Bezafibrate lowers very long‐chain fatty acids in X‐linked adrenoleukodystrophy fibroblasts by inhibiting fatty acid elongation
Autor: | Rob Ofman, Ronald J.A. Wanders, Robert-Jan Sanders, Aurora Pujol, Inge M. E. Dijkstra, Sander M. Houten, Marc Engelen, Bwee Tien Poll-The, Martin J.A. Schackmann, Stéphane Fourcade, Stephan Kemp |
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Přispěvatelé: | AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, ANS - Amsterdam Neuroscience, Neurology, Graduate School, Laboratory Genetic Metabolic Diseases, Laboratory for General Clinical Chemistry, Paediatric Metabolic Diseases, Paediatric Neurology |
Rok vydání: | 2012 |
Předmět: |
Male
endocrine system diseases Peroxisome Proliferator-Activated Receptors Peroxisome proliferator-activated receptor ATP-binding cassette transporter ATP Binding Cassette Transporter Subfamily D Member 1 Mice 0302 clinical medicine Genetics(clinical) Enzyme Inhibitors Adrenoleukodystrophy Cells Cultured Genetics (clinical) Hypolipidemic Agents chemistry.chemical_classification 0303 health sciences Fatty Acids Peroxisome Recombinant Proteins 3. Good health Biochemistry Microsomes Liver Fatty acid elongation Original Article Oxidation-Reduction medicine.drug endocrine system congenital hereditary and neonatal diseases and abnormalities medicine.medical_specialty Fatty Acid Elongases Mice Transgenic Biology 03 medical and health sciences Acetyltransferases Internal medicine Genetics medicine Animals Humans 030304 developmental biology Bezafibrate nutritional and metabolic diseases Fatty acid medicine.disease Endocrinology Enzyme chemistry ATP-Binding Cassette Transporters 030217 neurology & neurosurgery |
Zdroj: | Journal of Inherited Metabolic Disease Journal of inherited metabolic disease, 35(6), 1137-1145. Springer Netherlands Journal of Inherited Metabolic Disease; Vol 35 |
ISSN: | 1573-2665 0141-8955 |
Popis: | 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. |
Databáze: | OpenAIRE |
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