Liver X receptors as integrators of metabolic and inflammatory signaling

Abstract

The liver X receptors (LXRs) are nuclear receptors that play central roles in the transcriptional control of lipid metabolism. LXRs function as nuclear cholesterol sensors that are activated in response to elevated intracellular cholesterol levels in multiple cell types. Once activated, LXRs induce the expression of an array of genes involved in cholesterol absorption, efflux, transport, and excretion. In addition to their function in lipid metabolism, LXRs have also been found to modulate immune and inflammatory responses in macrophages. Synthetic LXR agonists promote cholesterol efflux and inhibit inflammation in vivo and inhibit the development of atherosclerosis in animal models. The ability of LXRs to integrate metabolic and inflammatory signaling makes them particularly attractive targets for intervention in human metabolic disease.

Figure 1

LXRs are cholesterol-sensing transcription factors. Within the nucleus, LXR/RXR heterodimers are bound to LXREs in the promoters of target genes and in complex with corepressors (e.g., SMRT, N-CoR). In response to the binding of oxysterol ligands, the corepressor complexes are exchanged for coactivator complexes, and target gene expression is induced.

Figure 2

Role of LXRs in reverse cholesterol transport from macrophages. The uptake of modified lipoproteins by macrophages results in increased LXR transcriptional activity and efflux of cholesterol to lipid-poor apoA-I by ABCA1 and to HDL by ABCG1. In humans, but not mice, induction of CETP expression transfers lipid from HDL to LDL. Once HDL/LDL is taken up by the liver, LXR promotes net cholesterol excretion. In rodents, but not humans, LXR induces expression of Cyp7a1, which initiates the conversion of cholesterol into bile acids. LXRs also induce cholesterol secretion into bile through the transporters ABCG5 and ABCG8. In the intestine, apical ABCG5 and ABCG8 also act to limit dietary cholesterol uptake.

Figure 3

Integration of lipid metabolic and inflammatory signaling in macrophages by LXRs. Recognition of cytokines, bacterial components, or intact pathogens by their corresponding receptors initiates expression of proinflammatory genes (e.g., iNOS). Activation of the TLR3/4 receptors by these signals blocks LXR-dependent gene transcription and cholesterol efflux from macrophages via an IFN regulatory factor 3–dependent (IRF3-dependent) pathway. On the other hand, ligand activation of LXRs inhibits NF-κB–dependent induction of inflammatory gene expression. Intracellular bacteria induce LXRα expression, possibly through a NOD2-dependent pathway, and promote macrophage survival, through induction of Api6 (also known as AIM and SPα) and other targets.