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: Marc Engelen, Martin J A Schackmann, Rob Ofman, Robert-Jan Sanders, Inge M E Dijkstra, Sander M Houten, Stéphane Fourcade, Aurora Pujol, Bwee Tien Poll-The, Ronald J A Wanders, Stephan Kemp
• Journal: Journal of inherited metabolic disease (J Inherit Metab Dis) Vol. 35 Issue 6 Pg. 1137-45 (Nov 2012) ISSN: 1573-2665 [Electronic] United States
• PMID: 22447153 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ABCD1 protein, human
• ATP Binding Cassette Transporter, Subfamily D, Member 1
• ATP-Binding Cassette Transporters
• ELOVL1 protein, human
• Enzyme Inhibitors
• Fatty Acids
• Hypolipidemic Agents
• Peroxisome Proliferator-Activated Receptors
• Recombinant Proteins
• hexacosanoic acid
• Acetyltransferases
• Fatty Acid Elongases
• Bezafibrate

Topics

• ATP Binding Cassette Transporter, Subfamily D, Member 1
• ATP-Binding Cassette Transporters (deficiency, genetics)
• Acetyltransferases (antagonists & inhibitors, genetics)
• Adrenoleukodystrophy (drug therapy, genetics, metabolism)
• Animals
• Bezafibrate (pharmacology)
• Cells, Cultured
• Enzyme Inhibitors (pharmacology)
• Fatty Acid Elongases
• Fatty Acids (chemistry, metabolism)
• Humans
• Hypolipidemic Agents (pharmacology)
• Male
• Mice
• Mice, Transgenic
• Microsomes, Liver (drug effects, metabolism)
• Oxidation-Reduction
• Peroxisome Proliferator-Activated Receptors (metabolism)
• Recombinant Proteins (antagonists & inhibitors, genetics)