Macrophage reverse cholesterol transport in mice expressing ApoA-I Milano.
OBJECTIVE
To compare the abilities of human wild-type apoA-I (WT apoA-I) and human apoA-I(Milano) (apoA-I(M)) to promote macrophage reverse cholesterol transport (RCT) in apoA-I-null mice infected with adeno-associated virus (AAV) expressing either WT apoA-I or apoA-I(M).


RESULTS
WT apoA-I- or apoA-I(M)-expressing mice were intraperitoneally injected with [H(3)]cholesterol-labeled J774 mouse macrophages. After 48 hours, no significant difference was detected in the amount of cholesterol removed from the macrophages and deposited in the feces via the RCT pathway between the WT apoA-I and apoA-I(M) groups. Analysis of the individual components of the RCT pathway demonstrated that the apoA-I(M)-expressing mice promoted ATP-binding cassette transporter A1 (ABCA1)-mediated cholesterol efflux as efficiently as WT apoA-I but that apoA-I(M) had a reduced ability to promote cholesterol esterification via lecithin cholesterol-acyltransferase (LCAT). This resulted in reduced cholesteryl ester (CE) and increased free cholesterol (FC) levels in the plasma of mice expressing apoA-I(M) compared to WT apoA-I. These differences did not affect the rate of delivery of labeled cholesterol to the liver via SR-BI-mediated selective uptake or its subsequent excretion in the feces.


CONCLUSIONS
Within the limits of the in vivo assay, WT apoA-I and apoA-I(M) are equally efficient at promoting macrophage RCT, suggesting that if apoA-I(M) is more atheroprotective than WT apoA-I it is not attributable to an enhancement of macrophage RCT.
Alexander
Eric T
ET
Lipid Research Group, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Weibel
Ginny L
GL
Joshi
Michelle R
MR
Vedhachalam
Charulatha
C
de la Llera-Moya
Margarita
M
Rothblat
George H
GH
Phillips
Michael C
MC
Rader
Daniel J
DJ
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000502:physiology; D000818:Animals; D016632:Apolipoprotein A-I / Q000235:genetics / Q000502:physiology*; D001692:Biological Transport; D002784:Cholesterol / Q000378:metabolism*; D008076:Cholesterol, HDL / Q000097:blood; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D051381:Rats; D051122:Scavenger Receptors, Class B / Q000502:physiology
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D008076:Cholesterol, HDL; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D002784:Cholesterol