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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 2/2 ), heterozygous (G5G8 1/2 ), and wild-type G5/ G8 1/1 mice. G5/G8 2/2 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 1/1 and G5G8 2/2 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 1/1 mice. However, T0901317 treatment had no effect on fecal [ 3 H]cholesterol excretion in G5G8 2/2 mice. Additionally, LXR activation stimulated the fecal excretion of labeled cholesterol after an intravenous injection of HDL-[ 3 H]cholesteryl oleate in G5/G8 1/1 mice, but failed to enhance fecal [ 3 H]cholesterol in G5/G8 2/2 mice. Our data provide direct in vivo evidence of the crucial role of ABCG5 and ABCG8 in LXR-mediated induction of macrophagespecific RCT.-Calpe-Berdiel, L., N. Rotllan, C. Fiévet, R. Roig, F. Blanco-Vaca, and J. C. Escolà-Gil. Liver X receptormediated activation of reverse cholesterol transport from macrophages to feces in vivo requires ABCG5/G8. J. Lipid Res. 2008Res. . 49: 1904Res. -1911. Supplementary key words HDLThe classic reverse cholesterol transport (RCT) pathway involves cholesterol efflux from peripheral tissues to HDL, which is taken up by the liver and finally excreted into bile and feces. Liver X receptor (LXR) a is a nuclear receptor activated by oxysterols (1) that upregulates expression of a number of target genes critical for RCT, including ABCA1, ABCG1, ABCG5, ABCG8, and murine cytochrome P450 family 7 subfamily A polypeptide 1 (CYP7A1) (2-6). LXRa is highly expressed in the liver and at lower levels in the adrenal glands, intestine, adipose tissue, macrophages, lung, and kidney, whereas LXRb is ubiquitously expressed (7). ABCG5 and ABCG8 heterodimerize into a functional complex (ABCG5/G8) that is crucial for hepatobiliary and intestinal sterol excretion. Genetic deficiency of ABCG5/ G8 in humans causes sitosterolemia (8, 9), which is characterized by plant sterol accumulation in plasma and tissues due to increased intestinal absorption and decreased biliary secretion of sterols (10,11).It is difficult at present to quantify RCT in humans (12, 13). A new approach was developed to measure RCT from labeled cholesterol incorporated into macrophages and injected into mice liver and feces (14). Follow-up studies demonstrated that the rate of RCT from macrophages to feces may not always be inferred from studies of to...

Rationale: Macrophages cannot limit the uptake of lipids and rely on cholesterol efflux mechanisms for maintaining cellular cholesterol homeostasis. Important mediators of macrophage cholesterol efflux are ATP-binding cassette transporter 1 (ABCA1), which mediates the efflux of cholesterol to lipid-poor apolipoprotein AI, and scavenger receptor class B type I (SR-BI), which promotes efflux to mature high-density lipoprotein. Objective:The aim of the present study was to increase the insight into the putative synergistic roles of ABCA1 and SR-BI in foam cell formation and atherosclerosis. ABCA1 is a full-size ABC-transporter that facilitates cholesterol efflux to lipid-poor apolipoprotein (apo)AI. 2,3 Totalbody ABCA1 knockout mice and Tangier disease patients with dysfunctional ABCA1 display a virtual absence of high-density lipoprotein (HDL), showing the essential role for ABCA1 in HDL metabolism. 3 Targeted inactivation of ABCA1 in bone marrow-derived cells in mice leads to increased atherosclerotic lesion formation, 4,5 whereas overexpression of ABCA1 inhibits the progression of atherosclerosis. 6 Macrophages lacking ABCA1, however, still have substantial ability to efflux cholesterol to HDL despite impaired efflux to lipid-poor apoAI, suggesting that macrophages have additional pathways via which cellular cholesterol can be exported. In addition to ABCA1, macrophages also express the ABC half-transporter ABCG1. In contrast to ABCA1, ABCG1 facilitates cellular cholesterol efflux from macrophages to mature HDL but not to lipid-free apolipopro- Methods and Results: