LXRs link metabolism to inflammation through Abca1-dependent regulation of membrane composition and TLR signaling

Elife. 2015 Jul 14;4:e08009. doi: 10.7554/eLife.08009.

Abstract

The liver X receptors (LXRs) are transcriptional regulators of lipid homeostasis that also have potent anti-inflammatory effects. The molecular basis for their anti-inflammatory effects is incompletely understood, but has been proposed to involve the indirect tethering of LXRs to inflammatory gene promoters. Here we demonstrate that the ability of LXRs to repress inflammatory gene expression in cells and mice derives primarily from their ability to regulate lipid metabolism through transcriptional activation and can occur in the absence of SUMOylation. Moreover, we identify the putative lipid transporter Abca1 as a critical mediator of LXR's anti-inflammatory effects. Activation of LXR inhibits signaling from TLRs 2, 4 and 9 to their downstream NF-κB and MAPK effectors through Abca1-dependent changes in membrane lipid organization that disrupt the recruitment of MyD88 and TRAF6. These data suggest that a common mechanism-direct transcriptional activation-underlies the dual biological functions of LXRs in metabolism and inflammation.

Keywords: LXR; Toll-like receptor; cell biology; chromosomes; genes; lipid metabolism; mouse; nuclear receptor.

Publication types

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

MeSH terms

  • ATP Binding Cassette Transporter 1 / metabolism*
  • Animals
  • Cell Membrane / chemistry*
  • Cells, Cultured
  • Chromatin Immunoprecipitation
  • Gene Expression Profiling
  • Inflammation*
  • Liver X Receptors
  • Mice
  • Orphan Nuclear Receptors / metabolism*
  • Signal Transduction*
  • Toll-Like Receptors / metabolism*

Substances

  • ABCA1 protein, mouse
  • ATP Binding Cassette Transporter 1
  • Liver X Receptors
  • Orphan Nuclear Receptors
  • Toll-Like Receptors