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

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

doi:10.1371/journal.pone.0063435

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.

Highlights

Nuclear receptors (NRs), a unique family of ligand-modulated transcription factors, orchestrate numerous aspects of mammalian physiology, such as lipid and glucose metabolism, reproduction, development, and homeostasis [1,2]
We previously showed that small heterodimer partner (SHP) negatively regulates toll-like receptor (TLR)-dependent inflammation through a biphasic interaction in the cytosol with the signaling molecules NF-kB and tumor necrosis factor receptor-associated factor 6 (TRAF6) [18]
Results are presented as the mean 6 SEM. n.s., non-specific. (C) Sera were collected from Shp+/+ and Shp2/2 mice (n = 5 each group) at 18 h post-LPS injection and the concentrations of tumor necrosis factor (TNF)-a, IL-6, and IL-1b were measured by ELISA. (D) Expression of Tnfa, Il6, Il1b, and Shp mRNA in spleen tissues was analyzed using RT-PCR at 6 h after i.p injection of LPS. (E) Sera were collected from mice at 24 h post-LPS injection and subjected to IB to detect HMGB1 expression. (F) Representative immunofluorescence images for expression of TNF-a, COX-2, and iNOS in spleen tissues from Shp+/+ and Shp2/2 mice

Summary

Introduction

Nuclear receptors (NRs), a unique family of ligand-modulated transcription factors, orchestrate numerous aspects of mammalian physiology, such as lipid and glucose metabolism, reproduction, development, and homeostasis [1,2]. 48 members of the NR superfamily are known, including NR with known ligands (retinoids or thyroid hormone) and orphan NRs with unidentified ligands [3,4,5]. Among the orphan members of the NR superfamily, ‘‘small heterodimer partner (SHP; called NR0B2)’’ contains a ligand-binding domain but lacks the conserved DNA binding domain that interacts with NR, including thyroid receptor, retinoic acid receptors, and estrogen receptors a and b [4,6]. SHP is a key transcriptional regulatory factor for a variety of genes that participate in diverse metabolic functions and pathways, including lipid and bile acid metabolism, as well as glucose homeostasis [4,5,7]. Previous studies showed that SHP expression is induced by numerous hormones, molecules, and drugs, including the anti-diabetic drug metformin [9], hepatocyte growth factors [10], fenofibrate [11], and sodium arsenite [12]

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Results

Conclusion