The role of ELOVL1 in very long‐chain fatty acid homeostasis and X‐linked adrenoleukodystrophy

Ofman, Rob; Dijkstra, Inge M. E.; Roermund, C. W. T. van; Burger, Nena; Turkenburg, Marjolein; Cruchten, Arno van; Engen, Catherine E. van; Wanders, Ronald J. A.; Kemp, Stephan

doi:10.1002/emmm.201000061

Cited by 143 publications

(153 citation statements)

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“…In contrast, ELOVL2 and 5, encoded by ELOVL2 and 5, respectively, are involved in poly-unsaturated fatty acid metabolism. In ALD, ELOVL1 is thought to mainly be involved in the accumulation of saturated VLCFAs, because the accumulation of C26:0 was decreased by a silencing of the ELOVL1 gene in ALD fibroblasts (Ofman et al 2010). However, the hepatic gene expression of Elovls was the same in the wildtype and abcd1-deficient mice.…”

Section: Changes In Hepatic Gene Expression In Lo-treated Micementioning

confidence: 99%

“…ABCD1 is a transporter of VLCFA-CoA into peroxisomes (van Roermund et al 2011). The dysfunction of ABCD1 causes a reduction in peroxisomal VLCFA b-oxidation and an increase in the VLCFA-CoA level in the cytosol (Ofman et al 2010). The increased cytosolic VLCFA-CoA is used as a substrate for microsomal fatty acid elongation, which results in the accumulation of VLCFAs (Schackmann et al 2015).…”

Section: Introductionmentioning

confidence: 99%

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Effect of Lorenzo’s Oil on Hepatic Gene Expression and the Serum Fatty Acid Level in abcd1-Deficient Mice

et al. 2017

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Lorenzo's oil is known to decrease the saturated very long chain fatty acid (VLCFA) level in the plasma and skin fibroblasts of X-linked adrenoleukodystrophy (ALD) patients. However, the involvement of Lorenzo's oil in in vivo fatty acid metabolism has not been well elucidated. To investigate the effect of Lorenzo's oil on fatty acid metabolism, we analyzed the hepatic gene expression together with the serum fatty acid level in Lorenzo's oiltreated wild-type and abcd1-deficient mice. The change in the serum fatty acid level in Lorenzo's oil-treated abcd1-defcient mice was quite similar to that in the plasma fatty acid level in ALD patients supplemented with Lorenzo's oil. In addition, we found that the hepatic gene expression of two peroxisomal enzymes, Dbp and Scp2, and three microsomal enzymes, Elovl1, 2, and 3, were significantly stimulated by Lorenzo's oil. Our findings indicate that Lorenzo's oil activates hepatic peroxisomal fatty acid boxidation at the transcriptional level. In contrast, the transcriptional stimulation of Elovl1, 2, and 3 by Lorenzo's oil does not cause changes in the serum fatty acid level. It seems likely that the inhibition of these elongation activities by Lorenzo's oil results in a decrease in saturated VLCFA. Thus, these results not only contribute to a clarification of the mechanism by which the saturated VLCFA level is reduced in the serum of ALD patients by Lorenzo's oiltreatment, but also suggest the development of a new therapeutic approach to peroxisomal b-oxidation enzyme deficiency, especially mild phenotype of DBP deficiency.

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Section: Changes In Hepatic Gene Expression In Lo-treated Micementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effect of Lorenzo’s Oil on Hepatic Gene Expression and the Serum Fatty Acid Level in abcd1-Deficient Mice

et al. 2017

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“…The mouse ELOVL6 protein elongates saturated FA from C12-C16 to C18 ( 104 ). When the human ELOVL6 protein was expressed in yeast cells, 16:0 levels decreased and 18:0, 18:1, and 20:0 levels increased ( 136 ). Also, levels of C20 and C22 FA were increased in yeast cells expressing human ELOVL6 ( 136 ).…”

Section: The Role Of Fa Elongase Complex In Vlc-fa and Vlc-pufa Biosymentioning

confidence: 99%

“…The fatty acyl-CoA chain elongation cycle mediated by the elongase complex involves the addition of two carbons from malonyl-CoA to an existing fatty acyl-CoA to form an acyl-CoA that is two carbons longer ( 103,116,117 ). The initial condensation reaction, which is the ratelimiting step in the elongation process, is catalyzed by en-not seem to be involved in elongations beyond C22 ( 104,124,136,138 ).…”

Section: The Role Of Fa Elongase Complex In Vlc-fa and Vlc-pufa Biosymentioning

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

146

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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Molecular Genetics of X‐linked Adrenoleukodystrophy

Kemp

2014

Encyclopedia of Life Sciences

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X‐linked adrenoleukodystrophy (X‐ALD), which affects 1 in 17 000 newborns, is one of the most puzzling inborn errors of metabolism of the central nervous system. All X‐ALD patients have mutations in the ABCD1 gene, which affect the function of the encoded protein ALDP, an adenosine triphosphate (ATP) ‐binding cassette transporter located in the peroxisomal membrane protein. ALDP deficiency impairs the peroxisomal beta‐oxidation of very long‐chain fatty acids (VLCFA) and facilitates their further chain elongation by ELOVL1 resulting in the accumulation of VLCFA in the plasma and tissues. The clinical spectrum ranges from progressive myelopathy in adults to fatal cerebral demyelinating disease in boys and adult males (cerebral ALD). In the absence of a genotype–phenotype correlation, the disease course remains completely unpredictable, even within families, and is therefore defined by modifier genes, epigenetics and the environment. For the majority of patients there is no curative therapy. Key Concepts: The clinical spectrum of X‐ALD ranges from a progressive myelopathy (adrenomyeloneuropathy) in adult males and females to a fatal cerebral demyelinating disease in boys and adult males (cerebral ALD). X‐ALD has been diagnosed in all geographic regions and ethnic groups, and there is no evidence that the prevalence varies with ethnic background. Mutations in the ABCD1 gene have no predictive value with respect to the clinical outcome of a patient. Approximately 65% of heterozygous females develop AMN by the age of 60 years. VLCFA accumulating in X‐ALD mostly result from endogenous synthesis through elongation of LCFA by ELOVL1, the VLCFA‐specific elongase. Newborn screening allows prospective monitoring and early intervention.

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The role of ELOVL1 in very long‐chain fatty acid homeostasis and X‐linked adrenoleukodystrophy

Cited by 143 publications

References 34 publications

Effect of Lorenzo’s Oil on Hepatic Gene Expression and the Serum Fatty Acid Level in abcd1-Deficient Mice

Effect of Lorenzo’s Oil on Hepatic Gene Expression and the Serum Fatty Acid Level in abcd1-Deficient Mice

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

Molecular Genetics of X‐linked Adrenoleukodystrophy

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