Cloning of a human cDNA encoding a novel enzyme involved in the elongation of long-chain polyunsaturated fatty acids

Leonard, Amanda E.; Bobik, E.; DORADO, Joseph; Kroeger, Paul E.; Chuang, Lu-Te; Thurmond, Jennifer M.; Parker-Barnes, Jennifer M.; Das, Tapas; Huang, Y. S.; Mukerji, Pradip

doi:10.1042/0264-6021:3500765

Cited by 130 publications

(138 citation statements)

References 31 publications

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“…An abundant amount of Elovl2 mRNA in testis suggested that ELOVL2 elongates PUFAs [8]. This was subsequently demonstrated in mouse [10], human [29] and rat [30,31] orthologs, and in this study (Fig. 1C).…”

Section: Discussionsupporting

confidence: 80%

ELOVL2 overexpression enhances triacylglycerol synthesis in 3T3‐L1 and F442A cells

2007

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Elongation of very long-chain fatty acids (ELOVL) members were overexpressed in two preadipocyte cell lines, ELOVL2 and ELOVL3 in 3T3-L1 cells, and ELOVL1-3 in F442A cells. Cells overexpressing ELOVL2, whose preferred substrates are arachidonic acid (AA, C20:4nÀ6) and eicosapentaenoic acid (EPA, C20:5nÀ3), showed an enhanced triacylglycerol (TAG) synthesis and subsequent accumulation of lipid droplets. Incorporation of fatty acid (FA) but not of glucose into TAG was enhanced by ELOVL2-overexpression. Two lipogenic genes encoding diacylglycerol acyltransferase-2 (DGAT2) and fatty acid-binding protein-4 (FABP4, aP2) were induced in ELOVL2-overexpressing cells, whereas no such effect was seen on the fatty acid synthase (FAS) gene.

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Section: Discussionsupporting

confidence: 80%

ELOVL2 overexpression enhances triacylglycerol synthesis in 3T3‐L1 and F442A cells

2007

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“…C. elegans lacks this elongation activity, and the pathway terminates with 20:5n3 as the most abundant PUFA. Interestingly, the human ELO1 homologue, HELO1, has been shown by expression in yeast to elongate 18:3n6, 18:4n3, 20:4n6, and 20:5n3 (41). Thus, this human elongase produces C20 PUFAs from C18 ⌬6 desaturated substrates, similar to the C. elegans activity, yet it also can convert 20:4n6 and 20:5n3 to 22:4n6 and 22:5n3, an activity absent in worms.…”

Section: Discussionmentioning

confidence: 95%

Genetic dissection of polyunsaturated fatty acid synthesis in Caenorhabditis elegans

Watts

Browse

2002

Proc. Natl. Acad. Sci. U.S.A.

