TY - JOUR
T1 - Metabolic rerouting via SCD1 induction impacts X-linked adrenoleukodystrophy
AU - Raas, Quentin
AU - van de Beek, Malu-Clair
AU - Forss-Petter, Sonja
AU - Dijkstra, Inge M. E.
AU - Deschiffart, Abigail
AU - Freshner, Briana C.
AU - Stevenson, Tamara J.
AU - Jaspers, Yorrick R. J.
AU - Nagtzaam, Liselotte
AU - Wanders, Ronald J. A.
AU - van Weeghe, Michel
AU - Engelen-Lee, Joo-Yeon
AU - Engelen, Marc
AU - Eichler, Florian
AU - Berger, Johannes
AU - Bonkowsky, Joshua L.
AU - Kemp, Stephan
N1 - Funding Information: We thank A.K. Groen for valuable discussions. We greatly appreciate F. Stet, H. van Lenthe, M.A. Vervaart, and G. Zeitler for excellent technical assistance. This work was supported by grants from the Netherlands Organisation for Scientific Research (91118006 to MVW) and the European Leukodystrophy Association (ELA 2011-024I1 and ELA 2014-014I1 to SK). Funding Information: Zebrafish work was performed in strict accordance with guidelines from the University of Utah IACUC, regulated under federal law (the Animal Welfare Act and Public Health Services Regulation Act) by the US Department of Agriculture (USDA) and the Office of Laboratory Animal Welfare at the NIH, and accredited by the Association for Assessment and Accreditation of Laboratory Care International (AAALAC). Funding Information: Authorship note: QR and MCVDB are co–first authors. JLB and SK are co–senior authors. Conflict of interest: ME has received unrestricted research grants from Vertex, Swanbio Therapeutics, Bluebird Bio, and Minoryx Therapeutics. FE is the principal investigator of Bluebird Bio and Minoryx Therapeutics clinical trials; consultant to Ionis, Alnylam, Sanofi Genzyme, Minoryx, and SwanBio Therapeutics; director of the Third Rock MGH Neuroscience Fellowship; and founder of SwanBio Therapeutics. JLB reports serving as consultant to Bluebird Bio Inc., Calico Inc., Denali Therapeutics, Neurogene Inc., Enzyvant Inc., and Passage Bio; receives royalties from Manson Publishing; and owns stock in Orchard Therapeutics. JLB’s spouse receives royalties from BioFire Diagnostics. SK reports serving as consultant to SwanBio Therapeutics and Autobahn Therapeutics and receives unrestricted research grants from SwanBio Therapeutics. Copyright: © 2021, American Society for Clinical Investigation. Submitted: July 22, 2020; Accepted: March 3, 2021; Published: April 15, 2021. Reference information: J Clin Invest. 2021;131(8):e142500. https://doi.org/10.1172/JCI142500. Publisher Copyright: © 2021, American Society for Clinical Investigation.
PY - 2021/4/15
Y1 - 2021/4/15
N2 - 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 ALDrelevant 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.
AB - 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 ALDrelevant 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.
UR - http://www.scopus.com/inward/record.url?scp=85104181611&partnerID=8YFLogxK
U2 - https://doi.org/10.1172/JCI142500
DO - https://doi.org/10.1172/JCI142500
M3 - Article
C2 - 33690217
SN - 0021-9738
VL - 131
JO - Journal of clinical investigation
JF - Journal of clinical investigation
IS - 8
M1 - e142500
ER -