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Journal of Lipid Research, Vol. 49, 1904-1911, September 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Liver X receptor-mediated activation of reverse cholesterol transport from macrophages to feces in vivo requires ABCG5/G8

Laura Calpe-Berdiel^1,*, Noemí Rotllan^1,*, Catherine Fiévet^,,**, Rosa Roig, Francisco Blanco-Vaca^2,,,*** and Joan Carles Escolà-Gil^2,*,***

^* Institut de Recerca, Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain
Servei de Bioquímica, Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain
Institut Pasteur de Lille, Lille, F-59019 France
Insitut National de la Santé et de la Recherche Médicale, U545, Lille, F-59019 France
^** Faculté des Sciences Pharmaceutiques et Biologiques et Faculté de Médecine, Université de Lille 2, Lille, F-59006 France
Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Barcelona, 08025 Spain
^*** CIBER de Diabetes y Enfermedades Metabólicas Asociadas, Barcelona, 08036 Spain

Published, JLR Papers in Press, May 28, 2008.

This work was funded by Ministerio de Sanidad y Consumo, Instituto de Salud Carlos III, Red FIS RD06/0015, and Grant FIS PI06/0551. N.R. is a predoctoral fellow of Fondo de Investigaciones Sanitarias (05/00221). J.C.E-G. is a Ramón y Cajal researcher, funded by the Ministerio de Educación y Ciencia.

¹ L. Calpe-Berdiel and N. Rotllan contributed equally to this work.

² To whom correspondence should be addressed. e-mail: fblancova{at}santpau.es (F.B-V.); jescola{at}santpau.es (J.C.E-G.)

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 [³H]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 [³H]cholesterol 24 h 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 ABCG8 in LXR-mediated induction of macrophage-specific RCT.

Supplementary key words HDL • LXR agonist • mice

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