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Bezafibrate lowers very long-chain fatty acids in X-linked adrenoleukodystrophy fibroblasts by inhibiting fatty acid elongation
X-linked adrenoleukodystrophy (X-ALD) is caused by mutations in the ABCD1 gene encoding ALDP, an ATP-binding-cassette (ABC) transporter located in the peroxisomal membrane. ALDP deficiency results in impaired peroxisomal β-oxidation and the subsequent accumulation of very long-chain fatty acids (VLC...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Netherlands
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3470694/ https://www.ncbi.nlm.nih.gov/pubmed/22447153 http://dx.doi.org/10.1007/s10545-012-9471-4 |
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author | Engelen, Marc Schackmann, Martin J. A. Ofman, Rob Sanders, Robert-Jan Dijkstra, Inge M. E. Houten, Sander M. Fourcade, Stéphane Pujol, Aurora Poll-The, Bwee Tien Wanders, Ronald J. A. Kemp, Stephan |
author_facet | Engelen, Marc Schackmann, Martin J. A. Ofman, Rob Sanders, Robert-Jan Dijkstra, Inge M. E. Houten, Sander M. Fourcade, Stéphane Pujol, Aurora Poll-The, Bwee Tien Wanders, Ronald J. A. Kemp, Stephan |
author_sort | Engelen, Marc |
collection | PubMed |
description | X-linked adrenoleukodystrophy (X-ALD) is caused by mutations in the ABCD1 gene encoding ALDP, an ATP-binding-cassette (ABC) transporter located in the peroxisomal membrane. ALDP deficiency results in impaired peroxisomal β-oxidation and the subsequent accumulation of very long-chain fatty acids (VLCFA; > C22:0) in plasma and tissues. VLCFA are primarily derived from endogenous synthesis by ELOVL1. Therefore inhibiting this enzyme might constitute a feasible therapeutic approach. In this paper we demonstrate that bezafibrate, a PPAR pan agonist used for the treatment of patients with hyperlipidaemia reduces VLCFA levels in X-ALD fibroblasts. Surprisingly, the VLCFA-lowering effect was independent of PPAR activation and not caused by the increase in either mitochondrial or peroxisomal fatty acid β-oxidation capacity. In fact, our results show that bezafibrate reduces VLCFA synthesis by decreasing the synthesis of C26:0 through a direct inhibition of fatty acid elongation activity. Taken together, our data indicate bezafibrate as a potential pharmacotherapeutic treatment for X-ALD. A clinical trial is currently ongoing to evaluate the effect in patients with X-ALD. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10545-012-9471-4) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-3470694 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Springer Netherlands |
record_format | MEDLINE/PubMed |
spelling | pubmed-34706942012-10-18 Bezafibrate lowers very long-chain fatty acids in X-linked adrenoleukodystrophy fibroblasts by inhibiting fatty acid elongation Engelen, Marc Schackmann, Martin J. A. Ofman, Rob Sanders, Robert-Jan Dijkstra, Inge M. E. Houten, Sander M. Fourcade, Stéphane Pujol, Aurora Poll-The, Bwee Tien Wanders, Ronald J. A. Kemp, Stephan J Inherit Metab Dis Original Article X-linked adrenoleukodystrophy (X-ALD) is caused by mutations in the ABCD1 gene encoding ALDP, an ATP-binding-cassette (ABC) transporter located in the peroxisomal membrane. ALDP deficiency results in impaired peroxisomal β-oxidation and the subsequent accumulation of very long-chain fatty acids (VLCFA; > C22:0) in plasma and tissues. VLCFA are primarily derived from endogenous synthesis by ELOVL1. Therefore inhibiting this enzyme might constitute a feasible therapeutic approach. In this paper we demonstrate that bezafibrate, a PPAR pan agonist used for the treatment of patients with hyperlipidaemia reduces VLCFA levels in X-ALD fibroblasts. Surprisingly, the VLCFA-lowering effect was independent of PPAR activation and not caused by the increase in either mitochondrial or peroxisomal fatty acid β-oxidation capacity. In fact, our results show that bezafibrate reduces VLCFA synthesis by decreasing the synthesis of C26:0 through a direct inhibition of fatty acid elongation activity. Taken together, our data indicate bezafibrate as a potential pharmacotherapeutic treatment for X-ALD. A clinical trial is currently ongoing to evaluate the effect in patients with X-ALD. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10545-012-9471-4) contains supplementary material, which is available to authorized users. Springer Netherlands 2012-03-24 2012 /pmc/articles/PMC3470694/ /pubmed/22447153 http://dx.doi.org/10.1007/s10545-012-9471-4 Text en © The Author(s) 2012 https://creativecommons.org/licenses/by/4.0/ This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited. |
spellingShingle | Original Article Engelen, Marc Schackmann, Martin J. A. Ofman, Rob Sanders, Robert-Jan Dijkstra, Inge M. E. Houten, Sander M. Fourcade, Stéphane Pujol, Aurora Poll-The, Bwee Tien Wanders, Ronald J. A. Kemp, Stephan Bezafibrate lowers very long-chain fatty acids in X-linked adrenoleukodystrophy fibroblasts by inhibiting fatty acid elongation |
title | Bezafibrate lowers very long-chain fatty acids in X-linked adrenoleukodystrophy fibroblasts by inhibiting fatty acid elongation |
title_full | Bezafibrate lowers very long-chain fatty acids in X-linked adrenoleukodystrophy fibroblasts by inhibiting fatty acid elongation |
title_fullStr | Bezafibrate lowers very long-chain fatty acids in X-linked adrenoleukodystrophy fibroblasts by inhibiting fatty acid elongation |
title_full_unstemmed | Bezafibrate lowers very long-chain fatty acids in X-linked adrenoleukodystrophy fibroblasts by inhibiting fatty acid elongation |
title_short | Bezafibrate lowers very long-chain fatty acids in X-linked adrenoleukodystrophy fibroblasts by inhibiting fatty acid elongation |
title_sort | bezafibrate lowers very long-chain fatty acids in x-linked adrenoleukodystrophy fibroblasts by inhibiting fatty acid elongation |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3470694/ https://www.ncbi.nlm.nih.gov/pubmed/22447153 http://dx.doi.org/10.1007/s10545-012-9471-4 |
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