Department of Pediatrics, University of Utah, Brain and Spine Center, Primary Children's Hospital, Salt Lake City, Utah, USA.
Laboratory Genetic Metabolic Diseases, Department of Clinical Chemistry, Amsterdam UMC, Amsterdam Gastroenterology & Metabolism, University of Amsterdam, Amsterdam, Netherlands.
J Clin Invest. 2021 Apr 15;131(8). doi: 10.1172/JCI142500.
X-linked adrenoleukodystrophy (ALD) is a progressive neurodegenerative disease caused by mutations in ABCD1, the peroxisomal very long-chain fatty acid (VLCFA) transporter. ABCD1 deficiency results in accumulation of saturated VLCFAs. A drug screen using a phenotypic motor assay in a zebrafish ALD model identified chloroquine as the top hit. Chloroquine increased expression of stearoyl-CoA desaturase-1 (scd1), the enzyme mediating fatty acid saturation status, suggesting that a shift toward monounsaturated fatty acids relieved toxicity. In human ALD fibroblasts, chloroquine also increased SCD1 levels and reduced saturated VLCFAs. Conversely, pharmacological inhibition of SCD1 expression led to an increase in saturated VLCFAs, and CRISPR knockout of scd1 in zebrafish mimicked the motor phenotype of ALD zebrafish. Importantly, saturated VLCFAs caused ER stress in ALD fibroblasts, whereas monounsaturated VLCFA did not. In parallel, we used liver X receptor (LXR) agonists to increase SCD1 expression, causing a shift from saturated toward monounsaturated VLCFA and normalizing phospholipid profiles. Finally, Abcd1-/y mice receiving LXR agonist in their diet had VLCFA reductions in ALD-relevant tissues. These results suggest that metabolic rerouting of saturated to monounsaturated VLCFAs may alleviate lipid toxicity, a strategy that may be beneficial in ALD and other peroxisomal diseases in which VLCFAs play a key role.
X 连锁肾上腺脑白质营养不良（ALD）是一种进行性神经退行性疾病，由 ABCD1 基因突变引起，该基因是过氧化物酶体极长链脂肪酸（VLCFA）转运蛋白。ABCD1 缺乏导致饱和 VLCFA 积累。在 ALD 斑马鱼模型中使用表型运动测定法进行的药物筛选发现氯喹是最佳选择。氯喹增加了硬脂酰辅酶 A 去饱和酶 1（scd1）的表达，该酶介导脂肪酸饱和状态，表明向单不饱和脂肪酸的转变缓解了毒性。在人类 ALD 成纤维细胞中，氯喹也增加了 SCD1 水平并减少了饱和 VLCFA。相反，SCD1 表达的药理学抑制导致饱和 VLCFA 增加，CRISPR 敲除斑马鱼 scd1 模拟了 ALD 斑马鱼的运动表型。重要的是，饱和 VLCFA 在 ALD 成纤维细胞中引起内质网应激，而单不饱和 VLCFA 则没有。与此同时，我们使用肝 X 受体（LXR）激动剂来增加 SCD1 的表达，导致从饱和向单不饱和 VLCFA 的转变，并使磷脂谱正常化。最后，在饮食中接受 LXR 激动剂的 Abcd1-/y 小鼠在与 ALD 相关的组织中减少了 VLCFA。这些结果表明，饱和至单不饱和 VLCFA 的代谢重路由可能减轻脂质毒性，这一策略在 VLCFA 起关键作用的 ALD 和其他过氧化物酶体疾病中可能有益。
