Fumonisin B-1-induced sphingolipid depletion inhibits vitamin uptake via the glycosylphosphatidylinositol-anchored folate receptor

The folate receptor, like many glycosylphosphatidylinositol-anchored proteins, is found associated with membrane domains that art? insoluble in Triton X-100 at low temperature and that are enriched in cholesterol and sphingolipids. Depletion of cellular cholesterol has been shown to inhibit vitamin uptake by this receptor (Chang, W.-J., Rothberg, K, G., Kamen, B. A,, and Anderson, BP. G. W. (1993) J, Cell Biol, IIS, 63-69), suggesting that these domains regulate this process. In this study, the importance of sphingolipids for folate receptor function was investigated in Caco-2 cells using fumonisin B-1, a mycotoxin that inhibits the biosynthesis of these lipids, The folate receptor-mediated transport of 5-methyltetrahydrofolate was almost completely blocked in cells in which sphingolipids had been reduced by similar to 40%. This inhibition was dependent on the concentration and duration of the treatment with the mycotoxin and was mediated by the sphingolipid decrease, Neither receptor-mediated nor facilitative transport was inhibited by fumonisin B-1 treatment, indicting that the effect of sphingolipid depletion was specific for folate receptor-mediated vitamin uptake, A concurrent loss in the total amount of folate binding capacity in the cells was seen as sphingolipids were depleted, suggesting a causal relationship between folate receptor number and vitamin uptake. These findings suggest that dietary exposure to fumonisin B-1 could adversely affect folate uptake and potentially compromise cellular processes dependent on this vitamin, Furthermore, because folate deficiency causes neural tube defects, some birth defects unexplained by other known risk factors may be caused by exposure to fumonisin B-1.