Journal
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
Volume 490, Issue 3, Pages 841-848Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2017.06.129
Keywords
Farnesoid X receptor; GW4064; Inflammatory bowel disease; Toll-like receptor 4; Mitochondrial dysfunction
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Funding
- Ministry of Science and Technology, Taipei, Taiwan [MOST 102-2320-B182-015-MY3, 103-2320-8182-002-MY3]
- Chang Gung Memorial Hospital, Taoyuan, Taiwan [CMRPD1D0351, CMRPD1D0352]
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Inflammatory bowel disease (IBD) is a complex and relapsing inflammatory condition of the gastro intestinal tract characterized by diarrhoea and abdominal pain. Farnesoid X receptor (FXR) plays an important role in enteroprotection and mucosal injury by regulating inflammatory responses and barrier function in the intestinal tract. Here we show the mechanisms of FXR agonist, GW4064, inhibits mucosal injury in ileum caused by lipopolysaccharides (LPS). Ileum injury was induced by intraperitoneal injection of LPS in Wild-type (WT) and FXR knockout (KO) mice. GW4064 alleviates LPS-mediated tight junction dysfunction as well as macrophage infiltration in WT mice, but not in FXR KO mice. Interesting, GW4064 suppresses NACHT, LRR and PYD domains-containing protein 3 (NALP3) inflammasome mediates tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6 and IL-1 beta, as well as mitochondrial respiratory complexes mRNA expression in WT and FXR KO mice treated with LPS. This results demonstrated that central roles of FXR in coordinating regulation of both inflammation and mitochondrial dysfunction. We propose that GW4064 is promising therapeutic agent for treatment of ileocolitis. (C) 2017 Elsevier Inc. All rights reserved.
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