ID 109570
Author
Sakashita, Naomi Department of Human Pathology, Institute of Health Biosciences, the University of Tokushima Graduate School Tokushima University Educator and Researcher Directory KAKEN Search Researchers
Lei, XiaoFeng Department of Biochemistry, Showa University
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 KAKEN Search Researchers
Keywords
ACAT1
late endosomes
macrophages
cholesterol metabolism
Niemann-Pick disease type C
Content Type
Journal Article
Description
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, in vivo 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.
Journal Title
The journal of medical investigation : JMI
ISSN
13431420
NCID
AA11166929
Volume
61
Issue
3-4
Start Page
270
End Page
277
Sort Key
270
Published Date
2014-08
EDB ID
FullText File
language
eng
TextVersion
Publisher
departments
Medical Sciences