| First Author | Karsai G | Year | 2020 |
| Journal | J Biol Chem | Volume | 295 |
| Issue | 7 | Pages | 1889-1897 |
| PubMed ID | 31862735 | Mgi Jnum | J:285343 |
| Mgi Id | MGI:6392563 | Doi | 10.1074/jbc.AC119.011883 |
| Citation | Karsai G, et al. (2020) FADS3 is a Delta14Z sphingoid base desaturase that contributes to gender differences in the human plasma sphingolipidome. J Biol Chem 295(7):1889-1897 |
| abstractText | Sphingolipids (SLs) are structurally diverse lipids that are defined by the presence of a long-chain base (LCB) backbone. Typically, LCBs contain a single Delta4E double bond (DB) (mostly d18:1), whereas the dienic LCB sphingadienine (d18:2) contains a second DB at the Delta14Z position. The enzyme introducing the Delta14Z 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 approximately 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 Delta14Z 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 Delta14Z DB containing LCBs, such as d18:2 and m18:1. Our results unravel FADS3 as a Delta14Z LCB desaturase, thereby disclosing the last missing enzyme of the SL de novo synthesis pathway. |
