title: Constitutive activation of LXR in macrophages regulates metabolic and inflammatory gene expression: identification of ARL7 as a direct target.
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.
authors.affiliation: Howard Hughes Medical Institute, Department of Pathology and Laboratory Medicine, University of California at Los Angeles, Los Angeles, CA, USA.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Hong
authors.forename: Robert
authors.initials: R
authors.lastname: Walczak
authors.forename: Helena
authors.initials: H
authors.lastname: Dhamko
authors.forename: Michelle N
authors.initials: MN
authors.lastname: Bradley
authors.forename: Chaitra
authors.initials: C
authors.lastname: Marathe
authors.forename: Rima
authors.initials: R
authors.lastname: Boyadjian
authors.forename: Jon V
authors.initials: JV
authors.lastname: Salazar
authors.forename: Peter
authors.initials: P
authors.lastname: Tontonoz
mesh_terms: D020727:ADP-Ribosylation Factors / Q000235:genetics*; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000235:genetics; D008024:Ligands; D050356:Lipid Metabolism / Q000235:genetics; D000071518:Liver X Receptors; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D057093:Orphan Nuclear Receptors / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics
chemical_list: D008024:Ligands; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D002784:Cholesterol; D020727:ADP-Ribosylation Factors; C541133:ARL4C protein, human