Journal Article ACID SPHINGOMYELINASE IS ESSENTIAL FOR CHOLESTEROLREDUCING AGENTS TO POSITIVELY AFFECT ACCUMULATED FREE CHOLESTEROL IN NIEMANN-PICK DISEASE TYPE C FIBROBLASTS

HIRAYAMA, Masashi  ,  NOGUCHI, Atsuko  ,  OYAMA, Chikako  ,  HIRAI, Daishi  ,  TAKAHASHI, Tsutomu

42 ( 3/4 )  , pp.137 - 146 , 2016-03-31 , 秋田医学会
ISSN:03866106
NCID:AN00009294
Description
Niemann-Pick disease (NP) is a group of lipid storage disorders that includes three types of diseases.While NP type A (NP-A) and NP type B (NP-B) are caused by a lysosomal acid sphingomyelinase(ASM) deficiency, NP type C (NP-C) is a neurovisceral disorder caused by a deficiencyof either the NPC1 or NPC2 protein. This deficiency causes impaired intracellular lipid trafficking,leading to the abundant accumulation of free cholesterol in the lysosome. Thus, NP-C isdiagnosed through a filipin test that microscopically detects intracellular free cholesterol in fibroblasts.However, the filipin test was reported to give a positive result even for NP-A and NP-B.Recently, some cholesterol-reducing agents have been reported to be useful candidate for NP-Ctherapies to reduce accumulated free cholesterol level. In this study, three cholesterol-reducingagents, methyl-β-cyclodextrin, histone deacetylase inhibitors, and thapsigargin, were tested todetermine their efficacy in reducing the accumulated free cholesterol level in NP-A and NP-Bfibroblasts and drug-induced, ASM-deficient fibroblasts. The results showed that the threeagents did not decrease the accumulated free cholesterol level in these cells, showing that ASM isessential for the cholesterol-reducing agents to be effective. This study also suggests that theaccumulated free cholesterol of ASM deficient fibroblasts may be originally different from that ofNP-C cells.
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