Preferential ATP-binding cassette transporter A1-mediated cholesterol efflux from late endosomes/lysosomes.
Recently, ATP-binding cassette transporter A1 (ABCA1), the defective molecule in Tangier disease, has been shown to stimulate phospholipid and cholesterol efflux to apolipoprotein A-I (apoA-I); however, little is known concerning the cellular cholesterol pools that act as the source of cholesterol for ABCA1-mediated efflux. We observed a higher level of isotopic and mass cholesterol efflux from mouse peritoneal macrophages labeled with [(3)H]cholesterol/acetyl low density lipoprotein (where cholesterol accumulates in late endosomes and lysosomes) compared with cells labeled with [(3)H]cholesterol with 10% fetal bovine serum, suggesting that late endosomes/lysosomes act as a preferential source of cholesterol for ABCA1-mediated efflux. Consistent with this idea, macrophages from Niemann-Pick C1 mice that have an inability to exit cholesterol from late endosomes/lysosomes showed a profound defect in cholesterol efflux to apoA-I. In contrast, phospholipid efflux to apoA-I was normal in Niemann-Pick C1 macrophages, as was cholesterol efflux following plasma membrane cholesterol labeling. These results suggest that cholesterol deposited in late endosomes/lysosomes preferentially acts as a source of cholesterol for ABCA1-mediated cholesterol efflux.
Chen
W
W
Division of Molecular Medicine, Department of Medicine, Columbia University, New York, New York 10032, USA.
Sun
Y
Y
Welch
C
C
Gorelik
A
A
Leventhal
A R
AR
Tabas
I
I
Tall
A R
AR
D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001692:Biological Transport; D002784:Cholesterol / Q000378:metabolism*; D011992:Endosomes / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D012333:RNA, Messenger / Q000235:genetics
D018528:ATP-Binding Cassette Transporters; D012333:RNA, Messenger; D002784:Cholesterol