NIEMANN-PICK DISEASE - COUPLING AND UNCOUPLING OF INHIBITED SPHINGOMYELINASE ACTIVITY AND EXOGENOUS CHOLESTEROL ESTERIFICATION IN FIBROBLASTS BY IONOPHORE TREATMENT

In order to elucidate a biochemical relationship between sphingomyelin and cholesterol metabolisms, we examined the effects of several ionop hores (monensin, nigericin, A23187, ionomycin, lasalocid) on sphingomy elinase activity and cholesterol esterification in cultured human fibr oblasts. Phase-contrast microscopy showed the presence of foamy cells with monensin and nigericin treatments only. Electron microscopic exam ination revealed lamellated membranous bodies and cytoplasmic vacuoles in cells treated with monensin and nigericin. Monensin and nigericin treatments led to reduction of acid sphingomyelinase activity and dist urbance of the esterification of lipoprotein-derived cholesterol in cu ltured fibroblasts, which is compatible with the biochemical changes o f Niemann-Pick disease, type C. A23187, ionomycin, and lasalocid treat ments showed only sphigomyelinase reduction in treated fibroblasts. Ex perimental models in this culture system could be produced in these wa ys, mimicking subtypes of Niemann-Pick disease, type A, B and type C.