文摘
D-threo-1-Phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP) is a frequently usedinhibitor of glycosphingolipid biosynthesis. However, some interesting characteristics of D-PDMP cannotbe explained by the inhibition of glycolipid synthesis alone. In the present study, we showed that D-PDMPinhibits the activation of lysosomal acid lipase by late endosome/lysosome specific lipid, bis(monoacylglycero)phosphate (also called as lysobisphosphatidic acid), through alteration of membranestructure of the lipid. When added to cultured fibroblasts, D-PDMP inhibits the degradation of low-densitylipoprotein (LDL) and thus accumulates both cholesterol ester and free cholesterol in late endosomes/lysosomes. This accumulation results in the inhibition of LDL-derived cholesterol esterification and thedecrease of cell surface cholesterol. We showed that D-PDMP alters cellular cholesterol homeostasis ina glycosphingolipid-independent manner using L-PDMP, a stereoisomer of D-PDMP, which does not inhibitglycosphingolipid synthesis, and mutant melanoma cell which is defective in glycolipid synthesis. Alteringcholesterol homeostasis by D-PDMP explains the unique characteristics of sensitizing multidrug resistantcells by this drug.