Academic Medical Center, Departments of Pediatrics and Clinical Chemistry, University of Amsterdam, The Netherlands.
EMBO Mol Med. 2010 Mar;2(3):90-7. doi: 10.1002/emmm.201000061.
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; > or =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 beta-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.
X 连锁肾上腺脑白质营养不良（X-ALD）是由 ABCD1 基因突变引起的，该基因编码过氧化物酶体 ABC 转运体肾上腺脑白质营养不良蛋白（ALDP）。X-ALD 的特征是血浆和组织中非常长链脂肪酸（VLCFA；>或=C24）的积累。在本文中，我们深入了解了导致 X-ALD 中 C26:0 水平升高的途径。ALDP 将 VLCFA-酰基辅酶 A 转运穿过过氧化物酶体膜。ALDP 的缺乏会损害 VLCFA 的过氧化物酶体β氧化，但也会提高细胞质中 VLCFA-酰基辅酶 A 的水平，这是进一步延伸的底物。我们确定 ELOVL1（非常长链脂肪酸的延伸）是催化合成饱和 VLCFA（C26:0）和单不饱和 VLCFA（C26:1）的单一延伸酶。在 X-ALD 成纤维细胞中，ELOVL1 的表达没有增加，这表明由于 ALDP 的主要缺乏，增加的 C26:0 水平是由于底物可用性增加所致。重要的是，ELOVL1 敲低可减少 C22:0 向 C26:0 的延伸，并降低 X-ALD 成纤维细胞中 C26:0 的水平。鉴于 C26:0 水平升高可能具有致病性影响，我们的发现强调了调节 ELOVL1 活性在治疗 X-ALD 中的潜在作用。
