FUMONISIN B-1-INDUCED SPHINGOLIPID DEPLETION INHIBITS VITAMIN UPTAKE VIA THE GLYCOSYLPHOSPHATIDYLINOSITOL-ANCHORED FOLATE RECEPTOR

The folate receptor, like many glycosylphosphatidylinositol-anchored p roteins, is found associated with membrane domains that art? insoluble in Triton X-100 at low temperature and that are enriched in cholester ol 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 s tudy, the importance of sphingolipids for folate receptor function was investigated in Caco-2 cells using fumonisin B-1, a mycotoxin that in hibits 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 tre atment with the mycotoxin and was mediated by the sphingolipid decreas e, 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 rel ationship between folate receptor number and vitamin uptake. These fin dings suggest that dietary exposure to fumonisin B-1 could adversely a ffect folate uptake and potentially compromise cellular processes depe ndent on this vitamin, Furthermore, because folate deficiency causes n eural tube defects, some birth defects unexplained by other known risk factors may be caused by exposure to fumonisin B-1.