| 論文名 |
ACAT1-associated Late Endosomes/Lysosomes Significantly Improve Impaired Intracellular Cholesterol Metabolism and the Survival of Niemann-Pick Type C Mice. |
| 著者 |
Masashi Kamikawa
XiaoFeng Lei
Yukio Fujiwara
Kazuchika Nishitsuji
Hiroshi Mizuta
Motohiro Takeya
Naomi Sakashita
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| キーワード |
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| 出版年月 |
1970年1月 |
| 発表先 |
Acta Histochem Cytochem. 2014 May 1;47(2):35-43. doi: 10.1267/ahc.13033. Epub 2014 Apr 25. |
| WEBサイト |
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| 論文概要（和文） |
ACAT1関連後期エンドソーム/リソソームは細胞内コレステロール代謝障害とニーマンピック型Cマウスの生存率を大幅に改善します |
| 論文概要（英文） |
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. |
