Studies for lipid transports in pathogenesis of child diseases

Niemann-Pick病是一组以鞘磷脂和胆固醇在细胞内蓄积为特征的疾病，由A/B型和C型组成。酸性鞘磷脂酶(ASM)是一种溶酶体酶，能将神经酰胺和磷胆碱降解为神经酰胺和磷胆碱，其缺乏导致Niemann-Pick病A/B型。NPC1是一种存在于晚期内切体和溶酶体中的膜蛋白，NPC2是一种溶酶体分泌蛋白，它们协调胆固醇的运输，胆固醇通过低密度脂蛋白受体途径进入溶酶体，进入胞浆。NPC1或NPC2基因突变导致Niemann-Pick C型。在我们的研究中，我们利用3岁大鼠的缺血缺氧状态和培养的大鼠肺泡巨噬细胞，认为ASM在早产儿缺血缺氧性脑损伤和慢性肺部疾病的发病机制中发挥了作用。提示抑制ASM激活是治疗儿童疾病的可能途径。此外，我们的研究表明，ASM酶的活性对溶酶体中胆固醇通过NPC1/NPC2系统的转运有一定的影响，提示ASM与细胞内胆固醇代谢有关。

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.