Liver X receptors as integrators of metabolic and inflammatory signaling
Noam Zelcer, Peter Tontonoz
Noam Zelcer, Peter Tontonoz
Published March 1, 2006
Citation Information: J Clin Invest. 2006;116(3):607-614. https://doi.org/10.1172/JCI27883.
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Category: Review Series

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.

Authors

Noam Zelcer, Peter Tontonoz

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Figure 3

Integration of lipid metabolic and inflammatory signaling in macrophages by LXRs.

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Integration of lipid metabolic and inflammatory signaling in macrophages...
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.