11% of the total soluble protein (TSP) in transgenic seeds and leaves of canola, respectively. Confirmatory analyses of 36 transgenic lines revealed that the HN-F gene was integrated into the genome. Subsequently, HN-F protein could be expressed and accumulated in the seed tissue. Specific pathogen-free (SPF) chickens immunized orally with recombinant HN-F showed a significant rise in specific and hemagglutination inhibition (HI) antibodies 35 to 42 days post the first administration. The results implied the potential of transgenic canola seed-based expression for oral delivery of NDV immunogenic glycoproteins.

Gentiana lutea Extract Modulates Ceramide Synthesis in Primary and Psoriasis-Like Keratinocytes.

Gentiana lutea is a bitter herb that is traditionally used to improve gastric disorders. Recently, we have shown that Gentiana lutea extract (GE) also modulates the lipid metabolism of human keratinocytes in vitro and in vivo. In the present study, we investigated the role of GE on ceramide synthesis in human primary keratinocytes (HPKs) and psoriasis-like keratinocytes. We could demonstrate that GE increased the concentrations of glucosylceramides and the ceramide AS/AdS subclass without affecting the overall ceramide content in HPKs. The expression of ceramide synthase 3 (CERS3) and elongases (ELOVL1 and 4) was reduced in psoriasis lesions compared to healthy skin. Psoriasis-like HPKs, generated by stimulating HPKs with cytokines that are involved in the pathogenesis of psoriasis (IL-17, TNF-α, IL-22 and IFN-γ) showed increased levels of IL-6, IL-8 and increased expression of DEFB4A, as well as decreased expression of ELOVL4. The treatment with GE partly rescued the reduced expression of ELOVL4 in psoriasis-like HPKs and augmented CERS3 expression. This study has shown that GE modulates ceramide synthesis in keratinocytes. Therefore, GE might be a novel topical treatment for skin diseases with an altered lipid composition such as psoriasis.

Genome-Wide Association Study for Serum Omega-3 and Omega-6 Polyunsaturated Fatty Acids: Exploratory Analysis of the Sex-Specific Effects and Dietary Modulation in Mediterranean Subjects with Metabolic Syndrome.

Many early studies presented beneficial effects of polyunsaturated fatty acids (PUFA) on cardiovascular risk factors and disease. However, results from recent meta-analyses indicate that this effect would be very low or nil. One of the factors that may contribute to the inconsistency of the results is that, in most studies, genetic factors have not been taken into consideration. It is known that fatty acid desaturase (FADS) gene cluster in chromosome 11 is a very important determinant of plasma PUFA, and that the prevalence of the single nucleotide polymorphisms (SNPs) varies greatly between populations and may constitute a bias in meta-analyses. Previous genome-wide association studies (GWAS) have been carried out in other populations and none of them have investigated sex and Mediterranean dietary pattern interactions at the genome-wide level. Our aims were to undertake a GWAS to discover the genes most associated with serum PUFA concentrations (omega-3, omega-6, and some fatty acids) in a scarcely studied Mediterranean population with metabolic syndrome, and to explore sex and adherence to Mediterranean diet (MedDiet) interactions at the genome-wide level. Serum PUFA were determined by NMR spectroscopy. We found strong robust associations between various SNPs in the FADS cluster and omega-3 concentrations (top-ranked in the adjusted model: FADS1-rs174547, p = 3.34 × 10-14; FADS1-rs174550, p = 5.35 × 10-14; FADS2-rs1535, p = 5.85 × 10-14; FADS1-rs174546, p = 6.72 × 10-14; FADS2-rs174546, p = 9.75 × 10-14; FADS2- rs174576, p = 1.17 × 10-13; FADS2-rs174577, p = 1.12 × 10-12, among others). We also detected a genome-wide significant association with other genes in chromosome 11: MYRF (myelin regulatory factor)-rs174535, p = 1.49 × 10-12; TMEM258 (transmembrane protein 258)-rs102275, p = 2.43 × 10-12; FEN1 (flap structure-specific endonuclease 1)-rs174538, p = 1.96 × 10-11). Similar genome-wide statistically significant results were found for docosahexaenoic fatty acid (DHA). However, no such associations were detected for omega-6 PUFAs or linoleic acid (LA). For total PUFA, we observed a consistent gene*sex interaction with the DNTTIP2 (deoxynucleotidyl transferase terminal interacting protein 2)-rs3747965 p = 1.36 × 10-8. For adherence to MedDiet, we obtained a relevant interaction with the ME1 (malic enzyme 1) gene (a gene strongly regulated by fat) in determining serum omega-3. The top-ranked SNP for this interaction was ME1-rs3798890 (p = 2.15 × 10-7). In the regional-wide association study, specifically focused on the FADS1/FASD2/FADS3 and ELOVL (fatty acid elongase) 2/ELOVL 5 regions, we detected several statistically significant associations at p < 0.05. In conclusion, our results confirm a robust role of the FADS cluster on serum PUFA in this population, but the associations vary depending on the PUFA. Moreover, the detection of some sex and diet interactions underlines the need for these associations/interactions to be studied in all specific populations so as to better understand the complex metabolism of PUFA.

