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

Details

Serval ID
serval:BIB_4F9B98961C35
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
FADS3 is a Δ14Z sphingoid base desaturase that contributes to gender differences in the human plasma sphingolipidome.
Journal
The Journal of biological chemistry
Author(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
Publication state
Published
Issued date
14/02/2020
Peer-reviewed
Oui
Volume
295
Number
7
Pages
1889-1897
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Abstract
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.
Keywords
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
Yes
Create date
07/09/2020 15:42
Last modification date
20/01/2021 6:27
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