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Desaturase and elongase-limiting endogenous long-chain polyunsaturated fatty acid biosynthesis.

ABSTRACT: Endogenous synthesis of the long-chain polyunsaturated fatty acids (LCPUFAs) is mediated by the fatty acid desaturase (FADS) gene cluster (11q12-13.1) and elongation of very long-chain fatty acids 2 (ELOVL2) (6p24.2) and ELOVL5 (6p12.1). Although older biochemical work identified the product of one gene, FADS2, rate limiting for LCPUFA synthesis, recent studies suggest that polymorphisms in any of these genes can limit accumulation of product LCPUFA.Genome-wide association study (GWAS) of Greenland Inuit shows strong adaptation signals within FADS gene cluster, attributed to high omega-3 fatty acid intake, while GWAS found ELOVL2 associated with sleep duration, age and DNA methylation. ELOVL5 coding mutations cause spinocerebellar ataxia 38, and epigenetic marks were associated with depression and suicide risk. Two sterol response element binding sites were found on ELOVL5, a SREBP-1c target gene. Minor allele carriers of a 3 single nucleotide polymorphism (SNP) haplotype in ELOVL2 have decreased 22?:?6n-3 levels. Unequivocal molecular evidence shows mammalian FADS2 catalyzes direct ?4-desaturation to yield 22?:?6n-3 and 22?:?5n-6. An SNP near FADS1 influences the levels of 5-lipoxygenase products and epigenetic alteration.Genetic polymorphisms within FADS and ELOVL can limit LCPUFA product accumulation at any step of the biosynthetic pathway.

SUBMITTER: Zhang JY

PROVIDER: S-EPMC4768719 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Desaturase and elongase-limiting endogenous long-chain polyunsaturated fatty acid biosynthesis.

Zhang Ji Yao JY Kothapalli Kumar S D KS Brenna J Thomas JT

Current opinion in clinical nutrition and metabolic care 20160301 2

<h4>Purpose of review</h4>Endogenous synthesis of the long-chain polyunsaturated fatty acids (LCPUFAs) is mediated by the fatty acid desaturase (FADS) gene cluster (11q12-13.1) and elongation of very long-chain fatty acids 2 (ELOVL2) (6p24.2) and ELOVL5 (6p12.1). Although older biochemical work identified the product of one gene, FADS2, rate limiting for LCPUFA synthesis, recent studies suggest that polymorphisms in any of these genes can limit accumulation of product LCPUFA.<h4>Recent findings< ...[more]

PMID: 26828581

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Project description:BackgroundΔ6-Desaturase (Fads2) is widely regarded as rate-limiting in the conversion of dietary α-linolenic acid (18:3n-3; ALA) to the long-chain omega-3 polyunsaturated fatty acid docosahexaenoic acid (22:6n-3; DHA). However, increasing dietary ALA or the direct Fads2 product, stearidonic acid (18:4n-3; SDA), increases tissue levels of eicosapentaenoic acid (20:5n-3; EPA) and docosapentaenoic acid (22:5n-3; DPA), but not DHA. These observations suggest that one or more control points must exist beyond ALA metabolism by Fads2. One possible control point is a second reaction involving Fads2 itself, since this enzyme catalyses desaturation of 24:5n-3 to 24:6n-3, as well as ALA to SDA. However, metabolism of EPA and DPA both require elongation reactions. This study examined the activities of two elongase enzymes as well as the second reaction of Fads2 in order to concentrate on the metabolism of EPA to DHA.Methodology/principal findingsThe substrate selectivities, competitive substrate interactions and dose response curves of the rat elongases, Elovl2 and Elovl5 were determined after expression of the enzymes in yeast. The competitive substrate interactions for rat Fads2 were also examined. Rat Elovl2 was active with C(20) and C(22) polyunsaturated fatty acids and this single enzyme catalysed the sequential elongation reactions of EPA→DPA→24:5n-3. The second reaction DPA→24:5n-3 appeared to be saturated at substrate concentrations not saturating for the first reaction EPA→DPA. ALA dose-dependently inhibited Fads2 conversion of 24:5n-3 to 24:6n-3.ConclusionsThe competition between ALA and 24:5n-3 for Fads2 may explain the decrease in DHA levels observed after certain intakes of dietary ALA have been exceeded. In addition, the apparent saturation of the second Elovl2 reaction, DPA→24:5n-3, provides further explanations for the accumulation of DPA when ALA, SDA or EPA is provided in the diet. This study suggests that Elovl2 will be critical in understanding if DHA synthesis can be increased by dietary means.

