ELOVL1 is a potential target for therapeutic intervention in X-linked adrenoleukodystrophy

Abstract

INTRODUCTION X-linked adrenoleukodystrophy (X-ALD) is a demyelinating disease characterized by high levels of very long-chain fatty acids (VLCFA) in plasma and tissues, due to defi cient transport of VLCFA into peroxisomes, where they would normally be degraded. Prevention or reduction of VLCFA synthesis could represent an interesting therapeutic approach to this disease. This could be achieved through inhibition of ELOVL1, the only elongase catalyzing the elongation of long chain-fatty acids to VLCFA. We have previously shown that VLCFA synthesis and levels were reduced in X-ALD fi broblasts upon treatment with bezafi brate. We have subsequently determined that the CoA ester of bezafi brate inhibits the elongation of C22:0-CoA by ELOVL1. Our research objectives in this study are two-fold: 1) Characterize ELOVL1 and determine the enzyme kinetics; 2) Compare the inhibitory eff ects of the CoA esters of diff erent fi brates on ELOVL1 enzymatic activity.