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PMID:21187453

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Citation

Hong, C, Walczak, R, Dhamko, H, Bradley, MN, Marathe, C, Boyadjian, R, Salazar, JV and Tontonoz, P (2011) Constitutive activation of LXR in macrophages regulates metabolic and inflammatory gene expression: identification of ARL7 as a direct target. J. Lipid Res. 52:531-9

Abstract

Ligand activation of liver X receptors (LXRs) has been shown to impact both lipid metabolism and inflammation. One complicating factor in studies utilizing synthetic LXR agonists is the potential for pharmacologic and receptor-independent effects. Here, we describe an LXR gain-of-function system that does not depend on the addition of exogenous ligand. We generated transgenic mice expressing a constitutively active VP16-LXRα protein from the aP2 promoter. These mice exhibit increased LXR signaling selectively in adipose and macrophages. Analysis of gene expression in primary macrophages derived from two independent VP16-LXRα transgenic lines confirmed the ability of LXR to drive expression of genes involved in cholesterol efflux and fatty acid synthesis. Moreover, VP16-LXRα expression also suppressed the induction of inflammatory genes by lipopolysaccharide to a comparable degree as synthetic agonist. We further utilized VP16-LXRα-expressing macrophages to identify and validate new targets for LXRs, including the gene encoding ADP-ribosylation factor-like 7 (ARL7). ARL7 has previously been shown to transport cholesterol to the membrane for ABCA1-associated removal and thus may be integral to the LXR-dependent efflux pathway. We show that the ARL7 promoter contains a functional LXRE and can be transactivated by LXRs in a sequence-specific manner, indicating that ARL7 is a direct target of LXR. These findings provide further support for an important role of LXRs in the coordinated regulation of lipid metabolic and inflammatory gene programs in macrophages.

Links

PubMed PMC3035689 Online version:10.1194/jlr.M010686

Keywords

ADP-Ribosylation Factors/genetics; Adipose Tissue/metabolism; Animals; Cell Line; Cholesterol/metabolism; Gene Expression Regulation; Humans; Inflammation/genetics; Ligands; Lipid Metabolism/genetics; Macrophages/metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Orphan Nuclear Receptors/genetics; Orphan Nuclear Receptors/metabolism; Promoter Regions, Genetic/genetics; Signal Transduction/genetics

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:NR1H3

involved_in

GO:0071222: cellular response to lipopolysaccharide

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:NR1H3

involved_in

GO:0050728: negative regulation of inflammatory response

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:NR1H3

involved_in

GO:0043031: negative regulation of macrophage activation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:NR1H3

involved_in

GO:0000122: negative regulation of transcription by RNA polymerase II

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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