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Cell Metab. 2017 Feb 7;25(2):412-427. doi: 10.1016/j.cmet.2016.11.009. Epub 2016 Dec 29.

SREBP1 Contributes to Resolution of Pro-inflammatory TLR4 Signaling by Reprogramming Fatty Acid Metabolism.

Author information

1
Department of Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Department of Cellular and Molecular Medicine, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan. Electronic address: yuooishi-circ@umin.ac.jp.
2
Department of Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
3
Department of Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Department II, Faculty of Biology, Ludwig-Maximilians Universität München, Planegg-Martinsried 82152, Germany.
4
Department of Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Scripps Translational Science Institute, La Jolla, CA 92037, USA.
5
Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
6
Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, Graduate School of Comprehensive Human Sciences, International Institute for Integrative Sleep Medicine (WPI-IIIS), and Center for Tsukuba Advanced Research Alliance, University of Tsukuba, Ibaraki Prefecture 305-8571, Japan.
7
Department of Cellular and Molecular Medicine, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
8
Department of Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland.
9
Department of Aging Research, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
10
Department of Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: ckg@ucsd.edu.

Abstract

Macrophages play pivotal roles in both the induction and resolution phases of inflammatory processes. Macrophages have been shown to synthesize anti-inflammatory fatty acids in an LXR-dependent manner, but whether the production of these species contributes to the resolution phase of inflammatory responses has not been established. Here, we identify a biphasic program of gene expression that drives production of anti-inflammatory fatty acids 12-24 hr following TLR4 activation and contributes to downregulation of mRNAs encoding pro-inflammatory mediators. Unexpectedly, rather than requiring LXRs, this late program of anti-inflammatory fatty acid biosynthesis is dependent on SREBP1 and results in the uncoupling of NFκB binding from gene activation. In contrast to previously identified roles of SREBP1 in promoting production of IL1β during the induction phase of inflammation, these studies provide evidence that SREBP1 also contributes to the resolution phase of TLR4-induced gene activation by reprogramming macrophage lipid metabolism.

KEYWORDS:

DHA; EPA; SREBP1; fatty acid metabolism; inflammation; innate immunity; lipid metabolism; resolution; transcriptional regulation; unsaturated fatty acids

PMID:
28041958
PMCID:
PMC5568699
DOI:
10.1016/j.cmet.2016.11.009
[Indexed for MEDLINE]
Free PMC Article

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