title: Linking lipid metabolism to the innate immune response in macrophages through sterol regulatory element binding protein-1a.
abstract: We show that mice with a targeted deficiency in the gene encoding the lipogenic transcription factor SREBP-1a are resistant to endotoxic shock and systemic inflammatory response syndrome induced by cecal ligation and puncture (CLP). When macrophages from the mutant mice were challenged with bacterial lipopolysaccharide, they failed to activate lipogenesis as well as two hallmark inflammasome functions, activation of caspase-1 and secretion of IL-1β. We show that SREBP-1a activates not only genes required for lipogenesis in macrophages but also the gene encoding Nlrp1a, which is a core inflammasome component. Thus, SREBP-1a links lipid metabolism to the innate immune response, which supports our hypothesis that SREBPs evolved to regulate cellular reactions to external challenges that range from nutrient limitation and hypoxia to toxins and pathogens.
authors.affiliation: Metabolic Signaling and Disease Program, Sanford-Burnham Medical Research Institute, Orlando, FL 32827, USA.
authors.forename: Seung-Soon
authors.initials: SS
authors.lastname: Im
authors.forename: Leyla
authors.initials: L
authors.lastname: Yousef
authors.forename: Christoph
authors.initials: C
authors.lastname: Blaschitz
authors.forename: Janet Z
authors.initials: JZ
authors.lastname: Liu
authors.forename: Robert A
authors.initials: RA
authors.lastname: Edwards
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Young
authors.forename: Manuela
authors.initials: M
authors.lastname: Raffatellu
authors.forename: Timothy F
authors.initials: TF
authors.lastname: Osborne
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D001853:Bone Marrow; D020170:Caspase 1 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D007113:Immunity, Innate; D058847:Inflammasomes; D053583:Interleukin-1beta / Q000378:metabolism; D050356:Lipid Metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012480:Salmonella Infections / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D012486:Salmonella typhimurium / Q000276:immunology; D051780:Sterol Regulatory Element Binding Protein 1 / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D016207:Cytokines; D058847:Inflammasomes; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; C529636:NALP1 protein, mouse; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D020170:Caspase 1