Preferential ATP-binding cassette transporter A1-mediated cholesterol efflux from late endosomes/lysosomes

Recently, ATP-binding cassette transporter Al (ABCA1), the defective molecu le in Tangier disease, has been shown to stimulate phospholipid and cholest erol efflux to apolipoprotein A-I (apoA-I); however, little is known concer ning the cellular cholesterol pools that act as the source of cholesterol f or ABCA1-mediated efflux. We observed a higher level of isotopic and mass c holesterol efflux from mouse peritoneal macrophages labeled with [H-3]chole sterol/acetyl low density lipoprotein (where cholesterol accumulates in lat e endosomes and lysosomes) compared with cells labeled with [H-3]cholestero l with 10% fetal bovine serum, suggesting that late endosomes/lysosomes act as a preferential source of cholesterol for ABCA1-mediated efflux. Consist ent with this idea, macrophages from Niemann-Pick C1 mice that have an inab ility to exit cholesterol from late endosomes/lysosomes showed a profound d efect 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.