Small Heterodimer Partner-Targeting Therapy Inhibits Systemic Inflammatory Responses through Mitochondrial Uncoupling Protein 2

Chul Su Yang, Jae Min Yuk, Jwa Jin Kim, Jung Hwan Hwang, Chul Ho Lee, Jin Man Kim, Goo Taeg Oh, Hueng Sik Choi, Eun Kyeong Jo

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

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.

Original languageEnglish
Article numbere63435
JournalPLoS ONE
Volume8
Issue number5
DOIs
StatePublished - 21 May 2013

Fingerprint

Dive into the research topics of 'Small Heterodimer Partner-Targeting Therapy Inhibits Systemic Inflammatory Responses through Mitochondrial Uncoupling Protein 2'. Together they form a unique fingerprint.

Cite this