Liver-specific LXR inhibition represses reverse cholesterol transport in cholesterol-fed mice

Abstract

ObjectiveHigh density lipoprotein (HDL) exerts an anti-atherosclerotic effect via reverse cholesterol transport (RCT). Several phases of RCT are transcriptionally controlled by Liver X receptors (LXRs). Although macrophage LXRs reportedly promote RCT, it is still uncertain whether hepatic LXRs affect RCT in vivo. Approach and ResultsTo address this question, we induced hepatic overexpression of sulfotransferase family cytosolic 2B member 1 (Sult2b1) in mice. Sult2b1 facilitates generation of sulfated cholesterol, resulting in reduced production of LXR ligands (oxysterols), which impairs LXR signaling. Adenoviral vectors expressing Sult2b1 (Ad-Sult2b1) or luciferase were intravenously injected into mice under a normal or high-cholesterol diet. Hepatic Sult2b1 overexpression resulted in reduced expression of LXR-target genes - ATP-binding cassette transporter G5/G8, cholesterol 7 hydroxylase and LXR itself - respectively reducing or increasing cholesterol levels in HDL and apolipoprotein B-containing lipoproteins (apoB-L). A macrophage RCT assay revealed that Sult2b1 overexpression inhibited fecal excretion of macrophage-derived 3H-cholesterol only under a high-cholesterol diet. In a HDL kinetic study, Ad-Sult2b1 promoted catabolism/hepatic uptake of HDL-derived cholesterol, thereby reducing fecal excretion. We next performed an in vitro lipoprotein production assay which revealed a Sult2b1-mediated reduction/increase in HDL or apoB-L secretion from hepatocytes, respectively. Finally, in LXR/{beta} double knockout mice, hepatic Sult2b1 overexpression increased apoB-L levels, but there were no differences in HDL levels or RCT compared to the control, indicating that Sult2b1-mediated effects on HDL/RCT and apoB-L were distinct: the former was LXR-dependent, but not the latter. ConclusionsHepatic LXR inhibition negatively regulates circulating HDL levels and RCT by reducing LXR-target gene expression. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=78 SRC="FIGDIR/small/527401v1_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@18ff927org.highwire.dtl.DTLVardef@12e776corg.highwire.dtl.DTLVardef@1a26ebaorg.highwire.dtl.DTLVardef@113b5c6_HPS_FORMAT_FIGEXP M_FIG C_FIG