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
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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