@article{oai:air.repo.nii.ac.jp:00001796,
 author = {Oyama, Chikako and Hirayama, Masashi and Noguchi, Atsuko and Arai, Hirokazu and Takahashi, Tsutomu},
 issue = {3/4},
 journal = {秋田医学},
 month = {Mar},
 note = {Niemann-Pick disease type C (NPC) is an inherited disorder caused by mutations in either the NPC1 or the NPC2 gene that affect intracellular free cholesterol trafficking. Most cases of NPC have mutations in the NPC1 gene. Acid sphingomyelinase (ASM) is a lysosomal enzyme in which an inherited deficiency leads to Niemann-Pick disease types A and B (NPDA/NPDB). Despite having a normal ASM gene, NPC cells have a secondary defect in ASM activity ; the mechanism remains to be fully elucidated. Butyrate, one of the short chain fatty acids, is known as an inducer of ASM. We investigated the effects of butyrate on ASM activity and mRNA expression in normal and NPC1 mutant (Nova Scotia form ; NPC1^<Nova Scotia>) lymphoblasts. After incubation with 10 mM butyric acid for 24 h, ASM activity was significantly increased by 3.3- and 4.6-fold in normal and NPC1^<Nova Scotia> cells, respectively (p<0.01). The secondary defect of ASM activity in NPC1^<Nova Scotia> cells was restored to normal levels by treatment of 10 mM butyric acid. In quantitative RT-PCR analysis, butyric acid significantly increased ASM mRNA levels in both types of cells (p<0.01). In addition, we investigated the effects of butyrate on intracellular free cholesterol levels in NPC1^<Nova Scotia> lymphoblasts. Free cholesterol levels in cells treated with or without 10 mM butyric acid were 0.019±0.002 and 0.026±0.006 μg/μg protein, respectively, demonstrating that butyric acid significantly decreased free cholesterol levels in NPC1^<Nova Scotia> cells (p<0.05). To determine whether ASM induced by butyric acid is directly associated with the reduction of free cholesterol accumulation in NPC1^<Nova Scotia> cells, NPDB and NPC1^<Nova Scotia> fibroblasts were treated with 10 mM butyric acid and stained with filipin. We found that butyric acid dramatically reduced the accumulation of intracellular free cholesterol in NPC1^<Nova Scotia> cells, but it did not affect NPDB cells. These data suggest that ASM induced by butyrate is related to intracellular cholesterol trafficking and metabolism in NPC1^<Nova Scotia> cells. ASM inducers, such as butyrate, may reduce the accumulation of intracellular free cholesterol in NPC1^<Nova Scotia> cells.},
 pages = {111--119},
 title = {BUTYRATE REDUCES FREE CHOLESTEROL ACCUMULATION IN NIEMANN-PICK DISEASE TYPE C1 CELLS (NOVA SCOTIA FORM) THROUGH THE INDUCTION OF ACID SPHINGOMYELINASE},
 volume = {38},
 year = {2012}
}