Project description:BackgroundIn randomized trials, supplementation of n-3 (ω-3) long-chain polyunsaturated fatty acids (LC-PUFAs) during pregnancy has resulted in increased size at birth, which is attributable to longer gestation.ObjectiveWe examined this finding by using a Mendelian randomization approach utilizing fatty acid desaturase (FADS) gene variants affecting LC-PUFA metabolism.DesignAs part of a tri-ethnic mother-offspring cohort in Singapore, 35 genetic variants in FADS1, FADS2, and FADS3 were genotyped in 898 mothers and 1103 offspring. Maternal plasma n-3 and n-6 PUFA concentrations at 26-28 wk of gestation were measured. Gestation duration was derived from an ultrasound dating scan in early pregnancy and from birth date. Birth length and weight were measured. Eight FADS variants were selected through a tagging-SNP approach and examined in association with PUFA concentrations, gestation duration among spontaneous labors, and birth size with the use of ethnicity-adjusted linear regressions and survival models that accounted for the competing risks of induced labor and prelabor cesarean delivery.ResultsMaternal FADS1 variant rs174546, tagging for 8 other variants located on FADS1 and FADS2, was strongly related to plasma n-6 but not n-3 LC-PUFA concentrations. Offspring and maternal FADS3 variants were associated with gestation duration among women who had spontaneous labor: each copy of rs174450 minor allele C was associated with a shorter gestation by 2.2 d (95% CI: 0.9, 3.4 d) and 1.9 d (0.7, 3.0 d) for maternal and offspring variants, respectively. In survival models, rs174450 minor allele homozygotes had reduced time to delivery after spontaneous labor compared with major allele homozygotes [HR (95% CI): 1.51 (1.18, 1.95) and 1.51 (1.20, 1.89) for mothers and offspring, respectively].ConclusionsWith the use of a Mendelian randomization approach, we observed associations between FADS variants and gestation duration. This suggests a potential role of LC-PUFAs in gestation duration. This trial was registered at http://www.clinicaltrials.gov as NCT01174875.

Project description:Docosahexaenoic acid (DHA, 22:6n-3) and arachidonic acid (ARA, 20:4n-6) are the major long chain polyunsaturated fatty acids (LCPUFA) of the central nervous system. We examined the alterations in transcriptional profiles in neonate baboon cerebral cortex brain tissue using high-density Affymetrix oligonucleotide arrays ("U133 plus 2.0"). Twelve neonates were divided into 3 groups: Control (C, no DHA-ARA); 1× LCPUFA (L, 0.33%DHA-0.67%ARA); 3× LCPUFA (L3, 1.00%DHA-0.67%ARA). Significance analysis (P < 0.05) of a total of >54,000 probe sets (ps) identified changes in expression levels of 1108 ps, representing 2.05% of the total ps on the oligoarray, with most ps showing <2-fold change. Comparing L and C, 534 ps were upregulated with supplementation, and 574 ps were downregulated. For the L3/C comparisons, 666 ps were upregulated and 442 ps were downregulated. Characterization of differentially regulated genes by gene ontology assign them to diverse biological functions, notably lipid metabolism, ion channel and transport, G-protein and signal transduction, development, visual perception, membrane function, apoptosis, cytoskeleton, peptidases, cell cycle, stress response, kinases and phosphatases, transcription regulation, receptors, and ubiquitin, with about 400 transcripts having no defined function. Of differentially expressed genes involved in lipid metabolism, PLA2G6, a phospholipase recently associated with infantile neuroaxonal dystrophy, was downregulated in both LCPUFA groups. ELOVL5, a PUFA elongase, was the only enzyme in the LCPUFA biosynthetic pathway that was differentially expressed. Mitochondrial fatty acid carrier, CPT2, was among several genes associated with mitochondrial fatty acid oxidation to be downregulated, while the mitochondrial proton carrier, UCP2, was upregulated. PUFA-regulated receptor, Retinoic acid receptor alpha (RARA) was repressed in both groups, while HNF4A, a PUFA regulated factor, was downregulated in L3/C. Genes involved in neural development, TIMM8A, NRG1, SEMA3D and NUMB, were upregulated while HES1 and SIM1 showed decreased expression. LUM, EML2, TIMP3 and TTC8 which have roles in visual perception were upregulated and TIA1, a silencer of COX2 gene translation is upregulated in L3/C. Ingenuity network analysis identified a top network associated with nervous system development and function with EGFR as the outstanding interaction partner. In this network EGFR interacts with genes involved in neural or visual perception, TIMP3, NRG1, ADAM17, EDG7 and FGF7. Quantitative real time-PCR analysis on selected genes confirmed the array results. The L and L3 groups have DHA and ARA content within the ranges observed in human and baboon breastmilk, and thus these data indicate that LCPUFA concentrations within the normal range of human breastmilk induce global changes in gene expression across numerous functions including transcripts involved in neural development, visual perception, etc. Keywords: dietary dose response

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Desaturase and elongase-limiting endogenous long-chain polyunsaturated fatty acid biosynthesis.

Publications

Desaturase and elongase-limiting endogenous long-chain polyunsaturated fatty acid biosynthesis.

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