FADS3 is a Δ14Z sphingoid base desaturase that contributes to gender differences in the human plasma sphingolipidome.

Détails

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Etat: Public
Version: Final published version
Licence: CC BY 4.0
ID Serval
serval:BIB_4F9B98961C35
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
FADS3 is a Δ14Z sphingoid base desaturase that contributes to gender differences in the human plasma sphingolipidome.
Périodique
The Journal of biological chemistry
Auteur⸱e⸱s
Karsai G., Lone M., Kutalik Z., Brenna J.T., Li H., Pan D., von Eckardstein A., Hornemann T.
ISSN
1083-351X (Electronic)
ISSN-L
0021-9258
Statut éditorial
Publié
Date de publication
14/02/2020
Peer-reviewed
Oui
Volume
295
Numéro
7
Pages
1889-1897
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: ppublish
Résumé
Sphingolipids (SLs) are structurally diverse lipids that are defined by the presence of a long-chain base (LCB) backbone. Typically, LCBs contain a single Δ4E double bond (DB) (mostly d18:1), whereas the dienic LCB sphingadienine (d18:2) contains a second DB at the Δ14Z position. The enzyme introducing the Δ14Z DB is unknown. We analyzed the LCB plasma profile in a gender-, age-, and BMI-matched subgroup of the CoLaus cohort (n = 658). Sphingadienine levels showed a significant association with gender, being on average ∼30% higher in females. A genome-wide association study (GWAS) revealed variants in the fatty acid desaturase 3 (FADS3) gene to be significantly associated with the plasma d18:2/d18:1 ratio (p = -log 7.9). Metabolic labeling assays, FADS3 overexpression and knockdown approaches, and plasma LCB profiling in FADS3-deficient mice confirmed that FADS3 is a bona fide LCB desaturase and required for the introduction of the Δ14Z double bond. Moreover, we showed that FADS3 is required for the conversion of the atypical cytotoxic 1-deoxysphinganine (1-deoxySA, m18:0) to 1-deoxysphingosine (1-deoxySO, m18:1). HEK293 cells overexpressing FADS3 were more resistant to m18:0 toxicity than WT cells. In summary, using a combination of metabolic profiling and GWAS, we identified FADS3 to be essential for forming Δ14Z DB containing LCBs, such as d18:2 and m18:1. Our results unravel FADS3 as a Δ14Z LCB desaturase, thereby disclosing the last missing enzyme of the SL de novo synthesis pathway.
Mots-clé
GWAS, ceramide, fatty acid desaturase 3 (FADS3), genomics, human genetics, lipid metabolism, molecular cell biology, single-nucleotide polymorphism (SNP), sphingolipid
Pubmed
Web of science
Open Access
Oui
Création de la notice
07/09/2020 16:42
Dernière modification de la notice
30/04/2021 7:10
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