title: Role of ACAT1-positive late endosomes in macrophages: cholesterol metabolism and therapeutic applications for Niemann-Pick disease type C.
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, 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.
authors.affiliation: Department of Human Pathology, Institute of Health Biosciences, the University of Tokushima Graduate School.
authors.forename: Naomi
authors.initials: N
authors.lastname: Sakashita
authors.forename: XiaoFeng
authors.initials: X
authors.lastname: Lei
authors.forename: Masashi
authors.initials: M
authors.lastname: Kamikawa
authors.forename: Kazuchika
authors.initials: K
authors.lastname: Nishitsuji
mesh_terms: D000101:Acetyl-CoA C-Acetyltransferase / Q000502:physiology*; D002784:Cholesterol / Q000378:metabolism*; D011992:Endosomes / Q000502:physiology*; D006801:Humans; D008264:Macrophages / Q000502:physiology*; D009542:Niemann-Pick Diseases / Q000503:physiopathology / Q000628:therapy*
chemical_list: D002784:Cholesterol; C506639:ACAT1 protein, human; D000101:Acetyl-CoA C-Acetyltransferase