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

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

Author information

1
Division of Endocrinology & Metabolism, Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, USA, 92093.
2
Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, USA, 92093.
3
Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, USA, 92093.
4
Lipomics Technologies, Inc., West Sacramento, CA, USA, 95691.
5
Laboratory of Integrative and Systems Physiology, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
#
Contributed equally

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.

PMID:
24074869
PMCID:
PMC4131699
DOI:
10.1016/j.cell.2013.08.054
[Indexed for MEDLINE]
Free PMC Article

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