Studies for lipid transports in pathogenesis of child diseases

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Niemann-Pick disease is a group of disorders characterized by the intracellular accumulation of sphingomyelin and cholesterol, composed of types A/B and type C. Acid sphingomyelinase (ASM) is a lysosomal enzyme to hydrolyze sphingomyelin into ceramide and phsphocholine, deficiency of which causes Niemann-Pick disease type A/B. Recently, ASM has been known as an enzyme to play a critical role in many cellular functions. NPC1, a membrane protein residing in late endosome and lysosome, and NPC2, a lysosomal secretory protein, coordinate in the transport of cholesterol, which enters into lysosome by the LDL receptor pathway, into the cytosol. Mutations in the gene of NPC1 or NPC2 cause Niemann-Pick type C. In our studies, we suggested that ASM play roles in the pathogeneses of ischemic-hypoxic brain damage and chronic lung disease in premature neonate, using 3-year-old rat conditioned with ischemic-hypoxic state and cultured cells of alveolar macrophage from rat. The results suggest the possible therapy through suppression of ASM activation in the diseases of children. In addition, our studies showed that ASM enzyme activity has some effect on the transport of cholesterol via NPC1/NPC2 system in lysosome, suggesting the relation of ASM with intracellular cholesterol metabolism.