Saturated and monounsaturated fatty acids in membranes are determined by the gene expression of their metabolizing enzymes SCD1 and ELOVL6 regulated by the intake of dietary fat.

PURPOSE: We investigated the effect of dietary fats on the incorporation of saturated (SAFAs) and monounsaturated dietary fatty acids (MUFAs) into plasma phospholipids and the regulation of the expression of lipid-metabolizing enzymes in the liver. METHODS: Mice were fed different diets containing commonly used dietary fats/oils (coconut fat, margarine, fish oil, sunflower oil, or olive oil) for 4 weeks (n = 6 per diet group). In a second experiment, mice (n = 6 per group) were treated for 7 days with synthetic ligands to activate specific nuclear hormone receptors (NHRs) and the hepatic gene expression of CYP26A1 was investigated. Hepatic gene expression of stearoyl-coenzyme A desaturase 1 (SCD1), elongase 6 (ELOVL6), and CYP26A1 was examined using quantitative real-time PCR (QRT-PCR). Fatty acid composition in mouse plasma phospholipids was analyzed by gas chromatography (GC). RESULTS: We found significantly reduced hepatic gene expression of SCD1 and ELOVL6 after the fish oil diet compared with the other diets. This resulted in reduced enzyme-specific fatty acid ratios, e.g., 18:1n9/18:0 for SCD1 and 18:0/16:0 and 18:1n7/16:1n7 for ELOVL6 in plasma phospholipids. Furthermore, CYP26A1 a retinoic acid receptor-specific target was revealed as a new player mediating the suppressive effect of fish oil-supplemented diet on SCD1 and ELOVL6 hepatic gene expression. CONCLUSION: Plasma levels of MUFAs and SAFAs strongly reflect an altered hepatic fatty acid-metabolizing enzyme expression after supplementation with different dietary fats/oils.

Effects of dietary α-linolenic acid/linoleic acid ratio on growth performance, tissue fatty acid profile, serum metabolites and Δ6 fad and elovl5 gene expression in silver barb (Puntius gonionotus).

BACKGROUND: Silver barb (Puntius gonionotus) is a medium-sized carp that is promising for freshwater aquaculture in Asia. This study's aim was to investigate the ideal dietary α-linolenic acid (ALA): linoleic acid (LA) ratio for maximizing long-chain polyunsaturated fatty acid (LC-PUFA) synthesis and their deposition in the muscle of silver barb, as that of fish oil based control diet. RESULT: Fish (with an initial body weight of 11.07 ± 0.12 g) were fed for 60 days with five experimental iso-proteinous, iso-lipidic, and iso-caloric diets, supplemented with linseed oil and peanut oil at varying levels to obtain ALA:LA ratios of 0.35, 0.51, 0.91, 2.04, 2.66. A control diet was prepared by supplementing fish oil. The dietary ALA:LA ratio did not influence the growth performance of fish. With increased dietary ALA:LA ratios, LA content decreased and ALA content increased in the muscle and liver of silver barb. The n-3 LC-PUFA level in muscle and liver was not influenced by feeding different ratios of ALA:LA, whereas n-6 LC-PUFA was decreased in the muscle and increased in the liver with increased dietary ALA:LA ratios. Increasing dietary ALA:LA ratio increased the Δ6fad and elovl5mRNA expression in the liver, muscle, brain, and intestinal tissues of silver barbs. CONCLUSION: Silver barb possess the ability to elongate and desaturate ALA and LA to their end products EPA and DHA. The highest level expression of Δ6 fad and elovl5 mRNA at the dietary ALA:LA ratio of 2.66 suggests greater affinity of these enzymes towards ALA than LA in silver barb. © 2019 Society of Chemical Industry.

Dietary Supplementation with Fish Oil or Conjugated Linoleic Acid Relieves Depression Markers in Mice by Modulation of the Nrf2 Pathway.

Inflammation and oxidative stress play an important role in the pathogenesis of depressive disorders and nuclear erythroid related factor 2 (Nrf2), a regulator of RedOx homeostasis and inflammation, is a promising target for depression prevention/treatment. As fish oil (FO) and conjugated linoleic acid (CLA) are known Nrf2 inducers, their protective ability is comparatively evaluated in a murine model of depression (MRL/MpJ-Faslpr ). Oxidative stress, fatty acids content, and critical factors reflecting brain functioning-namely brain-derived neurotrophic factor (BDNF), synaptic markers, and cholinergic signaling-are preliminarily evaluated in the frontal cortex of 8-week (Young) and in 22-week old animals (Old), which are used as model of depression. These markers are measured in Old mice at the end of a 5-week pretreatment with FO or CLA (728 or 650 mg kg-1 , respectively). Old mice exhibit disrupted Redox homeostasis, compensatory Nrf2 hyperactivation, lower docosaheaxaenoic acid (DHA), and lower BDNF and synaptic function proteins compared to Young mice. FO and CLA treatment relieves almost all the pathophysiological hallmarks at a level comparable to Young mice. Presented data provide the first evidence for the comparable efficacy of FO or CLA supplementation in preventing depression signs in Old MRL/lpr mice, likely through their ability of improving Nrf2-mediated antioxidant defenses.

