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

Laura Calpe-Berdiel, Noemí Rotllan, Catherine Fiévet, Rosa Roig, Francisco Blanco-Vaca, Joan Carles Escolà-Gil
2008 Journal of Lipid Research  
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
more » ... 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 HDL • LXR agonist • mice The 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 total RCT (14-17). This is an important point in the context of current efforts to better understand HDL antiatherogenic functions as well as to develop a new test for predicting those functions. Analysis of ABCG5/G8 function in RCT is, there-
doi:10.1194/jlr.m700470-jlr200 pmid:18509196 fatcat:lysfegqghve5vayfucgarqmoyq