ライ ショウホウ   RAI Shouho
  雷 小峰
   所属   埼玉医科大学  医学部 国際医療センター 皮膚科(皮膚腫瘍科)
   職種   助教
論文種別 学術雑誌(原著)
言語種別 英語
査読の有無 査読あり
表題 ACAT1-associated Late Endosomes/Lysosomes Significantly Improve Impaired Intracellular Cholesterol Metabolism and the Survival of Niemann-Pick Type C Mice
掲載誌名 正式名:ACTA HISTOCHEMICA ET CYTOCHEMICA
ISSNコード:0044-5991/1347-5800
出版社 JAPAN SOC HISTOCHEMISTRY & CYTOCHEMISTRY
巻・号・頁 47(2),35-43頁
著者・共著者 Masashi Kamikawa,XiaoFeng Lei,Yukio Fujiwara,Kazuchika Nishitsuji,Hiroshi Mizuta,Motohiro Takeya,Naomi Sakashita
発行年月 2014
概要 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-beta-cyclodextrin-cholesterol complex (mi beta CDcho), a cholesterol donor. lmmunofluorescence confocal microscopy revealed that mi beta CDcho 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. mi3CD-cho treatment also induced marked restoration of cholesterol esterification activity. mi3CD-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.
DOI 10.1267/ahc.13033
PMID 25221362