title: FXR agonist GW4064 alleviates endotoxin-induced hepatic inflammation by repressing macrophage activation.
abstract: OBJECTIVE
  To examine the effect of farnesoid X receptor (FXR) activation by GW4064 on endotoxin-induced hepatic inflammation in nonalcoholic fatty liver disease (NAFLD) and the underlying mechanism.
  
  
  METHODS
  Six-week-old male C57BL/6 mice were fed a normal diet or a high-fat (HF) diet for 8 wk. HF diet-fed mice were intraperitoneally injected with GW4064 (30 mg/kg) or DMSO (vehicle) once daily for a week and then sacrificed after lipopolysaccharide (LPS, 50 μg/mouse) administration. Hepatic inflammation, levels of the macrophage marker F4/80, and apoptosis were measured at the end of the study. Additionally, the expression of proinflammatory genes involved in NAFLD (interleukin-6, interleukin-1β, interferon-γ, MCP-1) were analyzed by real-time PCR in the murine macrophage cell line RAW 264.7 cultured with or without GW4064 (2 μmol/L) before treatment with LPS.
  
  
  RESULTS
  In patients with NAFLD, the expression of FXR was detected by immunohistochemical staining and the relation between FXR expression and NAFLD activity score (NAS) was analyzed. Activation of FXR by GW4064 alleviated hepatic inflammation induced by endotoxin in a murine NAFLD model fed an HF diet as reflected by reduced serum levels of aspartate aminotransferase and alanine aminotransferase. Apoptosis and proinflammatory cytokine levels in liver tissues were also reduced by GW4064, and GW4064 could reduce induction of proinflammatory cytokines by LPS in vitro. FXR levels were reduced in patients with non-alcoholic steatohepatitis compared with healthy controls and were negatively correlated with NAS.
  
  
  CONCLUSIONS
  FXR activation attenuates LPS-induced hepatic inflammation in murine NAFLD by reducing expression of proinflammatory cytokines in macrophages.
authors.affiliation: Jun Yao, Chun-Suo Zhou, Bai-Qing Fu, Li-Sheng Tao, Ya-Ping Xu, Department of Gastroenterology, the People's Hospital Affiliated to Jiangsu University, Zhenjiang 212002, Jiangsu Province, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Yao
authors.affiliation: Jun Yao, Chun-Suo Zhou, Bai-Qing Fu, Li-Sheng Tao, Ya-Ping Xu, Department of Gastroenterology, the People's Hospital Affiliated to Jiangsu University, Zhenjiang 212002, Jiangsu Province, China.
authors.forename: Chun-Suo
authors.initials: CS
authors.lastname: Zhou
authors.affiliation: Jun Yao, Chun-Suo Zhou, Bai-Qing Fu, Li-Sheng Tao, Ya-Ping Xu, Department of Gastroenterology, the People's Hospital Affiliated to Jiangsu University, Zhenjiang 212002, Jiangsu Province, China.
authors.forename: Xiong
authors.initials: X
authors.lastname: Ma
authors.affiliation: Jun Yao, Chun-Suo Zhou, Bai-Qing Fu, Li-Sheng Tao, Ya-Ping Xu, Department of Gastroenterology, the People's Hospital Affiliated to Jiangsu University, Zhenjiang 212002, Jiangsu Province, China.
authors.forename: Bai-Qing
authors.initials: BQ
authors.lastname: Fu
authors.affiliation: Jun Yao, Chun-Suo Zhou, Bai-Qing Fu, Li-Sheng Tao, Ya-Ping Xu, Department of Gastroenterology, the People's Hospital Affiliated to Jiangsu University, Zhenjiang 212002, Jiangsu Province, China.
authors.forename: Li-Sheng
authors.initials: LS
authors.lastname: Tao
authors.affiliation: Jun Yao, Chun-Suo Zhou, Bai-Qing Fu, Li-Sheng Tao, Ya-Ping Xu, Department of Gastroenterology, the People's Hospital Affiliated to Jiangsu University, Zhenjiang 212002, Jiangsu Province, China.
authors.forename: Miao
authors.initials: M
authors.lastname: Chen
authors.affiliation: Jun Yao, Chun-Suo Zhou, Bai-Qing Fu, Li-Sheng Tao, Ya-Ping Xu, Department of Gastroenterology, the People's Hospital Affiliated to Jiangsu University, Zhenjiang 212002, Jiangsu Province, China.
authors.forename: Ya-Ping
authors.initials: YP
authors.lastname: Xu
mesh_terms: D000328:Adult; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000943:Antigens, Differentiation / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007555:Isoxazoles / Q000494:pharmacology*; D008070:Lipopolysaccharides; D008099:Liver / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008262:Macrophage Activation / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D000893:Anti-Inflammatory Agents; D000943:Antigens, Differentiation; D018836:Inflammation Mediators; D007555:Isoxazoles; D008070:Lipopolysaccharides; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C036763:monocyte-macrophage differentiation antigen; C412815:GW 4064
keywords: Farnesoid X receptor; GW4064; Lipopolysaccharide-induced hepatic inflammation; Macrophage activation; Nonalcoholic fatty liver disease; Nonalcoholic fatty liver disease activity score