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Inhibition CerS leads to Reduced complex sphingolipids
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Ceramide synthase inhibition leading to neural tube defects||adjacent||High||Agnes Aggy (send email)||Open for citation & comment|
Life Stage Applicability
Key Event Relationship Description
Evidence Collection Strategy
Evidence Supporting this KER
Ceramide synthases (CerS) inhibition primarily results in accumulation of sphingoid bases and a decrease in levels of ceramides, which are the precursors of complex sphingolipids (for review, see Futerman and Hannun, 2004; Mullen et al., 2011). It is therefore highly plausible that the inhibition of ceramide synthase would result in a decrease in levels of complex sphingolipids.
Several studies report decrease in glycosphingolipids and SM after CerS inhibition, using mostly FB1 as an inhibitor of CerS (for example, Babenko and Kharchenko, 2015; Merrill et al., 1993; Stevens and Tang, 1997).
Uncertainties and Inconsistencies
it remains to be determined whether there are differences between different complex glycosphingolipids (e.g., sphingomyelin, gangliosides, etc.) - are some more impacted and/or more essential for the downstream events than the others?
Known modulating factors
Quantitative Understanding of the Linkage
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
metabolism on insulin-induced glucose uptake and glycogen synthesis in liver cells of old rats. Biochem. 80, 104–112. https://doi.org/10.1134/S0006297915010125
Futerman, A.H., Hannun, Y.A., 2004. The complex life of simple sphingolipids. EMBO Rep. 5, 777–782. https://doi.org/10.1038/sj.embor.7400208
Merrill, A.H., Van Echten, G., Wang, E., Sandhoff, K., 1993. Fumonisin B1 inhibits sphingosine (sphinganine) N-acyltransferase and de novo sphingolipid biosynthesis in cultured neurons in situ. J. Biol. Chem. 268, 27299–27306. https://doi.org/10.1016/s0021-9258(19)74249-5
Mullen, T.D., Jenkins, R.W., Clarke, C.J., Bielawski, J., Hannun, Y.A., Obeid, L.M., 2011. Ceramide synthase-dependent ceramide generation and programmed cell death: Involvement of salvage pathway in regulating postmitochondrial events. J. Biol. Chem. 286, 15929–15942. https://doi.org/10.1074/jbc.M111.230870
Stevens, V.L., Tang, J., 1997. Fumonisin B1-induced sphingolipid depletion inhibits vitamin uptake via the glycosylphosphatidylinositol-anchored folate receptor. J. Biol. Chem. 272, 18020–18025. https://doi.org/10.1074/jbc.272.29.18020