Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
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.
View: Text | PDF
Research Article Metabolism Neuroscience Article has an altmetric score of 4

Metabolic rerouting via SCD1 induction impacts X-linked adrenoleukodystrophy

  • Text
  • PDF
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

×

Figure 6

Lipid profiles in human ALD fibroblasts are corrected by LXR agonists.

Options: View larger image (or click on image) Download as PowerPoint
Lipid profiles in human ALD fibroblasts are corrected by LXR agonists.
(...
(A) Visualization of the comparison of the lipid profiles of control and ALD fibroblasts in a volcano plot. The x axis shows the log2 fold change in ALD cells and the y axis the significance of this change represented as –log10 (P value). Phospholipids are indicated as C(XX:Y), where XX indicates the total number of carbon atoms and Y the total number of double bonds in the fatty acyl chains. This analysis, without fragmentation, does not allow the specification of which fatty acid is located at the sn-1 or sn-2 position. Note an overall increase in PC species containing fatty acids with a total number of more than 44 carbon atoms, which indicates an enrichment in VLCFAs. Lipid species marked in red indicate a greater than 4-fold decrease and in green a less than 4-fold increase. (B) Heatmap showing the top 50 most changed lipid species based on the variable influence on projection (VIP) score extracted from the orthogonal projections to latent structures (OPLS). The left panel indicates samples from control fibroblasts (n = 8), the middle panel samples from ALD patient fibroblasts (n = 8), and the right panel samples from ALD fibroblasts treated with 5 μM TO901317 for 3 weeks (n = 4). Color in the heatmap reflects the logarithm of the relative lipid abundance, with red being higher and blue lower than the mean abundance value per lipid. (C) C26:0-LPC levels in control (n = 8), ALD (n = 8), and ALD fibroblasts after treatment with 5 μM TO901317 for 3 weeks (n = 4). Data are represented as mean ± SD.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Posted by 6 X users
44 readers on Mendeley
See more details