Inducible nitric oxide has protective effect on fumonisin B1 hepatotoxicity in mice via modulation of sphingosine kinase

Abstract

Fumonisin B 1 , a natural mycotoxin, is an inhibitor of ceramide synthase causing marked dysregulation of sphingolipid metabolism in cells. This mycotoxin causes accumulation of free sphingoid bases (sphingosine and dihydrosphingosine or sphinganine) and their metabolites, important messengers involved in signal transduction leading to either cell survival or death. Free sphingoid bases are known apoptotic molecules whereas their respective 1-phosphates are protective. We previously reported that fumonisin B 1 caused sphingosine kinase (SPHK) induction along with the increase of serine palmitoyltransferase (SPT). Fumonisin B 1 also increased inducible nitric oxide synthase (iNOS) expression. In the current study we employed mice strain with the targeted deletion of iNOS gene (Nos-KO) to evaluate the role of nitric oxide (NO) on fumonisin B 1 -induced hepatotoxicity. The Nos-KO mice exhibited increased hepatotoxicity after subacute fumonisin B 1 exposure compared to their wild type counterparts, the liver regeneration was lower in Nos-KO compared to that in the WT mice. Increased hepatotoxicity in Nos-KO was not related to the extent of free sphingoid base accumulation after fumonisin B 1 treatment; however, it was accompanied by a lack of fumonisin B 1 -induced SPHK induction. The fumonisin B 1 -induced SPT was unaffected by lack of iNOS gene. Deletion of iNOS gene did not prevent fumonisin B 1 -dependent induction of inflammatory cytokines, namely tumor necrosis factor α, interferon γ and interleukin-12. The lack of fumonisin B 1 -induced SPHK induction in Nos-KO was supported by a similar effect on phosphorylated metabolites of sphingoid bases; the equilibrium between sphingoid bases and their phosphates is maintained by SPHK. We therefore conclude that iNOS induction produced by fumonisin B 1 modulates SPHK activity; the lack of iNOS prevents generation of sphingosine 1-phosphate and deprives cells from its protective effects.

Dual and distinct roles for sphingosine kinase 1 and sphingosine 1 phosphate in the response to inflammatory stimuli in RAW macrophages

“…Another study showed that preventing ceramide formation in monocytes by inhibiting neutral sphingomylinase with C11AG, a selective inhibitor, led to blocking the translocation of NF-kB and the induction of iNOS (27). Since the SK1/S1P pathway has been implicated in NF-kB activation (28) and iNOS induction (29) these studies suggest that previous findings attributed to sphingosine and ceramide on innate stimulation are possibly due to their intracellular metabolism to S1P.…”

Silencing of enzymes involved in ceramide biosynthesis causes distinct global alterations of lipid homeostasis and gene expression

“…These figures are the first model combining changes in lipid subspecies and gene expression that highlights how Huh7 cells respond and adapt to the disruption of ceramide synthesis. Previous studies focused on the effects of altering SPTLC functions on cholesterol efflux (14), apoE secretion (37), necrosis (38), and inflammation (39). The changes observed in lipid synthesis clearly indicate that inhibiting SPTLC123 by siRNA-mediated knockdown is sufficient to reduce ceramide synthesis and alter certain subspecies (mainly C16:0) of other lipid classes, especially phospholipids.…”

FTY720 Inhibits Ceramide Synthases and Up-regulates Dihydrosphingosine 1-Phosphate Formation in Human Lung Endothelial Cells

“…However, despite the fact that FTY720 resembles sphingosine (Sph) and is a substrate of SphK2 (15)(16)(17), there are no reported studies on the effect of FTY720 on the intrinsic balance of signaling sphingolipids. Metabolic interconnections between proapoptotic (ceramides) and prosurvival (dihydrosphingosine 1-phosphate (DHS1P)) molecules are expected because it is known that fumonisin B1 (FB1), an inhibitor of (dihydro)ceramide synthases, not only blocks the formation of ceramides and up-regulates the intracellular content of dihydrosphingosine (DHSph) but also increases the cellular level of DHS1P (19,20).…”