Liver X receptor-mediated activation of reverse cholesterol transport from macrophages to feces in vivo requires ABCG5/G8.
Liver X receptor (LXR) agonists increase both total fecal sterol excretion and macrophage-specific reverse cholesterol transport (RCT) in vivo. In this study, we assessed the effects of ABCG5/G8 deficiency as well as those of LXR agonist-induction of RCT from macrophages to feces in vivo. A [(3)H]cholesterol-labeled macrophage cell line was injected intraperitoneally into ABCG5/G8-deficient (G5/G8(-/-)), heterozygous (G5G8(+/-)), and wild-type G5/G8(+/+) mice. G5/G8(-/-)mice presented increased radiolabeled HDL-bound [(3)H]cholesterol 24 h after the label injection. However, the magnitude of macrophage-derived [(3)H]cholesterol in liver and feces did not differ between groups. A separate experiment was conducted in G5G8(+/+) and G5G8(-/-) mice treated with or without the LXR agonist T0901317. Treatment with T0901317 increased liver ABCG5/G8 expression, which was associated with a 2-fold increase in macrophage-derived [(3)H]cholesterol in feces of G5/G8(+/+) mice. However, T0901317 treatment had no effect on fecal [(3)H]cholesterol excretion in G5G8(-/-) mice. Additionally, LXR activation stimulated the fecal excretion of labeled cholesterol after an intravenous injection of HDL-[(3)H]cholesteryl oleate in G5/G8(+/+) mice, but failed to enhance fecal [(3)H]cholesterol in G5/G8(-/-) mice. Our data provide direct in vivo evidence of the crucial role of ABCG5 and ABCG8 in LXR-mediated induction of macrophage-specific RCT.
Institut de Recerca, Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain.
Laura
L
Calpe-Berdiel
Noemí
N
Rotllan
Catherine
C
Fiévet
Rosa
R
Roig
Francisco
F
Blanco-Vaca
Joan Carles
JC
Escolà-Gil
D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters / Q000502:physiology*; D000818:Animals; D001692:Biological Transport; D002784:Cholesterol / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000502:physiology*; D005243:Feces / Q000737:chemistry*; D005260:Female; D008074:Lipoproteins / Q000172:deficiency / Q000502:physiology*; D000071518:Liver X Receptors; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*
C462600:ABCG5 protein, mouse; C462601:ABCG8 protein, mouse; D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters; D004268:DNA-Binding Proteins; D008074:Lipoproteins; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D002784:Cholesterol