Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 295, Issue 7, Pages 1889-1897Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.AC119.011883
Keywords
sphingolipid; lipid metabolism; human genetics; single-nucleotide polymorphism (SNP); molecular cell biology; ceramide; genomics; fatty acid desaturase 3 (FADS3); GWAS
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Funding
- Swiss National Foundation (SNF) [31003A/179371]
- Swiss Life Foundation
- Novartis Foundation
- GlaxoSmith Kline
- Faculty of Biology and Medicine of Lausanne
- Swiss National Science Foundation [33CSCO-122661, 33CS30-139468, 33CS30-148401]
- Hurka
- Swiss National Science Foundation (SNF) [31003A_179371] Funding Source: Swiss National Science Foundation (SNF)
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Sphingolipids (SLs) are structurally diverse lipids that are defined by the presence of a long-chain base (LCB) backbone. Typically, LCBs contain a single ?4E double bond (DB) (mostly d18:1), whereas the dienic LCB sphingadienine (d18:2) contains a second DB at the ?14Z position. The enzyme introducing the ?14Z 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 ?14Z 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 ?14Z DB containing LCBs, such as d18:2 and m18:1. Our results unravel FADS3 as a ?14Z LCB desaturase, thereby disclosing the last missing enzyme of the SL de novo synthesis pathway.
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