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Metabolic rerouting via SCD1 induction impacts X-linked adrenoleukodystrophy
Quentin Raas1, Malu-Clair van de Beek2, Sonja Forss-Petter3
1Department of Pediatrics, University of Utah, Brain and Spine Center, Primary Children's Hospital, Salt Lake City, Utah, USA.
The Journal of Clinical Investigation
|March 10, 2021
Summary
Chloroquine and LXR agonists reduce toxic very long-chain fatty acids (VLCFAs) in X-linked adrenoleukodystrophy (ALD) models by increasing SCD1. This metabolic shift alleviates lipid toxicity, offering a potential therapeutic strategy for ALD.
Area of Science:
- Biochemistry
- Genetics
- Neuroscience
Background:
- X-linked adrenoleukodystrophy (ALD) is a neurodegenerative disease linked to ABCD1 gene mutations.
- ALD causes the buildup of toxic very long-chain fatty acids (VLCFAs).
Purpose of the Study:
- To identify therapeutic strategies for ALD by targeting VLCFA accumulation.
- To investigate the role of stearoyl-CoA desaturase-1 (SCD1) in ALD pathogenesis and potential treatment.
Main Methods:
- Phenotypic screening in a zebrafish ALD model.
- Drug treatment with chloroquine and liver X receptor (LXR) agonists.
- Analysis of VLCFA levels, SCD1 expression, and endoplasmic reticulum (ER) stress in cellular and animal models.
- CRISPR-Cas9 gene editing in zebrafish.
Main Results:
- Chloroquine identified as a hit, increasing SCD1 and reducing saturated VLCFAs in zebrafish and human cells.
- SCD1 inhibition exacerbated VLCFA accumulation, while SCD1 knockout mimicked ALD phenotypes.
- Saturated VLCFAs induced ER stress, which was ameliorated by shifting to monounsaturated VLCFAs.
- LXR agonists increased SCD1, reduced VLCFAs in mice, and normalized phospholipid profiles.
Conclusions:
- Metabolically rerouting VLCFAs from saturated to monounsaturated forms alleviates lipid toxicity in ALD.
- Targeting SCD1 and modulating lipid saturation presents a promising therapeutic avenue for ALD and related peroxisomal disorders.
