title: Targeting hepatic TRAF1-ASK1 signaling to improve inflammation, insulin resistance, and hepatic steatosis.
abstract: Tumor necrosis factor receptor-associated factor 1 (TRAF1) is an important adapter protein that is largely implicated in molecular events regulating immunity/inflammation and cell death. Although inflammation is closely related to and forms a vicious circle with insulin dysfunction and hepatic lipid accumulation, the role of TRAF1 in hepatic steatosis and the related metabolic disorders remains unclear.
  
  
  
  The participation of TRAF1 in the initiation and progression of hepatic steatosis was evaluated in high fat diet (HFD)-induced and genetic obesity. Mice with global TRAF1 knockout or liver-specific TRAF1 overexpression were employed to investigate the role of TRAF1 in insulin resistance, inflammation, and hepatic steatosis based on various phenotypic examinations. Molecular mechanisms underlying TRAF1-regulated hepatic steatosis were further explored in vivo and in vitro.
  
  
  
  TRAF1 expression was significantly upregulated in the livers of NAFLD patients and obese mice and in palmitate-treated hepatocytes. In response to HFD administration or in ob/ob mice, TRAF1 deficiency was hepatoprotective, whereas the overexpression of TRAF1 in hepatocytes contributed to the pathological development of insulin resistance, inflammatory response and hepatic steatosis. Mechanistically, hepatocyte TRAF1 promotes hepatic steatosis through enhancing the activation of ASK1-mediated P38/JNK cascades, as evidenced by the fact that ASK1 inhibition abolished the exacerbated effect of TRAF1 on insulin dysfunction, inflammation, and hepatic lipid accumulation.
  
  
  
  TRAF1 functions as a positive regulator of insulin resistance, inflammation, and hepatic steatosis dependent on the activation of ASK1-P38/JNK axis.
authors: Department of Cardiology, The Central Hospital of Wuhan, Wuhan, China; Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China; Animal Experiment Center/Animal Biosafety Level-III Laboratory, Wuhan University, Wuhan 430060, China.
authors: Mei
authors: M
authors: Xiang
authors: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China; Animal Experiment Center/Animal Biosafety Level-III Laboratory, Wuhan University, Wuhan 430060, China.
authors: Pi-Xiao
authors: PX
authors: Wang
authors: College of Veterinary Medicine, Hunan Agricultural University, Changsha 410128, China.
authors: Ai-Bing
authors: AB
authors: Wang
authors: State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China.
authors: Xiao-Jing
authors: XJ
authors: Zhang
authors: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China; Animal Experiment Center/Animal Biosafety Level-III Laboratory, Wuhan University, Wuhan 430060, China.
authors: Yaxing
authors: Y
authors: Zhang
authors: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China; Animal Experiment Center/Animal Biosafety Level-III Laboratory, Wuhan University, Wuhan 430060, China.
authors: Peng
authors: P
authors: Zhang
authors: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China; Animal Experiment Center/Animal Biosafety Level-III Laboratory, Wuhan University, Wuhan 430060, China.
authors: Fang-Hua
authors: FH
authors: Mei
authors: Department of Cardiology, The Central Hospital of Wuhan, Wuhan, China. Electronic address: chenmh@aliyun.com.
authors: Man-Hua
authors: MH
authors: Chen
authors: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China; Animal Experiment Center/Animal Biosafety Level-III Laboratory, Wuhan University, Wuhan 430060, China. Electronic address: lihl@whu.edu.cn.
authors: Hongliang
authors: H
authors: Li
mesh_terms: D000818:Animals; D059305:Diet, High-Fat; D006801:Humans; D007249:Inflammation / Q000209:etiology*; D007333:Insulin Resistance; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology; D048848:MAP Kinase Kinase Kinase 5 / Q000037:antagonists & inhibitors / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D065626:Non-alcoholic Fatty Liver Disease / Q000209:etiology*; D015398:Signal Transduction / Q000502:physiology; D047990:TNF Receptor-Associated Factor 1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
chemical_list: D047990:TNF Receptor-Associated Factor 1; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; C482858:MAP3K5 protein, human
keywords: ASK1; Hepatic steatosis; Inflammation; Insulin resistance; TRAF1