Ceramides and Sphingomyelins with High Proportions of Very Long-chain Polyunsaturated Fatty acids in Mammalian Germ Cells

Furland, Natalia Edith; Zanetti, Samanta Romina; Oresti, Gerardo Martín; Maldonado, Eduardo N.; Aveldaño, Marta I.

doi:10.1074/jbc.m700708200

Cited by 64 publications

(57 citation statements)

References 51 publications

(43 reference statements)

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“…In rat testes, 28:4n6 and 30:5n6 constitute the most abundant VLC-PUFA found in ceramides and sphingolipids ( 19 ). The VLC-PUFA content increased with the onset of spermatogenesis, reaching almost 15% and 40% of the total FA in sphingomyelin and ceramides, respectively.…”

Section: Distribution Abundance and Biosynthesis Of Vlc-pufamentioning

confidence: 98%

“…Ram, boar, bull, and human spermatozoa also contain both odd-chain (for ram and boar) and even-chain VLC-PUFA (C26-C38) ( 54 ). Interestingly, most of the testis-and spermatozoa-related VLC-PUFA are amide bound in sphingomyelin and ceramides instead of ester bound in phosphatidylcholine (PC), as found in the retina ( 18,19,55 ).…”

Section: Distribution Abundance and Biosynthesis Of Vlc-pufamentioning

confidence: 99%

“…The VLC-PUFA content increased with the onset of spermatogenesis, reaching almost 15% and 40% of the total FA in sphingomyelin and ceramides, respectively. As in the retina, these FA, together with 22:6n3, remain at high levels during adult life in fertile rats and then decrease during older age ( 19,56 ).…”

Section: Distribution Abundance and Biosynthesis Of Vlc-pufamentioning

confidence: 99%

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Retinal very long-chain PUFAs: new insights from studies on ELOVL4 protein

Agbaga

Mandal

Anderson

2010

Journal of Lipid Research

142

147

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This article is available online at http://www.jlr.org tively rare compared with the abundance of FA containing 16-22 carbons, they are widely distributed in higher plants and animals ( 1-10 ). They are found in most living organisms from humans to autotrophic and heterotrophic lower organisms, including microalgae, sponges, bacteria, and fungi ( 1,9,(11)(12)(13)(14)(15). VLC-FA are found mainly in seed oils, plant waxes, cutin, suberin, skin, hair, and wax glands ( 1 ), whereas VLC-PUFA are found primarily in retina, brain ( 1, 16 ), testis, and spermatozoa ( 17-19 ).The unusually long hydrocarbon chains with 3 -9 double bonds, which are prone to oxidative damage, combined with the small quantities found in mammalian tissues, have made them diffi cult to isolate and analyze in detail over the years ( 9 ). Very little is therefore known about the metabolism and function of VLC-PUFA and VLC-FA in mammals, except for their increase in disorders of peroxisomal function ( 3,16,20,21 ), as components of the secretions of meibomian glands (22)(23)(24)(25)(26)(27), and their reduction in animal models of autosomal dominant Stargardt-like macular dystrophy (STGD3) ( 28-32 ), a juvenile form of macular degeneration. In contrast, the roles of long-chain PUFA (LC-PUFA) with carbon chains that range from C18 to C24 are fairly well understood, especially in the retina and other neural tissues. A detailed account on the role and function of LC-PUFA in the retina was reviewed earlier (33)(34)(35)(36).Recent interest in the molecular and physiological roles of VLC-PUFA in the retina came from the fi nding that the gene associated with STGD3 shared sequence homologies with genes involved in FA elongation ( 37,38 ) Abbreviations: AOX, acyl-CoA oxidase; DHA or 22:6n3, docosahexaenoic acid; ELOVL, elongation of very long-chain FA; ELOVL4, elongation of very long-chain FA-4; ERG, electroretinogram; LC-PUFA, long-chain PUFA; PC, phosphatidylcholine; ROS, retinal outer segments; RPE, retinal pigment epithelium; STGD1, recessive Stargardt degeneration; STGD3, autosomal dominant Stargardt-like macular dystrophy; VLC-FA, very long-chain saturated or monounsaturated FA; VLC-PUFA, very long-chain PUFA.

