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

Objective High 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 Results To 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 7α hydroxylase and LXRα 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 LXRα/β 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. Conclusions Hepatic LXR inhibition negatively regulates circulating HDL levels and RCT by reducing LXR-target gene expression. ![Figure][1] ### Competing Interest Statement The authors have declared no competing interest. * ABCA1 : ATP-binding cassette transporter A1 ABCG5 : ATP-binding cassette transporter G5 ABCG8 : ATP-binding cassette transporter G8 Ad-Luc : adenoviral vector harboring luciferase Ad-Sult2b1 : adenovirus expressing mouse Sult2b1 CEs : cholesteryl oleate CYP7A1 : cholesterol 7α hydroxylase DKO : LXRα/β double knockout mice FCR : fractional catabolic rates HDL-C : high-density lipoprotein-cholesterol LDL-C : low-density lipoprotein-cholesterol LXR : liver X receptor LSC : liquid scintillation counting RCT : reverse cholesterol transport Sult2b1 : sulfotransferase family cytosolic 2B member 1 Wild-type : C57BL/6J mice [1]: pending:yes