Constitutive activation of LXR in macrophages regulates metabolic and inflammatory gene expression: identification of ARL7 as a direct target

J Lipid Res. 2011 Mar;52(3):531-9. doi: 10.1194/jlr.M010686. Epub 2010 Dec 27.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • Ligands
  • Liver X Receptors
  • NR1H3 protein, human
  • Nr1h3 protein, mouse
  • Orphan Nuclear Receptors
  • Cholesterol
  • ADP-Ribosylation Factors
  • ARL4C protein, human