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Section: Distribution Abundance and Biosynthesis Of Vlc-pufamentioning

confidence: 98%

Section: Distribution Abundance and Biosynthesis Of Vlc-pufamentioning

confidence: 99%

Section: Distribution Abundance and Biosynthesis Of Vlc-pufamentioning

confidence: 99%

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Retinal very long-chain PUFAs: new insights from studies on ELOVL4 protein

Agbaga

Mandal

Anderson

2010

Journal of Lipid Research

142

147

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“…Results obtained by gas chromatography-mass spectrometry (GC-MS) show that ELOVL4 protein is indeed a component of a fatty acid elongation system that catalyzes synthesis of 28:0 and 30:0 VLC-FA and of C28-C38 VLC-PUFA, the latter being uniquely found in retina (28,29), sperm (29,30), and brain (31). We propose that these steps are important in these tissues for the local synthesis of VLC-PUFA (C28-C36) that are esterified into phosphatidylcholine in rod outer segment membranes and brain, or amidebound into sphingolipids and ceramides in germ cells (32) and sperm of some mammals (33).…”

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confidence: 99%

Role of Stargardt-3 macular dystrophy protein (ELOVL4) in the biosynthesis of very long chain fatty acids

Agbaga

Brush

Mandal

et al. 2008

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

238

346

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Stargardt-like macular dystrophy (STGD3) is a dominantly inherited juvenile macular degeneration that eventually leads to loss of vision. Three independent mutations causing STGD3 have been identified in exon six of a gene named Elongation of very long chain fatty acids 4 (ELOVL4). The ELOVL4 protein was predicted to be involved in fatty acid elongation, although evidence for this and the specific step(s) it may catalyze have remained elusive. Here, using a gain-of-function approach, we provide direct and compelling evidence that ELOVL4 is required for the synthesis of C28 and C30 saturated fatty acids (VLC-FA) and of C28-C38 very long chain polyunsaturated fatty acids (VLC-PUFA), the latter being uniquely expressed in retina, sperm, and brain. Rat neonatal cardiomyocytes and a human retinal epithelium cell line (ARPE-19) were transduced with recombinant adenovirus type 5 carrying mouse Elovl4 and supplemented with 24:0, 20:5n3, or 22:5n3. The 24:0 was elongated to 28:0 and 30:0; 20:5n3 and 22:5n3 were elongated to a series of C28-C38 PUFA. Because retinal degeneration is the only known phenotype in STGD3 disease, we propose that reduced VLC-PUFA in the retinas of these patients may be the cause of photoreceptor cell death.fatty acid biosynthesis ͉ macular degeneration T hree independent mutations in the last exon (exon-VI) of the ELOVL4 gene are associated with dominant Stargardt-like macular dystrophy (STGD3) in humans (1-4). These mutations cause a frame-shift that introduces a stop codon, resulting in premature termination of the protein and removal of the signal sequence for targeting the protein to its putative cellular location, the endoplasmic reticulum (1, 4). As a result, the mutant protein mis-localizes and aggregates (3,5,6), and, when coexpressed with the wild type protein, the mutant and wild-type proteins associate and mis-localize (3, 7). Based on sequence homology with a group of functional yeast genes and other mammalian ELOVLs, the ELOVL4 protein was predicted to be involved in elongation of very long chain fatty acids (1,5,8). For example, the yeast microsomal Elo1p is responsible for elongation of carbon chains between 14:0 and 16:0 (9). Yeast Elo2p and Elo3p, and mammalian ELOVL1, 2, 3, and 5 have been shown to be involved in elongation of saturated, monounsaturated, or polyunsaturated fatty acids (PUFA) from 18 to 26 carbons (10-12). However, a role for ELOVL4 protein in fatty acid elongation and the specific step(s) it may catalyze have remained elusive (13,14). Based on the abundant expression of ELOVL4 protein in photoreceptor cells of the retina (15-17) and to lesser extents in brain, testis, and skin (17), it was first hypothesized that ELOVL4 may be involved in the biosynthetic pathway of docosahexaenoic acid (22:6n3, DHA), the most abundant PUFA in the retina and the brain (1,16,18). A series of experiments carried out in our laboratory (unpublished data) does not support this hypothesis.Recent reports establish ELOVL4 as an essential protein for growth and development, as neonatal ...

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“…These, coincidentally, are the stages that express low SOD levels [22][23][24][25]. Moreover, post-ischemic reperfusion, conditions that lead to selective death of germ cells in vivo, caused the very long chain poly unsaturated fatty acids (VLCPUFA) to disappear from the testicular sphingomyelin and cerebrosides of adult fertile rats, showing that these lipids are specific traits of spermatogenic cells [26,27].…”

Section: Discussionmentioning

confidence: 99%