359

425

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Polyunsaturated fatty acids (PUFAs) are important membrane components and precursors of signaling molecules. To investigate the roles of these fatty acids in growth, development, and neurological function in an animal system, we isolated Caenorhabditis elegans mutants deficient in PUFA synthesis by direct analysis of fatty acid composition. C. elegans possesses all the desaturase and elongase activities to synthesize arachidonic acid and eicosapentaenoic acid from saturated fatty acid precursors. In our screen we identified mutants with defects in each fatty acid desaturation and elongation step of the PUFA biosynthetic pathway. The fatty acid compositions of the mutants reveal the substrate preferences of the desaturase and elongase enzymes and clearly demarcate the steps of this pathway. The mutants show that C. elegans does not require n3 or ⌬5-unsaturated PUFAs for normal development under laboratory conditions. However, mutants with more severe PUFA deficiencies display growth and neurological defects. The mutants provide tools for investigating the roles of PUFAs in membrane biology and cell function in this animal model. P olyunsaturated fatty acid (PUFA) components of phospholipids are necessary to create a fluid membrane environment. In mammals, specific PUFA composition affects many cellular processes including modulation of ion channels (1, 2), endocytosis͞exocytosis (3), and activities of membrane-associated enzymes that are sensitive to the biophysical properties of lipid membranes (4). In addition, certain classes of PUFAs are precursors of powerful eicosanoid effectors such as prostaglandins and leukotrienes (5). Disruptions in proper PUFA intake and metabolism are associated with certain human disease states such as coronary artery disease, hypertension, diabetes, inflammatory disorders, and cancer (6). In most cases the mechanisms through which fatty acid composition affects these conditions are not well understood.Mammals require the essential fatty acids linoleic acid (18:2n6) and linolenic acid (18:3n3) in their diet. Desaturation and elongation of these fatty acids produce the C20 PUFAs that become membrane components and precursors for eicosanoids. Plants produce these essential n6 and n3 PUFAs by desaturating oleic acid (18:1n9) at C12 and C15 positions to produce 18:2n6 and 18:3n3 but rarely possess the enzymes necessary to desaturate and elongate them further into C20 PUFAs. The free-living nematode Caenorhabditis elegans synthesizes a wide range of PUFAs including arachidonic acid (20:4n6) and eicosapentaenoic acid (20:5n3) by using saturated fatty acids obtained from their Escherichia coli diet (7). To this end, C. elegans expresses the full range of desaturase activities found in plants (⌬12 and n3 desaturase) and animals (⌬5 and ⌬6 desaturase) as well as n6 and n3 PUFA elongase activities found in animals. cDNAs corresponding to C. elegans n3, ⌬12, ⌬6, and ⌬5 desaturase genes have been expressed in Arabidopsis and yeast to confirm their desaturase activity (8-11). Another C. elegans ...

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“…Members of the elongation-of-very-long-chain-fatty-acids (ELOVL) gene family encode elongases specific for substrate chain length and degree of unsaturation. Human elongase-5 (ELOVL5) elongates C 18 and C 20 PUFA (Leonard et al 2000) and elongase-2 (ELOVL2) is active with C 20 and C 22 PUFA (Leonard et al 2002). In the n-3 LC-PUFA biosynthetic sequence, the delta-5 desaturase FADS1 catalyses the formation of EPA.…”

Section: Introductionmentioning

confidence: 99%

ELOVL2 gene polymorphisms are associated with increases in plasma eicosapentaenoic and docosahexaenoic acid proportions after fish oil supplement

et al. 2013

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Fish oil supplementation provides an inconsistent degree of protection from cardiovascular disease (CVD), which may be attributed to genetic variation. Single nucleotide polymorphisms (SNPs) in the elongation-ofvery-long-chain-fatty-acids-2 (ELOVL2) gene have been strongly associated with plasma proportions of n-3 longchain polyunsaturated fatty acids (LC-PUFA). We investigated the effect of genotype interaction with fish oil dosage on plasma n-3 LC-PUFA proportions in a parallel doubleblind controlled trial, involving 367 subjects randomised to treatment with 0.45, 0.9 and 1.8 g/day eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (1.51:1) or olive oil placebo for 6 months. We genotyped 310 subjects for ELOVL2 gene SNPs rs3734398, rs2236212 and rs953413. At baseline, carriers of all minor alleles had lower proportions of plasma DHA than non-carriers (P = 0.021-0.030). Interaction between genotype and treatment was a significant determinant of plasma EPA (P \ 0.0001) and DHA (P = 0.004-0.032). After the 1.8 g/day dose, carriers of ELOVL2 SNP minor alleles had approximately 30 % higher proportions of EPA (P = 0.002-0.004) and 9 % higher DHA (P = 0.013-0.017) than non-carriers. Minor allele carriers could therefore particularly benefit from a high intake of EPA and DHA in maintaining high levels of plasma n-3 PUFA conducive to protection from CVD.

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Cloning of a human cDNA encoding a novel enzyme involved in the elongation of long-chain polyunsaturated fatty acids

Cited by 130 publications

References 31 publications

ELOVL2 overexpression enhances triacylglycerol synthesis in 3T3‐L1 and F442A cells

ELOVL2 overexpression enhances triacylglycerol synthesis in 3T3‐L1 and F442A cells

Genetic dissection of polyunsaturated fatty acid synthesis in Caenorhabditis elegans

ELOVL2 gene polymorphisms are associated with increases in plasma eicosapentaenoic and docosahexaenoic acid proportions after fish oil supplement

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