Elongation of very long-chain fatty acids is enhanced in X-linked adrenoleukodystrophy

Kemp, Stephan; Valianpour, Fredoen; Denis, Simone; Ofman, Rob; Sanders, Robert-Jan; Mooyer, Petra; Barth, Peter; Wanders, Ronald J. A.

doi:10.1016/j.ymgme.2004.09.015

Cited by 87 publications

(56 citation statements)

References 37 publications

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“…In the present study, although we could not quantify C26:0 in serum lipids of apparently healthy subjects as the concentrations were too low to detect, other saturated and monounsaturated VLCFAs showed different results to previous studies. Elevated plasma and tissue levels of both saturated increased elongation of chain length in fatty acids, in addition to reduced peroxisomal beta-oxidation activity 30 . The treatment of X-ALD patients with Lorenzo s oil 31 , which consists of supplements of C18:1 and erucic acid C22:1 , resulted not only in normalization of C26:0 levels, but also a significant increase in C24:1 30 , probably by competition for the microsomal elongation system 32 .…”

Section: Discussionmentioning

confidence: 99%

“…Elevated plasma and tissue levels of both saturated increased elongation of chain length in fatty acids, in addition to reduced peroxisomal beta-oxidation activity 30 . The treatment of X-ALD patients with Lorenzo s oil 31 , which consists of supplements of C18:1 and erucic acid C22:1 , resulted not only in normalization of C26:0 levels, but also a significant increase in C24:1 30 , probably by competition for the microsomal elongation system 32 . Gene expression of Elovl3, a microsomal enzyme involved in VLCFA elongation, may be under the control of PPARα 33 , which is well known to regulate peroxisomal beta-oxidation.…”

Section: Discussionmentioning

confidence: 99%

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The Proportion of Nervonic Acid in Serum Lipids is Associated with Serum Plasmalogen Levels and Metabolic Syndrome

Yamazaki¹,

Kondo²,

Maeba

et al. 2014

J. Oleo Sci.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The Proportion of Nervonic Acid in Serum Lipids is Associated with Serum Plasmalogen Levels and Metabolic Syndrome

Yamazaki¹,

Kondo²,

Maeba

et al. 2014

J. Oleo Sci.

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“…[1][2][3][4][5][6][7][8][9][10][11][12][13][14] C]palmitic acid and 125 I-labeled protein A were obtained from ICN (Cleveland, OH).…”

Section: Reagentsmentioning

confidence: 99%

HDAC inhibitor SAHA normalizes the levels of VLCFAs in human skin fibroblasts from X-ALD patients and downregulates the expression of proinflammatory cytokines in Abcd1/2-silenced mouse astrocytes

Singh

Khan

Singh

2011

Journal of Lipid Research

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This article is available online at http://www.jlr.org Supplementary key words peroxisome • very long chain FA • glia • nitric oxide • cytokine • suberoylanilide hydroxamic acid • X-adrenoleukodystrophy X-adrenoleukodystrophy (X-ALD) is the most common peroxisomal disorder, with an incidence of approximately 1:17,000 ( 1, 2 ). It is a postnatal progressive demyelinating disorder that primarily affects nervous system white matter and axons, the adrenal cortex, and testis ( 3-5 ). The biochemical signature of X-ALD is increased levels of saturated straight-chain very long chain FAs (VLCFAs; >22:0). VLCFA accumulates in all tissues and lipid classes; however, the degree of accumulation is higher in the cholesterol ester and sphingolipid fractions of brain white matter and adrenal cortex ( 6 ). The elevation of VLCFAs is the consequence of reduced VLCFA peroxisomal ␤ -oxidation ( 7 ) and/or increased activity of FA elongases ( 8, 9 ). The ALD gene (ABCD1), identifi ed by positional cloning ( 10 ), encodes a protein that is related to the peroxisomal ATP binding cassette (ABCD) transmembrane transporter proteins ( 11,12 ). The function of the adrenoleukodystrophy protein (ALDP) and its role in VLCFA metabolism and in the pathogenesis of X-ALD is not well understood at present. However, the VLCFA, especially C26:0, has been documented to cause metabolic alterations leading to membrane perturbation, redox imbalance ( 13 ), and changes in membrane lipid composition ( 14-18 ), as well as the induction of infl ammatory mediators in cultured astrocytes ( 19 ). This study was supported in part by grants from the National Institutes of Health (Grants NS-22576, NS-37766, C06 RR-018823, and C06 RR-015455, and VA merit award BX1072-01. Its Abbreviations: ALDP, adrenoleukodystrophy protein; ALDRP, adrenoleukodystrophy-related protein; AMN, adrenomyeloneuropathy; BBB, blood-brain barrier; cALD, cerebral adrenoleukodystrophy; FAME, FA methyl ester; HDAC, histone deacetylase; iNOS, inducible nitric oxide synthase; 5-LOX, 5-lipoxygenase; PA, phenylacetate; PBA, phenylbutyrate; ROS, reactive oxygen species; SAHA, suberoylanilide hydroxamic acid; TNF-␣ , tumor necrosis factor-␣ ; X-ALD, X-adrenoleukodystrophy; VLCFA, very long chain FA.