DHA intake interacts with ELOVL2 and ELOVL5 genetic variants to influence polyunsaturated fatty acids in human milk.

Endogenous synthesis of PUFAs is mediated by genes controlling fatty acid elongases 2 and 5 (ELOVL2 and ELOVL5) and by exogenous DHA intake. Associations between elongases and PUFA levels probably involve genetic variants of ELOVL and changes in DHA intake, but data about their combined effect on PUFA levels are sparse. We hypothesized that each factor would directly affect PUFAs and that interactions between haplotypes and DHA intake would influence PUFAs. We explored four levels of DHA intake in pregnant Chinese Han women and 10 SNPs in the ELOVL genes to determine associations with PUFAs in breast milk. The SNP rs3798713 and 3-SNP haplotype (rs2281591, rs12332786, and rs3798713) in ELOVL2 were associated with linoleic acid (LA) concentrations. However, carriers of the 3-SNP haplotype with higher DHA intake (second quartile: 14.58-43.15 mg/day) had higher concentrations of LA, arachidonic acid, EPA, and DHA compared with the interaction baseline. In ELOVL5, five SNPs (rs2294867, rs9357760, rs2397142, rs209512, and rs12207094) correlated with PUFA changes. Compared with those who had the 5-SNP haplotype C-A-C-G-A and low DHA intake (<14.58 mg/day), carriers with other haplotypes (A-A-C-A-A or C-A-C-A-A) and high DHA intake (≥118.82 mg/day) had increased EPA levels after adjustments for age and BMI. This study showed that maternal genetic variants in ELOVL2 and ELOVL5 were associated with PUFA levels in breast milk and that the combination of SNP haplotypes and higher DHA intake increased PUFA concentrations.

Long-term efficacy of docosahexaenoic acid (DHA) for Spinocerebellar Ataxia 38 (SCA38) treatment: An open label extension study.

INTRODUCTION: Spinocerebellar Ataxia 38 (SCA38) is caused by ELOVL5 gene mutation, with significant reduction of serum docosahexaenoic acid (DHA) levels. DHA supplementation has been proven effective at short-term follow-up. In the present paper, we evaluated long-term safety and efficacy of 600 mg/day oral DHA in SCA38 by a 2-year open label extension study. METHODS: Nine SCA38 patients underwent standardised clinical assessment at 62 (T1), 82 (T2) and 104 (T3) weeks, and compared to pre-treatment scores (T0). Brain 18-Fluorodeoxyglucose Positron Emission Tomography and electroneurography were performed at T0 and T3. RESULTS: We found a significant maintenance of clinical symptom improvement at each follow-up time-point (p < 0.001) as compared to T0, a sustained increase of cerebellar metabolism at T3 as compared to T0 (p = 0.013), and no worsening of neurophysiological parameters. No side effect was recorded. CONCLUSIONS: Long-term DHA supplementation is an eligible treatment for SCA38.

Natural variation in acyl editing is a determinant of seed storage oil composition.

Seeds exhibit wide variation in the fatty acid composition of their storage oil. However, the genetic basis of this variation is only partially understood. Here we have used a multi-parent advanced generation inter-cross (MAGIC) population to study the genetic control of fatty acid chain length in Arabidopsis thaliana seed oil. We mapped four quantitative trait loci (QTL) for the quantity of the major very long chain fatty acid species 11-eicosenoic acid (20:1), using multiple QTL modelling. Surprisingly, the main-effect QTL does not coincide with FATTY ACID ELONGASE 1 and a parallel genome wide association study suggested that LYSOPHOSPHATIDYLCHOLINE ACYLTRANSFERASE 2 (LPCAT2) is a candidate for this QTL. Regression analysis also suggested that LPCAT2 expression and 20:1 content in seeds of the 19 MAGIC founder accessions are related. LPCAT is a key component of the Lands cycle; an acyl editing pathway that enables acyl-exchange between the acyl-Coenzyme A and phosphatidylcholine precursor pools used for microsomal fatty acid elongation and desaturation, respectively. We Mendelianised the main-effect QTL using biparental chromosome segment substitution lines and carried out complementation tests to show that a single cis-acting polymorphism in the LPCAT2 promoter causes the variation in seed 20:1 content, by altering the LPCAT2 expression level and total LPCAT activity in developing siliques. Our work establishes that oilseed species exhibit natural variation in the enzymic capacity for acyl editing and this contributes to the genetic control of storage oil composition.