title: SREBP1 Contributes to Resolution of Pro-inflammatory TLR4 Signaling by Reprogramming Fatty Acid Metabolism.
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.
authors.affiliation: 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.
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Oishi
authors.affiliation: Department of Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Nathanael J
authors.initials: NJ
authors.lastname: Spann
authors.affiliation: 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.
authors.forename: Verena M
authors.initials: VM
authors.lastname: Link
authors.affiliation: 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.
authors.forename: Evan D
authors.initials: ED
authors.lastname: Muse
authors.affiliation: Department of Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Tobias
authors.initials: T
authors.lastname: Strid
authors.affiliation: Department of Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Chantle
authors.initials: C
authors.lastname: Edillor
authors.affiliation: Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Kolar
authors.affiliation: 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.
authors.forename: Takashi
authors.initials: T
authors.lastname: Matsuzaka
authors.affiliation: Department of Cellular and Molecular Medicine, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
authors.forename: Sumio
authors.initials: S
authors.lastname: Hayakawa
authors.affiliation: Department of Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Jenhan
authors.initials: J
authors.lastname: Tao
authors.affiliation: 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.
authors.forename: Minna U
authors.initials: MU
authors.lastname: Kaikkonen
authors.affiliation: Department of Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Aaron F
authors.initials: AF
authors.lastname: Carlin
authors.affiliation: Department of Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Lam
authors.affiliation: Department of Aging Research, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Manabe
authors.affiliation: 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.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Shimano
authors.affiliation: Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Saghatelian
authors.affiliation: Department of Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: ckg@ucsd.edu.
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Glass
mesh_terms: D000818:Animals; D001483:Base Sequence; D053898:Biosynthetic Pathways / Q000187:drug effects / Q000235:genetics; D004742:Enhancer Elements, Genetic / Q000235:genetics; D005227:Fatty Acids / Q000378:metabolism*; D007249:Inflammation / Q000235:genetics / Q000473:pathology*; D050356:Lipid Metabolism / Q000187:drug effects; D008070:Lipopolysaccharides / Q000494:pharmacology; D000071518:Liver X Receptors / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D010641:Phenotype; D015398:Signal Transduction / Q000187:drug effects; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism*; D013997:Time Factors; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: D005227:Fatty Acids; C506188:Kdo2-lipid A; D008070:Lipopolysaccharides; D000071518:Liver X Receptors; D051780:Sterol Regulatory Element Binding Protein 1; D051197:Toll-Like Receptor 4
keywords: DHA; EPA; SREBP1; fatty acid metabolism; inflammation; innate immunity; lipid metabolism; resolution; transcriptional regulation; unsaturated fatty acids