Characterization of an arachidonic acid-deficient (Fads1 knockout) mouse model

Fan, Yang; Monk, Jennifer M.; Hou, Tim Y.; Callway, Evelyn; Vincent, Logan; Weeks, Brad R.; Yang, Peiying; Chapkin, Robert S.

doi:10.1194/jlr.m024216

Cited by 69 publications

(79 citation statements)

References 46 publications

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“…These results demonstrated that recombinant FADS3 displayed no ⌬ 5-and ⌬ 6-desaturase activities, consistent with previous reports describing FADS2-null and FADS1-null mice. In these studies, FADS1 or FADS2 defi ciency ( 6,35,36 ) was not rescued by the presence of FADS3 in terms of PUFA composition of tissues. These data and the present study therefore support the idea that FADS3 is not a ⌬ 5-or ⌬ 6-desaturase isoform capable of compensating the absence of FADS1 or FADS2.…”

Section: Biosynthesis Of the Suspected Trans 11 Cis 13-cla In Rat Hementioning

confidence: 84%

Trans-vaccenate is Δ13-desaturated by FADS3 in rodents

Rioux

Pédrono

Blanchard

et al. 2013

Journal of Lipid Research

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This article is available online at http://www.jlr.org "methyl-end" FA desaturases. Therefore, linoleic acid and ␣ -linolenic acid must be provided by the diet ( 3 ). These dietary essential FAs then serve as precursors for longer PUFAs of the n-6 and n-3 series, including arachidonic acid (20:4 n-6) and docosahexaenoic acid (22:6 n-3) required for many important physiological functions in humans ( 4,5 ). In this PUFA biosynthesis, only "front-end" desaturases ( ⌬ 5-and ⌬ 6-desaturases) are involved to introduce new double bonds between the preexisting double bonds and the carboxyl end of FAs ( 6 ).In 2000, the genomic structure of the fatty acid desaturase (FADS) cluster, located on chromosome 11 in humans, was reported ( 7 ). This cluster includes the FADS1 and FADS2 genes that code, respectively, for the well-known ⌬ 5-and ⌬ 6-desaturases involved in PUFA biosynthesis ( 8-10 ). A third gene was identifi ed on this cluster with high degree of nucleotide sequence homology with both FADS1 (62%) and FADS2 (70%) and was therefore named FADS3. Since its fi rst description in humans ( 7 ), FADS3 has been identifi ed in rats ( 11 ), baboons ( 12 ), mice ( 3 ), and many other mammals showing a similar nucleotide sequence and intron/exon organization ( 12 ). When analyzing the peptide sequence deduced from the FADS3 nucleotide sequence, FADS3 protein was identifi ed as a putative desaturase, according to its similarity with FADS1 and FADS2. Indeed, the predicted structure of FADS3 is composed of an N-terminal cytochrome b5-like domain characterized by a HPGG motif shown to be essential for the ⌬ 6-desaturase activity of FADS2 ( 13 ) QIEHH in the rat) characteristic of front-end-desaturases ( 14 ). According to its amino acid sequence, FADS3 was thereafter supposed to Abstract Fatty acid desaturases play critical roles in regulating the biosynthesis of unsaturated fatty acids in all biological kingdoms. As opposed to plants, mammals are so far characterized by the absence of desaturases introducing additional double bonds at the methyl-end site of fatty acids. However, the function of the mammalian fatty acid desaturase 3 (FADS3) gene remains unknown. This gene is located within the FADS cluster and presents a high nucleotide sequence homology with FADS1 ( ⌬ 5-desaturase) and FADS2 ( ⌬ 6-desaturase). Here, we show that rat FADS3 displays no common ⌬ 5-, ⌬ 6-or ⌬ 9-desaturase activity but is able to catalyze the unexpected ⌬ 13-desaturation of trans -vaccenate. Although there is no standard for complete conclusive identifi cation, structural characterization strongly suggests that the ⌬ 11,13-conjugated linoleic acid (CLA) produced by FADS3 from trans -vaccenate is the trans 11, cis 13-CLA isomer. In rat hepatocytes, knockdown of FADS3 expression specifically reduces trans -vaccenate ⌬ 13-desaturation. Evidence is presented that FADS3 is the fi rst "methyl-end" fatty acid desaturase functionally characterized in mammals. FA desaturases introduce double bonds between defi ned carbons of the fatty acyl chain and catalyze ...

