Role of ACAT1-positive late endosomes in macrophages: Cholesterol metabolism and therapeutic applications for Niemann-Pick disease type C

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Author(s)

    • Sakashita Naomi
    • Department of Human Pathology, Institute of Health Biosciences, the University of Tokushima Graduate School
    • Kamikawa Masashi
    • 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

Abstract

Macrophages in hyperlipidemic conditions accumulate cholesterol esters and develop into foamy transformed macrophages. During this transformation, macrophages demonstrate endoplasmic reticulum fragmentation and consequently produce acyl coenzyme A: cholesterol acyltransferase 1 (ACAT1)-positive late endosomes (ACAT1-LE). ACAT1-LE-positive macrophages effectively esterify modified or native low-density lipoprotein-derived free cholesterol, which results in efficient cholesterol esterification as well as atherosclerotic plaque formation. These macrophages show significant cholesterol ester formation even when free cholesterol egress from late endosomes is impaired, which indicates that free cholesterol is esterified at ACAT1-LE. Genetic blockade of cholesterol egress from late endosomes causes Niemann-Pick disease type C (NPC), an inherited lysosomal storage disease with progressive neurodegeneration. Induction of ACAT1-LE in macrophages with the NPC phenotype led to significant recovery of cholesterol esterification. In addition, <i>in vivo </i>ACAT1-LE induction significantly extended the lifespan of mice with the NPC phenotype. Thus, ACAT1-LE not only regulates intracellular cholesterol metabolism but also ameliorates NPC pathophysiology. J. Med. Invest. 61: 270-277, August, 2014

Journal

  • The Journal of Medical Investigation

    The Journal of Medical Investigation 61(3.4), 270-277, 2014

    The University of Tokushima Faculty of Medicine

Codes

  • NII Article ID (NAID)
    130004822731
  • NII NACSIS-CAT ID (NCID)
    AA11166929
  • Text Lang
    ENG
  • Article Type
    journal article
  • ISSN
    1343-1420
  • Data Source
    IR  J-STAGE 
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