Liver X receptor-mediated activation of reverse cholesterol transport from macrophages to feces in vivo requires ATP-binding cassette (ABC) G5/G8

Laura Calpe-Berdiel, Noemí Rotllan, Catherine Fiévet, Rosa Roig, Francisco Blanco-Vaca, and Joan Carles Escola-Gil

Bioquímica, Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau, Barcelona, Barcelona 08025

Corresponding Author: jescola{at}santpau.cat

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 on LXR agonist-induction of RCT from macrophages to feces in vivo. A [³H]cholesterol-labeled macrophage cell line was injected intraperitoneally into ABCG5/G8-deficient (G5/G8^-/-), G5G8^+/- and wild-type G5/G8^+/+ mice. G5/G8^-/-mice presented increased radiolabeled HDL-bound [³H]cholesterol 24 hours after the label injection. However, the magnitude of macrophage-derived [³H]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 [³H]cholesterol in feces of G5/G8^+/+ mice. However, T0901317 treatment had no effect on fecal [³H]cholesterol excretion in G5G8^-/- mice. Additionally, LXR activation stimulated the fecal excretion of labeled cholesterol after an intravenous injection of HDL-[³H]cholesteryl oleate in G5/G8^+/+ mice, but failed to enhance fecal [³H]cholesterol in G5/G8^-/- mice. Our data provide direct in vivo evidence of the crucial role of ABCG5 and G8 in LXR-mediated induction of macrophage-specific RCT.

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