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Section: Biosynthesis Of the Suspected Trans 11 Cis 13-cla In Rat Hementioning

confidence: 84%

Trans-vaccenate is Δ13-desaturated by FADS3 in rodents

Rioux

Pédrono

Blanchard

et al. 2013

Journal of Lipid Research

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“…Fads1 knockout mice [genotypes: wild-type (Wt), heterozygous (Het), and null (Null)] represent a Δ5 desaturase knockout strain that produces AA deficiency without the underlying complication of essential fatty acid deficiency [i.e., linoleic acid (LA) or DGLA] [48]. Fat-1 transgenic mice (genotypes: Wt and Fat-1 ) synthesize long chain n-3 PUFA de novo [46].…”

Section: Methodsmentioning

confidence: 99%

Antagonizing Arachidonic Acid-Derived Eicosanoids Reduces Inflammatory Th17 and Th1 Cell-Mediated Inflammation and Colitis Severity

Monk

Turk

Fan

et al. 2014

Mediators of Inflammation

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During colitis, activation of two inflammatory T cell subsets, Th17 and Th1 cells, promotes ongoing intestinal inflammatory responses. n-6 polyunsaturated fatty acid- (PUFA-) derived eicosanoids, such as prostaglandin E2 (PGE2), promote Th17 cell-mediated inflammation, while n-3 PUFA antagonize both Th17 and Th1 cells and suppress PGE2 levels. We utilized two genetic mouse models, which differentially antagonize PGE2 levels, to examine the effect on Th17 cells and disease outcomes in trinitrobenzene sulfonic acid- (TNBS-) induced colitis. Fat-1 mice contain the ω3 desaturase gene from C. elegans and synthesize n-3 PUFA de novo, thereby reducing the biosynthesis of n-6 PUFA-derived eicosanoids. In contrast, Fads1 Null mice contain a disrupted Δ5 desaturase gene and produce lower levels of n-6 PUFA-derived eicosanoids. Compared to Wt littermates, Fat-1 and Fads1 Null mice exhibited a similar colitic phenotype characterized by reduced colonic mucosal inflammatory eicosanoid levels and mRNA expression of Th17 cell markers (IL-17A, RORγτ, and IL-23), decreased percentages of Th17 cells and, improved colon injury scores (P ≤ 0.05). Thus, during colitis, similar outcomes were obtained in two genetically distinct models, both of which antagonize PGE2 levels via different mechanisms. Our data highlight the critical impact of n-6 PUFA-derived eicosanoids in the promotion of Th17 cell-mediated colonic inflammation.

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“…In this sense, FADS1 competes successfully with FADS2 when FADS2 expression is negligible. Disruption of the Fads1 gene in mouse causes massive accumulation of the 20:3n-6 substrate and 1-series-derived prostaglandins, with a concurrent decrease in the product 20:4n-6 and 2-series-derived prostaglandins [19]. Fads1 ablated mice fail to thrive beyond 12 weeks of age; the phenotype is rescued by dietary supplementation of 20:4n-6 [19].…”

Section: Fads1 (δ5-desaturase)mentioning

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

159

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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Characterization of an arachidonic acid-deficient (Fads1 knockout) mouse model

Cited by 69 publications

References 46 publications

Trans-vaccenate is Δ13-desaturated by FADS3 in rodents

Trans-vaccenate is Δ13-desaturated by FADS3 in rodents

Antagonizing Arachidonic Acid-Derived Eicosanoids Reduces Inflammatory Th17 and Th1 Cell-Mediated Inflammation and Colitis Severity

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

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