TY - JOUR
T1 - FADS3 is a Δ14Z sphingoid base desaturase that contributes to gender differences in the human plasma sphingolipidome
AU - Karsai, Gergely
AU - Lone, Museer
AU - Kutalik, Zoltán
AU - Thomas Brenna, J.
AU - Li, Hongde
AU - Pan, Duojia
AU - von Eckardstein, Arnold
AU - Hornemann, T.
N1 - Funding Information:
This work was supported by Swiss National Foundation (SNF) Grant 31003A/ 179371 and the Hurka and Swiss Life Foundation (to T. H.) and by the Novartis Foundation (to A. v. E.). The CoLaus study is supported by research grants from GlaxoSmith Kline, the Faculty of Biology and Medicine of Lausanne, and the Swiss National Science Foundation (Grants 33CSCO-122661, 33CS30-139468, and 33CS30-148401). The authors declare that they have no conflicts of interest with the contents of this article.
Funding Information:
This work was supported by Swiss National Foundation (SNF) Grant 31003A/ 179371 and the Hurka and Swiss Life Foundation (to T. H.) and by the Novartis Foundation (to A. v. E.). The CoLaus study is supported by research grants from GlaxoSmith Kline, the Faculty of Biology and Medi-cine of Lausanne, and the Swiss National Science Foundation (Grants 33CSCO-122661, 33CS30-139468, and 33CS30-148401). The authors declare that they have no conflicts of interest with the contents of this article.
Publisher Copyright:
© 2020 Karsai et al. Published by The American Society for Biochemistry and Molecular Biology, Inc.
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.AC119.011883
DO - 10.1074/jbc.AC119.011883
M3 - Article
C2 - 31862735
AN - SCOPUS:85079470174
SN - 0021-9258
VL - 295
SP - 1889
EP - 1897
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 7
ER -