title: Bezafibrate lowers very long-chain fatty acids in X-linked adrenoleukodystrophy fibroblasts by inhibiting fatty acid elongation.
abstract: 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.
authors.affiliation: Department of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Marc
authors.initials: M
authors.lastname: Engelen
authors.forename: Martin J A
authors.initials: MJ
authors.lastname: Schackmann
authors.forename: Rob
authors.initials: R
authors.lastname: Ofman
authors.forename: Robert-Jan
authors.initials: RJ
authors.lastname: Sanders
authors.forename: Inge M E
authors.initials: IM
authors.lastname: Dijkstra
authors.forename: Sander M
authors.initials: SM
authors.lastname: Houten
authors.forename: Stéphane
authors.initials: S
authors.lastname: Fourcade
authors.forename: Aurora
authors.initials: A
authors.lastname: Pujol
authors.forename: Bwee Tien
authors.initials: BT
authors.lastname: Poll-The
authors.forename: Ronald J A
authors.initials: RJ
authors.lastname: Wanders
authors.forename: Stephan
authors.initials: S
authors.lastname: Kemp
mesh_terms: D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters / Q000172:deficiency / Q000235:genetics; D000123:Acetyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics; D000326:Adrenoleukodystrophy / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001629:Bezafibrate / Q000494:pharmacology*; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000081031:Fatty Acid Elongases; D005227:Fatty Acids / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics
chemical_list: C115572:ABCD1 protein, human; D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters; C000630949:ELOVL1 protein, human; D004791:Enzyme Inhibitors; D005227:Fatty Acids; D000960:Hypolipidemic Agents; D047492:Peroxisome Proliferator-Activated Receptors; D011994:Recombinant Proteins; C017364:hexacosanoic acid; D000123:Acetyltransferases; D000081031:Fatty Acid Elongases; D001629:Bezafibrate