PUBLICATION

Metabolic rerouting via SCD1 induction impacts X-linked adrenoleukodystrophy

Authors
Raas, Q., van de Beek, M.C., Forss-Petter, S., Dijkstra, I.M., DeSchiffart, A., Freshner, B.C., Stevenson, T.J., Jaspers, Y.R., Nagtzaam, L.M., Wanders, R.J., van Weeghel, M., Engelen-Lee, J.Y., Engelen, M., Eichler, F., Berger, J., Bonkowsky, J.L., Kemp, S.
ID
ZDB-PUB-210311-7
Date
2021
Source
The Journal of Clinical Investigation   131(8): (Journal)
Registered Authors
Keywords
Fatty acid oxidation, Metabolism, Neuroscience
MeSH Terms
  • ATP Binding Cassette Transporter, Subfamily D, Member 1/genetics
  • ATP Binding Cassette Transporter, Subfamily D, Member 1/metabolism
  • Adrenoleukodystrophy/drug therapy
  • Adrenoleukodystrophy/enzymology*
  • Adrenoleukodystrophy/genetics
  • Animals
  • Cell Line
  • Chloroquine/pharmacology*
  • Fatty Acids/metabolism
  • Gene Expression Regulation, Enzymologic/drug effects*
  • Humans
  • Liver X Receptors/agonists*
  • Liver X Receptors/genetics
  • Liver X Receptors/metabolism
  • Mice
  • Mice, Knockout
  • Mutation
  • Stearoyl-CoA Desaturase/biosynthesis*
  • Stearoyl-CoA Desaturase/genetics
  • Zebrafish
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
PubMed
33690217 Full text @ Journal of Clin. Invest.
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 towards mono-unsaturated 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 mono-unsaturated VLCFA did not. In parallel, we used liver X receptor (LXR) agonists to increase SCD1 expression, causing a shift from saturated towards mono-unsaturated 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 mono-unsaturated VLCFAs may alleviate lipid toxicity, a strategy that may be beneficial in ALD and other peroxisomal diseases in which VLCFAs play a key role.
Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping