NCoR repression of LXRs restricts macrophage biosynthesis of insulin-sensitizing omega 3 fatty acids

Cell. 2013 Sep 26;155(1):200-214. doi: 10.1016/j.cell.2013.08.054.

Abstract

Macrophage-mediated inflammation is a major contributor to obesity-associated insulin resistance. The corepressor NCoR interacts with inflammatory pathway genes in macrophages, suggesting that its removal would result in increased activity of inflammatory responses. Surprisingly, we find that macrophage-specific deletion of NCoR instead results in an anti-inflammatory phenotype along with robust systemic insulin sensitization in obese mice. We present evidence that derepression of LXRs contributes to this paradoxical anti-inflammatory phenotype by causing increased expression of genes that direct biosynthesis of palmitoleic acid and ω3 fatty acids. Remarkably, the increased ω3 fatty acid levels primarily inhibit NF-κB-dependent inflammatory responses by uncoupling NF-κB binding and enhancer/promoter histone acetylation from subsequent steps required for proinflammatory gene activation. This provides a mechanism for the in vivo anti-inflammatory insulin-sensitive phenotype observed in mice with macrophage-specific deletion of NCoR. Therapeutic methods to harness this mechanism could lead to a new approach to insulin-sensitizing therapies.

Publication types

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

MeSH terms

  • Animals
  • Fatty Acids, Omega-3 / metabolism*
  • Insulin Resistance*
  • Liver X Receptors
  • Macrophages / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nuclear Receptor Co-Repressor 1 / genetics
  • Nuclear Receptor Co-Repressor 1 / metabolism*
  • Orphan Nuclear Receptors / genetics*

Substances

  • Fatty Acids, Omega-3
  • Liver X Receptors
  • Nuclear Receptor Co-Repressor 1
  • Orphan Nuclear Receptors

Associated data

  • GEO/GSE50944