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Reciprocal regulation of inflammation and lipid metabolism by liver X receptors

Abstract

Macrophages have important roles in both lipid metabolism and inflammation and are central to the pathogenesis of atherosclerosis. The liver X receptors (LXRs) are established mediators of lipid-inducible gene expression, but their role in inflammation and immunity is unknown. We demonstrate here that LXRs and their ligands are negative regulators of macrophage inflammatory gene expression. Transcriptional profiling of lipopolysaccharide (LPS)-induced macrophages reveals reciprocal LXR-dependent regulation of genes involved in lipid metabolism and the innate immune response. In vitro, LXR ligands inhibit the expression of inflammatory mediators such as inducible nitric oxide synthase, cyclooxygenase (COX)-2 and interleukin-6 (IL-6) in response to bacterial infection or LPS stimulation. In vivo, LXR agonists reduce inflammation in a model of contact dermatitis and inhibit inflammatory gene expression in the aortas of atherosclerotic mice. These findings identify LXRs as lipid-dependent regulators of inflammatory gene expression that may serve to link lipid metabolism and immune functions in macrophages.

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Figure 1: LXR agonists inhibit the macrophage response to bacterial pathogens.
Figure 2: LXR-dependent inhibition of iNOS expression and NO production by natural and synthetic LXR ligands.
Figure 3: Transcriptional profiling of LXR agonist effects in LPS-activated macrophages.
Figure 4: Activation of LXR inhibits the expression of multiple NF-κB target genes in macrophages.
Figure 5: LXRs antagonize the action of NF-κB on the iNOS and COX-2 promoters.
Figure 6: LXRs are negative regulators of inflammation in vivo.

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Acknowledgements

We thank T.M. Willson and J. Collins for GW3965 and T1317, and L. Bosca and P. Martin for reagents and comments. P.T. is an Assistant Investigator of the Howard Hughes Medical Institute at the University of California, Los Angeles. This work was supported by grants from the NIH (HL 660881) the Human Frontier Science Project (RGY-021) to P.T.

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Correspondence to Peter Tontonoz.

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Joseph, S., Castrillo, A., Laffitte, B. et al. Reciprocal regulation of inflammation and lipid metabolism by liver X receptors. Nat Med 9, 213–219 (2003). https://doi.org/10.1038/nm820

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