title: Tumor necrosis factor receptor-associated factor 5 (Traf5) acts as an essential negative regulator of hepatic steatosis.
abstract: Obesity-related metabolic inflammation, insulin resistance (IR), and excessive fat accumulation are linked phenomena that promote the progression of nonalcoholic fatty liver disease (NAFLD). Previous research has indicated that CD40-TRAF5 signaling protects against obesity-related metabolic disorders; however, the precise roles and underlying mechanisms of TRAF5 in obesity-induced pathological processes have not been fully elucidated.
  
  
  
  TRAF5 expression was evaluated in the livers of NAFLD patients, high-fat diet (HFD)-induced or genetically (ob/ob) induced obese mice, and in palmitate-treated hepatocytes. Gain- or loss-of-function approaches were used to investigate the specific roles and mechanisms of hepatic Traf5 under obesity-related pathological conditions.
  
  
  
  TRAF5 expression was decreased in the fatty livers of both NAFLD patients and obese mice, and in palmitate-treated hepatocytes in vitro. Traf5 overexpression significantly suppressed nonalcoholic steatohepatitis (NASH)-like phenotypes in mice after HFD treatment for 24weeks and inhibited the progression of NAFLD in ob/ob mice. Conversely, Traf5 deficiency resulted in the deterioration of metabolic disorders induced by HFD. Investigations of the underlying mechanisms revealed that Traf5 regulates hepatic steatosis by targeting Jnk signaling. Specifically, Jnk1 rather than Jnk2 is responsible for the function of Traf5 in metabolic disorders, as evidenced by the fact that Jnk1 ablation markedly ameliorates the detrimental effects of Traf5 deficiency on obesity, inflammation, IR, hepatic steatosis and fibrosis.
  
  
  
  Traf5 negatively regulates NAFLD/NASH and related metabolic dysfunctions by blocking Jnk1 activity, which represents a potential therapeutic target for obesity-related metabolic disorders.
  
  
  
  Lipid accumulation in the liver induces degradation of Traf5. Increasing Traf5 ameliorates nonalcoholic fatty liver by blocking Jnk1 activity.
authors.affiliation: Department of Endocrinology, Renmin Hospital of Wuhan University, Wuhan 430060, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Gao
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China; Animal Experiment Center/Animal Biosafety Level-III Laboratory, Wuhan University, Wuhan 430071, China; Medical Research Institute, School of Medicine, Wuhan University, Wuhan 430071, China.
authors.forename: Pi-Xiao
authors.initials: PX
authors.lastname: Wang
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China; Animal Experiment Center/Animal Biosafety Level-III Laboratory, Wuhan University, Wuhan 430071, China; Medical Research Institute, School of Medicine, Wuhan University, Wuhan 430071, China.
authors.forename: Yaxing
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Harbin Medical University Cancer Hospital, Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, Harbin 150086, China.
authors.forename: Chang-Jiang
authors.initials: CJ
authors.lastname: Yu
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China; Animal Experiment Center/Animal Biosafety Level-III Laboratory, Wuhan University, Wuhan 430071, China; Medical Research Institute, School of Medicine, Wuhan University, Wuhan 430071, China.
authors.forename: Yanxiao
authors.initials: Y
authors.lastname: Ji
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China; Animal Experiment Center/Animal Biosafety Level-III Laboratory, Wuhan University, Wuhan 430071, China.
authors.forename: Xiaozhan
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China; Animal Experiment Center/Animal Biosafety Level-III Laboratory, Wuhan University, Wuhan 430071, China; Medical Research Institute, School of Medicine, Wuhan University, Wuhan 430071, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China; Animal Experiment Center/Animal Biosafety Level-III Laboratory, Wuhan University, Wuhan 430071, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Department of Endocrinology, Renmin Hospital of Wuhan University, Wuhan 430060, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Jin
authors.affiliation: College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China.
authors.forename: Zan
authors.initials: Z
authors.lastname: Huang
authors.affiliation: Harbin Medical University Cancer Hospital, Institute of Metabolic Disease, Heilongjiang Academy of Medical Science, Harbin 150086, China. Electronic address: zhirenz@yahoo.com.
authors.forename: Zhi-Ren
authors.initials: ZR
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China; Animal Experiment Center/Animal Biosafety Level-III Laboratory, Wuhan University, Wuhan 430071, China; Medical Research Institute, School of Medicine, Wuhan University, Wuhan 430071, China. Electronic address: lihl@whu.edu.cn.
authors.forename: Hongliang
authors.initials: H
authors.lastname: Li
mesh_terms: D000818:Animals; D059305:Diet, High-Fat; D006801:Humans; D007333:Insulin Resistance; D008099:Liver; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease; D009765:Obesity; D048015:TNF Receptor-Associated Factor 5; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
chemical_list: D048015:TNF Receptor-Associated Factor 5; D047988:Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
keywords: Hepatic steatosis; Insulin resistance; JNK; TRAF5