HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

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.
AuthorsNaomi Sakashita, XiaoFeng Lei, Masashi Kamikawa, Kazuchika Nishitsuji
JournalThe journal of medical investigation : JMI (J Med Invest) Vol. 61 Issue 3-4 Pg. 270-7 ( 2014) ISSN: 1349-6867 [Electronic] Japan
PMID25264044 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)
Chemical References
  • Cholesterol
  • ACAT1 protein, human
  • Acetyl-CoA C-Acetyltransferase
Topics
  • Acetyl-CoA C-Acetyltransferase (physiology)
  • Cholesterol (metabolism)
  • Endosomes (physiology)
  • Humans
  • Macrophages (physiology)
  • Niemann-Pick Diseases (physiopathology, therapy)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: