LXR-induced redistribution of ABCG1 to plasma membrane in macrophages enhances cholesterol mass efflux to HDL.
OBJECTIVE
This study examines the ABCG1-mediated cholesterol efflux and intracellular cholesterol transport by studying the ABCG1 localization and function in macrophages.


RESULTS
HEK 293 cell overexpressing ABCG1, RNA interference, or macrophages from ABCG1 or ABCG4 knockout mice were used. ABCG1 but not ABCG4 had a major role in the increased cholesterol mass efflux produced by treatment of macrophages with LXR activators. In 293 cells, ABCG1 was found in the plasma membrane, Golgi, and recycling endosomes. In contrast, in basal macrophages, ABCG1 was predominantly intracellular, and redistributed to the plasma membrane after LXR activation. LXR activation increased macrophage cholesterol efflux to high-density lipoprotein (HDL), low-density lipoprotein (LDL), and cyclodextrin in an ABCG1-dependent fashion. Suppression of ABCG1 expression increased cholesteryl ester formation and decreased SREBP2 target gene expression in macrophages, even in the absence of HDL acceptors.


CONCLUSIONS
LXR activation induces redistribution of ABCG1 from intracellular sites to the plasma membrane and increases cholesterol mass efflux to HDL in an ABCG1-dependent fashion. ABCG1 acts in the macrophage plasma membrane to increase the availability of cholesterol to a variety of lipoprotein and nonlipoprotein acceptors while limiting the accumulation of cholesterol in the endoplasmic reticulum.
Division of Molecular Medicine, Department of Medicine, Columbia University, New York, NY 10032, USA. nw30@columbia.edu
Nan
N
Wang
Mollie
M
Ranalletta
Fumihiko
F
Matsuura
Felix
F
Peng
Alan R
AR
Tall
D000070996:ATP Binding Cassette Transporter, Subfamily G; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D001692:Biological Transport; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism*; D002788:Cholesterol Esters / Q000378:metabolism; D003505:Cyclodextrins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000502:physiology*; D015870:Gene Expression; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D008074:Lipoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008075:Lipoproteins, HDL / Q000378:metabolism*; D000071518:Liver X Receptors; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D057093:Orphan Nuclear Receptors; D034622:RNA Interference; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D051782:Sterol Regulatory Element Binding Protein 2 / Q000037:antagonists & inhibitors; D013347:Subcellular Fractions / Q000378:metabolism; D014018:Tissue Distribution; D014162:Transfection
C487540:ABCG1 protein, mouse; D000070996:ATP Binding Cassette Transporter, Subfamily G; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; C486685:Abcg4 protein, mouse; D002788:Cholesterol Esters; D003505:Cyclodextrins; D004268:DNA-Binding Proteins; D008074:Lipoproteins; D008075:Lipoproteins, HDL; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D051782:Sterol Regulatory Element Binding Protein 2; D002784:Cholesterol