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“…In several inherited peroxisomal diseases, including X-linked adrenoleukodystrophy, peroxisomal biogenesis disorders, and two single peroxisomal enzyme deficiencies, acyl-CoA oxidase deficiency and peroxisomal bifunctional protein deficiency, VLCFAs are increased in plasma as a result of reduced ␤ -oxidation of these fatty acids. In contrast, plasma levels of docosanoic acid (C22:0) are decreased in these patients (18). An excess of long-chain hydroxylated fatty acids and dicarboxylic acids was found in urine of patients with peroxisomal biogenesis disorders (19).…”

mentioning

confidence: 90%

Evidence for two enzymatic pathways for ω-oxidation of docosanoic acid in rat liver microsomes

Sanders

Ofman

Valianpour

et al. 2005

Journal of Lipid Research

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We studied the -oxidation of docosanoic acid (C22:0) in rat liver microsomes. C22:0 and 22-hydroxydocosanoic acid ( -hydroxy-C22:0) were used as substrates, and the reaction products were analyzed by electrospray ionization mass spectrometry. In the presence of NADPH, -oxidation of C22:0 produced not only the hydroxylated product, -hydroxy-C22:0, but also the dicarboxylic acid of C22:0, docosanedioic acid (C22:0-DCA). When rat liver microsomes were incubated with -hydroxy-C22:0 in the presence of either NAD ؉ or NADPH, C22:0-DCA was formed readily. Formation of C22:0-DCA from either C22:0 or -hydroxy-C22:0 with NADPH as cofactor was inhibited strongly by miconazole and disulfiram, whereas no inhibition was found with NAD ؉ as cofactor. Furthermore, -oxidation of C22:0 was reduced significantly when molecular oxygen was depleted. The high sensitivity toward the more specific cytochrome P450 inhibitors ketoconazole and 17-octadecynoic acid suggests that hydroxylation of C22:0 and -hydroxy-C22:0 may be catalyzed by one or more cytochrome P450 hydroxylases belonging to the CYP4A and/or CYP4F subfamily. This study demonstrates that C22:0 is a substrate for the -oxidation system in rat liver microsomes and that the product of the first hydroxylation step, -hydroxy-C22:0, may undergo further oxidation via two distinct pathways driven by NAD ؉ or NADPH. -Sanders, R-J., R. Ofman, F. Valianpour, S. Kemp, and R. J. A. Wanders. Evidence for two enzymatic pathways for -oxidation of docosanoic acid in rat liver microsomes. J. Lipid Res. 2005. 46: 1001-1008.

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Elongation of very long-chain fatty acids is enhanced in X-linked adrenoleukodystrophy

Cited by 87 publications

References 37 publications

The Proportion of Nervonic Acid in Serum Lipids is Associated with Serum Plasmalogen Levels and Metabolic Syndrome

The Proportion of Nervonic Acid in Serum Lipids is Associated with Serum Plasmalogen Levels and Metabolic Syndrome

HDAC inhibitor SAHA normalizes the levels of VLCFAs in human skin fibroblasts from X-ALD patients and downregulates the expression of proinflammatory cytokines in Abcd1/2-silenced mouse astrocytes

Evidence for two enzymatic pathways for ω-oxidation of docosanoic acid in rat liver microsomes

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