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Metabolic rerouting via SCD1 induction impacts X-linked adrenoleukodystrophy
Quentin Raas, … , Joshua L. Bonkowsky, Stephan Kemp
Quentin Raas, … , Joshua L. Bonkowsky, Stephan Kemp
Published March 9, 2021
Citation Information: J Clin Invest. 2021;131(8):e142500. https://doi.org/10.1172/JCI142500.
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Research Article Metabolism Neuroscience Article has an altmetric score of 4

Metabolic rerouting via SCD1 induction impacts X-linked adrenoleukodystrophy

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Abstract

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.

Authors

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

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Figure 3

Characterization of CQ effects in zebrafish ALD mutant and identification of potential for mechanism via increased scd expression.

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Characterization of CQ effects in zebrafish ALD mutant and identificatio...
(A) No effect of bafilomycin A1 (BMA1) on the motor behavior of WT or abcd1sa509 mutant larvae. Distance moved after 24 hours of treatment (5 dpf) or 72 hours of treatment (7 dpf) with bafilomycin A1 at the indicated dose. (B) Effect of CQ (10 μm) on the number of Olig2+ cells in the spinal cord of 5 dpf abcd1sa509 mutant larvae. Olig2+ cells were counted in spinal cord (region for quantification indicated by dotted line) (Z-stack confocal images of spinal cord: dorsal, top; rostral, left) using olig2:dsRed transgenic line in the abcd1sa509 mutant background. Scale bar: 25 μM. (C) The effect of CQ (10 μm) on the expression of genes involved in fatty acid metabolism and myelin synthesis was analyzed by qRT-PCR at 7 dpf in WT or abcd1sa509 mutant larvae (fold change of mRNA levels compared with WT control normalized to β-actin expression). abcd2, ATP-binding cassette transporter D2; mpz, myelin protein zero; plp1a, proteolipid protein 1a; mbp, myelin basic protein. (D) Loss of scd phenocopies does not worsen ALD mutant zebrafish behavior. Motor behavior of abcd1sa509, scd/scdb, and abcd1sa509/scd/scdb mutant 6 dpf larvae. Statistical significance by 1-way ANOVA, followed by Bonferroni’s multiple comparison test. *P < 0.05; **P < 0.01; ***P < 0.001.

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