Cellular cholesterol levels reflect a balance between uptake, efflux and endogenous synthesis. Here we show that the sterol-responsive nuclear receptor LXR helps maintain cholesterol homeostasis not only through promotion of cholesterol efflux, but also through suppression of low-density lipoprotein (LDL) uptake. LXR inhibits the LDL receptor (LDLR) pathway through transcriptional induction of Idol (Inducible Degrader of the LDLR), an E3 ubiquitin ligase that triggers ubiquitination of the LDLR on its cytoplasmic domain, thereby targeting it for degradation. LXR ligand reduces, whereas LXR knockout increases, LDLR protein levels in vivo in a tissue-selective manner. Idol knockdown in hepatocytes increases LDLR protein levels and promotes LDL uptake. Conversely, adenovirusmediated expression of Idol in mouse liver promotes LDLR degradation and elevates plasma LDL levels. The LXR-Idol-LDLR axis defines a complementary pathway to sterol response element binding proteins for sterol regulation of cholesterol uptake.

Summary Effective clearance of apoptotic cells by macrophages is essential for immune homeostasis. The transcriptional pathways that allow macrophages to sense and respond to apoptotic cells are poorly defined. We demonstrate here that LXR signaling is important for both apoptotic cell clearance and the maintenance of immune tolerance. Apoptotic cell engulfment activates LXR and thereby induces the expression of Mer, a receptor tyrosine kinase critical for phagocytosis. LXR null macrophages exhibit a selective defect in phagocytosis of apoptotic cells and an aberrant pro-inflammatory response to them. As a consequence of these defects, mice lacking LXRs manifest a breakdown in self-tolerance and develop autoantibodies and autoimmune glomerulonephritis. Treatment with an LXR agonist ameliorates disease progression in mouse models of Lupus-like autoimmunity. Thus, activation of LXR by apoptotic cells engages a virtuous cycle that promotes their own clearance and couples engulfment to the suppression of inflammatory pathways.

The liver X receptors (LXRs) are pivotal regulators of lipid homeostasis in mammals. These transcription factors control the expression of a battery of genes involved in the uptake, transport, efflux and excretion of cholesterol in a tissue-dependent manner. The identification of the LXRs, and an increased understanding of the mechanisms by which LXR signalling regulates lipid homeostasis in different tissues (including the liver, intestine and brain), has highlighted new opportunities for therapeutic intervention in human metabolism. New strategies for the pharmacological manipulation of LXRs and their target genes offer promise for the treatment of human diseases in which lipids have a central role, including atherosclerosis and Alzheimer's disease.