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 ionophores (monensin, nigericin, A23187, ionomycin, lasalocid) on sphingomyelinase activity and cholesterol esterification in cultured human fibroblasts. Phase-contrast microscopy showed the presence of foamy cells with monensin and nigericin treatments only. Electron microscopic examination 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 disturbance of the esterification of lipoprotein-derived cholesterol in cultured fibroblasts, which is compatible with the biochemical changes of Niemann-Pick disease, type C. A23187, ionomycin, and lasalocid treatments showed only sphingomyelinase reduction in treated fibroblasts. Experimental models in this culture system could be produced in these ways, mimicking subtypes of Niemann-Pick disease, type A, B and type C.