The role of ELOVL1 in very long‐chain fatty acid homeostasis and X‐linked adrenoleukodystrophy

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Abstract
X‐linked adrenoleukodystrophy (X‐ALD) is caused by mutations in the ABCD1 gene encoding the peroxisomal ABC transporter adrenoleukodystrophy protein (ALDP). X‐ALD is characterized by the accumulation of very long‐chain fatty acids (VLCFA; ≥C24) in plasma and tissues. In this manuscript we provide insight into the pathway underlying the elevated levels of C26:0 in X‐ALD. ALDP transports VLCFacyl‐CoA across the peroxisomal membrane. A deficiency in ALDP impairs peroxisomal β‐oxidation of VLCFA but also raises cytosolic levels of VLCFacyl‐CoA which are substrate for further elongation. We identify ELOVL1 (elongation of very‐long‐chain‐fatty acids) as the single elongase catalysing the synthesis of both saturated VLCFA (C26:0) and mono‐unsaturated VLCFA (C26:1). ELOVL1 expression is not increased in X‐ALD fibroblasts suggesting that increased levels of C26:0 result from increased substrate availability due to the primary deficiency in ALDP. Importantly, ELOVL1 knockdown reduces elongation of C22:0 to C26:0 and lowers C26:0 levels in X‐ALD fibroblasts. Given the likely pathogenic effects of high C26:0 levels, our findings highlight the potential of modulating ELOVL1 activity in the treatment of X‐ALD.