ACAT1-associated Late Endosomes/Lysosomes Significantly Improve Impaired Intracellular Cholesterol Metabolism and the Survival of Niemann-Pick Type C Mice

• Kamikawa Masashi

  Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kumamoto University

• Lei XiaoFeng

  Department of Biochemistry, Showa University School of Medicine

• Fujiwara Yukio

  Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University

• Nishitsuji Kazuchika

  Department of Human Pathology, Institute of Health Biosciences, The University of Tokushima Graduate School

• Mizuta Hiroshi

  Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kumamoto University

• Takeya Motohiro

  Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University

• Sakashita Naomi

  Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University Department of Human Pathology, Institute of Health Biosciences, The University of Tokushima Graduate School

抄録

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.

収録刊行物

• Ａｃｔａ　Ｈｉｓｔｏｃｈｅｍｉｃａ　ｅｔ　Ｃｙｔｏｃｈｅｍｉｃａ

  Ａｃｔａ　Ｈｉｓｔｏｃｈｅｍｉｃａ　ｅｔ　Ｃｙｔｏｃｈｅｍｉｃａ 47 (2), 35-43, 2014

  日本組織細胞化学会

キーワード

• Niemann-Pick type C disease
• acyl-coenzyme A: cholesterol acyltransferase 1
• late endosomes
• cholesterol
• methyl-β-cyclodextrin

詳細情報

• CRID: 1390282679839622656
• NII論文ID: 130003390848
• NII書誌ID: AA00508022
• DOI: 10.1267/ahc.13033
• ISSN: 13475800
• ISSN: 00445991
• Web Site: http://repo.lib.tokushima-u.ac.jp/114978
• Web Site: https://www.jstage.jst.go.jp/article/ahc/47/2/47_13033/_pdf
• Web Site: https://search.jamas.or.jp/link/ui/2015049269
• 本文言語コード: en
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