Fumonisin B1-induced Sphingolipid Depletion Inhibits Vitamin Uptake via the Glycosylphosphatidylinositol-anchored Folate Receptor

Abstract

The folate receptor, like many glycosylphosphatidylinositol-anchored proteins, is found associated with membrane domains that are 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, R. G. W. (1993) J. Cell Biol. 118, 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 ϳ40%. 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, indicating 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 .

Metabolic labelling of membrane microdomains/rafts in Jurkat cells indicates the presence of glycerophospholipids implicated in signal transduction by the CD3 T-cell receptor

“…This is worth remembering that our results corroborate previous data obtained in Caco-2 cells [35]. These glycerophospholipids were labelled preferentially with saturated fatty acid, supporting the observation that the partioning of a saturated fluorescent phospholipid analogue into the raft phase, after cross-linking by an antibody, is increased significantly, whereas cross-linking of a doubly unsaturated phospholipid analogue does not change its redistribution [36].…”

Impact of mycotoxins on human health in developing countries

“…Studies in the former Transkei region of South Africa and in Linxian and Cixian counties, China, have demonstrated an association between fumonisin exposure in rural subsistence farming areas and a high incidence of oesophageal cancer (Rheeder et al 1992;Zhang et al 1997). Fumonisins, which inhibit the uptake of folic acid via the folate receptor (Stevens and Tang 1997), have also been implicated in the high incidence of neural tube defects in rural populations known to consume contaminated maize, such as the former Transkei region of South Africa and areas of Northern China .…”

Dynamics of membrane lipid domains in neuronal cells differentiated in culture

“…A very promising experimental approach to a better understanding of the involvement of lipids in the structural and functional properties of membrane domains is represented by the artificial manipulation of lipid composition and/or organization within these structures. To this purpose, a wide variety of experimental approaches allowing the downregulation of the biosynthesis of membrane lipids (15)(16)(17)(18)(19)(20)(21) or the lowering of cholesterol levels in the plasma membrane by external ligands (20)(21)(22)(23)(24)(25)(26)(27)(28) has been introduced. Among these tools, the extraction of cholesterol from cells by treatment with cyclodextrins is certainly the most widely used, as evidenced by the hundreds of papers found combining the two key words "cyclodextrin" and "cholesterol" in a Medline search from 1996 to the present.…”