title: DKK3 expression in hepatocytes defines susceptibility to liver steatosis and obesity.
abstract: Dickkopf-3 (DKK3), a protein belonging to the DKK family, has been extensively investigated in the context of cancer, including liver cancer. However, the role of DKK3 in hepatic steatosis and related metabolic disorders remains largely unexplored.
  
  
  
  We detected the expression of DKK3 in the fatty livers of NAFLD patients and of obese mice and investigated the function of DKK3 in hepatic steatosis and related metabolic disorders by using hepatocyte-specific DKK3 deficiency or overexpression obese mice induced by high fat diet (HFD) or genetic defect (ob/ob). The molecular mechanisms underlying DKK3-regulated hepatic steatosis were further explored and verified in mice.
  
  
  
  DKK3 expression was significantly decreased in the livers of NAFLD patients and of obese mice as well as in cultured hepatocytes stimulated with palmitate. Further investigation indicated that specific overexpression of DKK3 in hepatocytes enhanced insulin sensitivity and glucose tolerance, reduced the inflammatory response, and ameliorated the imbalance of lipid metabolism in response to HFD or genetic defects. In contrast, DKK3 deficiency in hepatocytes led to an almost complete reversal of these pathologies. Mechanistically, DKK3 combined with Apoptosis signal-regulating kinase 1 (ASK1) under palmitate stimulation, and thus inhibited the activation of the downstream P38/JNK pathway. Importantly, dominant-negative ASK1 blocked the accelerated effects of DKK3 deficiency, while the constitutively active form of ASK1 overcame the inhibitory effects of DKK3 overexpression on HFD-induced metabolic disorders in vivo.
  
  
  
  DKK3 functions as a negative regulator of insulin resistance, hepatic steatosis, and associated inflammatory responses, which depends on its inhibitory regulation of ASK1 activity.
  
  
  
  DKK3 expression is decreased in the non-alcoholic fatty liver of humans and mice. Adding DKK3 expression alleviates fatty liver in mice by inhibiting ASK1 activity.
authors.affiliation: Department of Hepatology and Infection, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200336, China; Animal Experiment Center/Animal Biosafety Level-III Laboratory, Wuhan University, Wuhan 430071, China.
authors.forename: Lanfeng
authors.initials: L
authors.lastname: Xie
authors.affiliation: 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: 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: Animal Experiment Center/Animal Biosafety Level-III Laboratory, Wuhan University, Wuhan 430071, China.
authors.forename: Xiao-Jing
authors.initials: XJ
authors.lastname: Zhang
authors.affiliation: 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: Guang-Nian
authors.initials: GN
authors.lastname: Zhao
authors.affiliation: College of Veterinary Medicine, Hunan Agricultural University, Changsha 410128, China.
authors.forename: Aibing
authors.initials: A
authors.lastname: Wang
authors.affiliation: 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: Junhong
authors.initials: J
authors.lastname: Guo
authors.affiliation: 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: Xueyong
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Department of Hepatology and Infection, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200336, China. Electronic address: Zhangq1030@163.com.
authors.forename: Qin
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: 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; D022781:Hepatocytes; D006801:Humans; D007333:Insulin Resistance; D008099:Liver; D048848:MAP Kinase Kinase Kinase 5; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease; D009765:Obesity
chemical_list: D048848:MAP Kinase Kinase Kinase 5
keywords: ASK1; Dickkopf-3; Hepatic steatosis; Inflammation; Insulin resistance