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ACAT1-associated Late Endosomes/Lysosomes Significantly Improve Impaired Intracellular Cholesterol Metabolism and the Survival of Niemann-Pick Type C Mice.
MedLine Citation:
PMID:  25221362     Owner:  NLM     Status:  PubMed-not-MEDLINE    
Abstract/OtherAbstract:
We previously demonstrated that macrophages exhibit endoplasmic reticulum fragmentation under cholesterol-rich conditions, which results in the generation of acyl-coenzyme A: cholesterol acyltransferase 1 (ACAT1)-associated late endosomes/lysosomes (ACAT1-LE). ACAT1-LE efficiently esterify free cholesterol in loco, even with abnormal egress of free cholesterol from late endosomes. Because impaired free cholesterol transport from late endosomes results in Niemann-Pick type C disease (NPC), the induction of ACAT1-LE is a potential therapeutic intervention for NPC. To examine the effects of ACAT1-LE induction on intracellular cholesterol metabolism, we incubated bone marrow-derived macrophages possessing NPC phenotype (npc1 (-/-)) with methyl-β-cyclodextrin-cholesterol complex (mβCD-cho), a cholesterol donor. Immunofluorescence confocal microscopy revealed that mβCD-cho treatment of npc1 (-/-) macrophages resulted in significant colocalization of signals from ACAT1 and lysosome-associated membrane protein 2, a late endosome/lysosome marker. npc1 (-/-) macrophages contained significant amounts of free cholesterol with negligible amounts of cholesteryl ester, while wild-type macrophages possessed the same amounts of both cholesterols. mβCD-cho treatment also induced marked restoration of cholesterol esterification activity. mβCD-cho administration in neonate npc1 (-/-) mice improved survival. These results indicate that ACAT1-LE induction in npc1 (-/-) mice corrects impaired intracellular cholesterol metabolism and that restoring cholesterol esterification improves prognosis of npc1 (-/-). These data suggest that ACAT1-LE induction is a potential alternative therapeutic strategy for NPC.
Authors:
Masashi Kamikawa; XiaoFeng Lei; Yukio Fujiwara; Kazuchika Nishitsuji; Hiroshi Mizuta; Motohiro Takeya; Naomi Sakashita
Publication Detail:
Type:  Journal Article     Date:  2014-04-25
Journal Detail:
Title:  Acta histochemica et cytochemica     Volume:  47     ISSN:  0044-5991     ISO Abbreviation:  Acta Histochem Cytochem     Publication Date:  2014 May 
Date Detail:
Created Date:  2014-09-15     Completed Date:  2014-09-15     Revised Date:  2014-09-17    
Medline Journal Info:
Nlm Unique ID:  0147110     Medline TA:  Acta Histochem Cytochem     Country:  Japan    
Other Details:
Languages:  eng     Pagination:  35-43     Citation Subset:  -    
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