Journal Article

Metabolic rerouting via SCD1 induction impacts X-linked adrenoleukodystrophy

Eichler, Florian, Deschiffart, Abigail, van Weeghel, Michel, Engelen, Marc, Kemp, Stephan, Berger, Johannes, Dijkstra, Inge M.E, Bonkowsky, Joshua L, Freshner, Briana C, Raas, Quentin, Stevenson, Tamara J, Nagtzaam, Liselotte, Forss-Petter, Sonja, Engelen-Lee, Joo-Yeon, Jaspers, Yorrick R.J, van de Beek, Malu-Clair, Wanders, Ronald J.A

2021

Overview

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, [Abcd.sup.1-/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.

• Publisher: American Society for Clinical Investigation
• Subject: Adrenoleukodystrophy / Care and treatment / Carrier proteins / Cell metabolism / Development and progression / Genetic aspects / Health aspects / Oxidoreductases