title: Mechanisms of the prevention and inhibition of the progression and development of non-alcoholic steatohepatitis by genetic and pharmacological decoy receptor 3 supplementation.
abstract: OBJECTIVE
  Treatment of non-alcoholic steatohepatitis (NASH) is difficult due to the absence of a proven treatment and its comprehensive mechanisms. In the NASH animal model, upregulated hepatic inflammation and oxidative stress, with the resultant M1 polarization of macrophages as well as imbalanced adipocytokines, all accelerate NASH progression. As a member of the tumor necrosis factor receptor superfamily, decoy receptor 3 (DcR3) not only neutralizes the death ligands, but also performs immune modulations. In this study, we aimed to investigate the possible non-decoy effects of DcR3 on diet-induced NASH mice.
  
  
  METHODS
  Methionine- and choline-deficient (MCD) diet feeding for 9 weeks was applied to induce NASH in BALB/c mice. Decoy receptor 3 heterozygous transgenesis or pharmacological pretreatment with DcR3a for 1 month were designed as interventions. Intrahepatic inflammatory status as well as macrophage polarization, oxidative stress, and steatosis as well as lipogenic gene expression and fibrotic status were analyzed. Additionally, acute effects of DcR3a on HepG2 cells, Hep3B cells, and primary mouse hepatocytes in various MCD medium-stimulated changes were also evaluated.
  
  
  RESULTS
  Both DcR3 genetic and pharmacologic supplement significantly reduced MCD diet-induced hepatic M1 polarization. In addition, DcR3 supplement attenuated MCD diet-increased hepatic inflammation, oxidative stress, adipocytokine imbalance, steatosis, and fibrogenesis. Moreover, acute DcR3a incubation in HepG2 cells, Hep3B cells, and mouse hepatocytes could normalize the expression of genes related to lipid oxidation along with inflammation and oxidative stress.
  
  
  CONCLUSIONS
  The ability of DcR3 to attenuate hepatic steatosis and inflammation through its non-decoy effects of immune modulation and oxidative stress attenuation makes it a potential treatment for NASH.
authors.affiliation: Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan.|Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan.|Division of Gastroenterology and Hepatology, Department of Medicine, Yuanshan Branch, Taipei Veterans General Hospital, Yilan, Taiwan.
authors.forename: Pei-Chang
authors.initials: PC
authors.lastname: Lee
authors.affiliation: Department of Medical Education, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Ling-Yu
authors.initials: LY
authors.lastname: Yang
authors.affiliation: Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan.|Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Ying-Wen
authors.initials: YW
authors.lastname: Wang
authors.affiliation: Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan.|Division of Infection, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Shiang-Fen
authors.initials: SF
authors.lastname: Huang
authors.affiliation: Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan.|Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Kuei-Chuan
authors.initials: KC
authors.lastname: Lee
authors.affiliation: Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan.|Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan.|Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Yun-Cheng
authors.initials: YC
authors.lastname: Hsieh
authors.affiliation: Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan.|Department of Medical Education, Taipei Veterans General Hospital, Taipei, Taiwan.|Division of General Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.|Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Ying-Ying
authors.initials: YY
authors.lastname: Yang
authors.affiliation: Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.|Genomics Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: Shie-Liang
authors.initials: SL
authors.lastname: Hsieh
authors.affiliation: Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan.|Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Ming-Chih
authors.initials: MC
authors.lastname: Hou
authors.affiliation: Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan.|Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Han-Chieh
authors.initials: HC
authors.lastname: Lin
authors.affiliation: Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan.|Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Fa-Yuah
authors.initials: FY
authors.lastname: Lee
authors.affiliation: Cheng Hsin General Hospital, Taipei, Taiwan.
authors.forename: Shou-Dong
authors.initials: SD
authors.lastname: Lee
keywords: M1 polarization; decoy receptor 3; non-alcoholic steatohepatitis