title: Small heterodimer partner-targeting therapy inhibits systemic inflammatory responses through mitochondrial uncoupling protein 2.
abstract: The orphan nuclear receptor, small heterodimer partner (SHP), appears to play a negative regulatory role in innate immune signaling. Emerging evidence warrants further study on the therapeutic targeting of SHP to suppress excessive and deleterious inflammation. Here we show that fenofibrate, which targets SHP, is required for inhibiting systemic inflammation via mitochondrial uncoupling protein 2 (UCP2). In vivo administration of fenofibrate ameliorated systemic inflammatory responses and increased survival upon experimental sepsis through SHP. An abundance of SHP was observed in mice fed fenofibrate and in cultured macrophages through LKB1-dependent activation of the AMP-activated protein kinase pathway. Fenofibrate significantly blocked endotoxin-triggered inflammatory signaling responses via SHP, but not via peroxisome proliferator-activated receptor (PPAR)-α. In addition to the known mechanism by which SHP modulates innate signaling, we identify a new role of fenofibrate-induced SHP on UCP2 induction, which is required for the suppression of inflammatory responses through modulation of mitochondrial ROS production. These data strongly suggest that the SHP-inducing drug fenofibrate paves the way for novel therapies for systemic inflammation by targeting SHP.
authors.affiliation: Department of Microbiology, Chungnam National University School of Medicine, Daejeon, S. Korea.
authors.forename: Chul-Su
authors.initials: CS
authors.lastname: Yang
authors.forename: Jae-Min
authors.initials: JM
authors.lastname: Yuk
authors.forename: Jwa-Jin
authors.initials: JJ
authors.lastname: Kim
authors.forename: Jung Hwan
authors.initials: JH
authors.lastname: Hwang
authors.forename: Chul-Ho
authors.initials: CH
authors.lastname: Lee
authors.forename: Jin-Man
authors.initials: JM
authors.lastname: Kim
authors.forename: Goo Taeg
authors.initials: GT
authors.lastname: Oh
authors.forename: Hueng-Sik
authors.initials: HS
authors.lastname: Choi
authors.forename: Eun-Kyeong
authors.initials: EK
authors.lastname: Jo
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D011345:Fenofibrate / Q000494:pharmacology / Q000627:therapeutic use; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D007473:Ion Channels / Q000378:metabolism*; D008070:Lipopolysaccharides; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism*; D058990:Molecular Targeted Therapy; D047493:PPAR alpha / Q000378:metabolism; D020011:Protective Agents / Q000494:pharmacology / Q000627:therapeutic use; D011485:Protein Binding / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012772:Shock, Septic / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects; D000071246:Uncoupling Protein 2
chemical_list: D007473:Ion Channels; D008070:Lipopolysaccharides; D024101:Mitochondrial Proteins; D047493:PPAR alpha; D020011:Protective Agents; D017382:Reactive Oxygen Species; D018160:Receptors, Cytoplasmic and Nuclear; D048029:TNF Receptor-Associated Factor 6; D051197:Toll-Like Receptor 4; D051996:Transcription Factor RelA; C000604389:UCP2 protein, human; C000604390:Ucp2 protein, mouse; D000071246:Uncoupling Protein 2; C099713:nuclear receptor subfamily 0, group B, member 2; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases; D011345:Fenofibrate