Relationship between a Common Variant in the Fatty Acid Desaturase (FADS) Cluster and Eicosanoid Generation in Humans

Hester, Austin G.; Murphy, Robert C.; Uhlson, Charis L.; Ivester, Priscilla; Lee, Tammy C.; Sergeant, Susan; Miller, Leslie R.; Howard, Timothy D.; Mathias, Rasika A.; Chilton, Floyd H.

doi:10.1074/jbc.m114.579557

Cited by 62 publications

(61 citation statements)

References 54 publications

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“…A SNP in ELOVL5 was associated with late onset primary open-angle glaucoma [39]. Recent studies show SNPs near FADS1 (rs174537) influencing the levels of 5-lipoxygenase products [40] and another found rs174537 associated with epigenetic alteration [41]. A minor allele of FADS3 SNP (rs174455) was negatively associated with 22:6n-3 in erythrocyte phospholipids in the AVON longitudinal study of parents and children (ALSPAC) cohort [42].…”

Section: Candidate (Fads Gene Cluster Elovl2 and Elovl5) Gene Studiesmentioning

confidence: 99%

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

Zhang

Kothapalli

Brenna

2016

Current Opinion in Clinical Nutrition and Metabolic Care

164

147

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Purpose of Review Endogenous synthesis of the long chain polyunsaturated fatty acids (LCPUFA) 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). Though 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. Recent findings Genome-wide association study (GWAS) of Greenland Inuit show 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 Δ4-desaturation to yield 22:6n-3 and 22:5n-6. A SNP near FADS1 influences the levels of 5-lipoxygenase products and epigenetic alteration. Summary Genetic polymorphisms within FADS and ELOVL can limit LCPUFA product accumulation at any step of the biosynthetic pathway.

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Section: Candidate (Fads Gene Cluster Elovl2 and Elovl5) Gene Studiesmentioning

confidence: 99%

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

Zhang

Kothapalli

Brenna

2016

Current Opinion in Clinical Nutrition and Metabolic Care

164

147

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“…Plasma VLDL particles undergo intravascular metabolism to become LDL particles, a major atherogenic lipoprotein particle in plasma. Deletion of the cholesterol esterifi cation enzyme, steroyl O-acyltransferase 2 (SOAT2), strikingly reduces atherosclerosis regardless of dietary fat saturation ( 38 ), supporting a critical role for SOAT2 in the generation of and 5-hydroxyeicosatetraenoic acids in zymosan-stimulated blood, suggesting that genetic polymorphisms may infl uence tissue AA content and infl ammatory response to external pathogens ( 48 ). Thus, individuals harboring rs174537 homozygous GG alleles may be hyperresponsive to diets enriched in LA and GLA.…”

Section: Downloaded Frommentioning

confidence: 99%

Botanical oils enriched in n-6 and n-3 FADS2 products are equally effective in preventing atherosclerosis and fatty liver

Shewale

Boudyguina

Zhu

et al. 2015

Journal of Lipid Research

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“…A potential reason for these findings could involve the high LA intakes in the Western diet, resulting in reduced synthesis of LC n-3 PUFA from αLNA (32) . The higher n-6 conversion also leads to increased levels of AA, which is a direct precursor of many pro-inflammatory eicosanoids (33,34) . Hester et al (33) recently showed that subjects with the major allele for FADS SNP rs174537 had significantly higher levels of pro-inflammatory eicosanoids, LTB4 and 5-HETE, compared with minor allele carriers (33) .…”

Section: Impact Of Fatty Acid Desaturase Genotype On Cardiovascular Hmentioning

confidence: 99%

“…The higher n-6 conversion also leads to increased levels of AA, which is a direct precursor of many pro-inflammatory eicosanoids (33,34) . Hester et al (33) recently showed that subjects with the major allele for FADS SNP rs174537 had significantly higher levels of pro-inflammatory eicosanoids, LTB4 and 5-HETE, compared with minor allele carriers (33) . However, a few studies have reported contradictory results (35)(36)(37) which could be due to the ethnicity of the participants or differences in the n-6 : n-3 PUFA content of the habitual diet.…”

Section: Impact Of Fatty Acid Desaturase Genotype On Cardiovascular Hmentioning

confidence: 99%

The impact of fatty acid desaturase genotype on fatty acid status and cardiovascular health in adults

O’Neill

Minihane

2016

Proc. Nutr. Soc.

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The aim of this review was to determine the impact of the fatty acid desaturase (FADS) genotype on plasma and tissue concentrations of the long-chain (LC) n-3 PUFA, including EPA and DHA, which are associated with the risk of several diet-related chronic diseases, including CVD. In addition to dietary intakes, which are low for many individuals, tissue EPA and DHA are also influenced by the rate of bioconversion from α-linolenic acid (αLNA). Δ-5 and Δ-6 desaturase enzymes, encoded for by FADS1 and FADS2 genes, are key desaturation enzymes involved in the bioconversion of essential fatty acids (αLNA and linoleic acid (LA)) to longer chained PUFA. In general, carriers of FADS minor alleles tend to have higher habitual plasma and tissue levels of LA and αLNA, and lower levels of arachidonic acid, EPA and also to a lesser extent DHA. In conclusion, available research findings suggest that FADS minor alleles are also associated with reduced inflammation and CVD risk, and that dietary total fat and fatty acid intake have the potential to modify relationships between FADS gene variants and circulating fatty acid levels. However to date, neither the size-effects of FADS variants on fatty acid status, nor the functional SNP in FADS1 and 2 have been identified. Such information could contribute to the refinement and targeting of EPA and DHA recommendations, whereby additional LC n-3 PUFA intakes could be recommended for those carrying FADS minor alleles.

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Relationship between a Common Variant in the Fatty Acid Desaturase (FADS) Cluster and Eicosanoid Generation in Humans

Cited by 62 publications

References 54 publications

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

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

Botanical oils enriched in n-6 and n-3 FADS2 products are equally effective in preventing atherosclerosis and fatty liver

The impact of fatty acid desaturase genotype on fatty acid status and cardiovascular health in adults

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