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Bezafibrate lowers very long‐chain fatty acids in X‐linked adrenoleukodystrophy fibroblasts by inhibiting fatty acid elongation
Author(s) -
Engelen Marc,
Schackmann Martin J. A.,
Ofman Rob,
Sanders RobertJan,
Dijkstra Inge M. E.,
Houten Sander M.,
Fourcade Stéphane,
Pujol Aurora,
PollThe Bwee Tien,
Wanders Ronald J. A.,
Kemp Stephan
Publication year - 2012
Publication title -
journal of inherited metabolic disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 102
eISSN - 1573-2665
pISSN - 0141-8955
DOI - 10.1007/s10545-012-9471-4
Subject(s) - adrenoleukodystrophy , bezafibrate , peroxisome , peroxisomal disorder , biochemistry , fatty acid , atp binding cassette transporter , chemistry , transporter , medicine , biology , endocrinology , gene
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.