Effect of LXR activation on LPS-induced inflammatory response in primary bone marrow macrophages from ABCA1fl/fl LysM Cre and control wildtype mice. Mus musculus

The liver X receptors (LXRs) are transcriptional regulators of lipid homeostasis that also have potent anti-inflammatory effects. The molecular basis for their anti-inflammatory effects is incompletely understood, but has been proposed to involve indirect tethering of sumoylated LXRs to inflammatory gene promoters. Here we demonstrate that the ability of LXRs to repress endogenous inflammatory gene expression in cells and mice derives from their ability to regulate lipid metabolism through transcriptional activation and does not require sumoylation or transrepression. Moreover, we identify the putative lipid transporter ABCA1 as a critical mediator of LXR’s anti-inflammatory effects. Ligand activation of LXR inhibits signaling from TLR4 to its downstream NF-κB and MAPK effectors through ABCA1-dependent changes in membrane lipid composition and organization that disrupt the recruitment of MyD88 and TRAF6. These data suggest that a common mechanism–direct transcriptional activation–underlies the dual biological functions of LXRs in metabolism and inflammation. Overall design: Cells were placed in DMEM containing 0.5% FBS, 5 μM simvastatin, 100 μM mevalonic acid and 1μM GW3965 or DMSO overnight. Cells were then stimulated with 10ng/ml LPS or vehicle for 4 hours.Each sample contain contains pooled RNA from n=3-4 biological replicates.