title: RORα decreases oxidative stress through the induction of SOD2 and GPx1 expression and thereby protects against nonalcoholic steatohepatitis in mice.
abstract: OBJECTIVE
  Increased hepatic oxidative stress and inflammation is the main cause of exacerbating nonalcoholic steatohepatitis (NASH). Retinoic acid-related orphan receptor α (RORα) regulates diverse target genes associated with lipid metabolism, and its expression level is low in the liver of patients with NASH. Here, we investigated the role of RORα in regulating hepatic oxidative stress and inflammation.
  
  
  RESULTS
  First, cholesterol sulfate (CS), an agonist of RORα, lowered oxidative stress that was induced by 1.5 mM oleic acid in the primary cultures of hepatocytes. Second, exogenously introduced RORα or CS treatment induced the mRNA level of antioxidant enzymes, superoxide dismutase 2 (SOD2) and glutathione peroxidase 1 (GPx1), through the RORα response elements located in the upstream promoters of Sod2 and Gpx1. Third, RORα significantly decreased reactive oxygen species levels and mRNA levels of tumor necrosis factor α (TNFα) and interleukin-1β that were induced by lipopolysaccharide or TNFα in Kupffer cells. Finally, the administration of JC1-40 decreased the signs of liver injury, lipid peroxidation, and inflammation in the MCD diet-induced NASH mice.
  
  
  CONCLUSIONS
  We showed for the first time that RORα and its ligands protect NASH in mice by reducing hepatic oxidative stress and inflammation. Further, the molecular mechanism of the protective function of RORα against oxidative stress in the liver was revealed. These findings may offer a rationale for developing therapeutic strategies against NASH using RORα ligands.
authors.affiliation: Bio-MAX Institute, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University , Seoul, Korea.
authors.forename: Yong-Hyun
authors.initials: YH
authors.lastname: Han
authors.forename: Hyeon-Ji
authors.initials: HJ
authors.lastname: Kim
authors.forename: Eun-Jin
authors.initials: EJ
authors.lastname: Kim
authors.forename: Kyu-Seo
authors.initials: KS
authors.lastname: Kim
authors.forename: Suckchang
authors.initials: S
authors.lastname: Hong
authors.forename: Hyeung-Geun
authors.initials: HG
authors.lastname: Park
authors.forename: Mi-Ock
authors.initials: MO
authors.lastname: Lee
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism; D004790:Enzyme Induction; D005979:Glutathione Peroxidase / Q000235:genetics / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D007728:Kupffer Cells / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism*; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1 / Q000502:physiology*; D018384:Oxidative Stress; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D020218:Response Elements; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D000094765:Glutathione Peroxidase GPX1; D000099156:Superoxide Dismutase 2
chemical_list: D016207:Cytokines; D005979:Glutathione Peroxidase; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase; D000094765:Glutathione Peroxidase GPX1; D000099156:Superoxide Dismutase 2; C539739:Rora protein, mouse