RORα Decreases Oxidative Stress Through the Induction of SOD2 and GPx1 Expression and Thereby Protects Against Nonalcoholic Steatohepatitis in Mice

Aims: Increased hepatic oxidative stress and inflammation is the main cause of exacerbating nonalcoholic steatohepatitis (NASH). Retinoic acid-related orphan receptor alpha (ROR alpha) 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 ROR alpha in regulating hepatic oxidative stress and inflammation. Results: First, cholesterol sulfate (CS), an agonist of ROR alpha, lowered oxidative stress that was induced by 1.5 mM oleic acid in the primary cultures of hepatocytes. Second, exogenously introduced ROR alpha or CS treatment induced the mRNA level of antioxidant enzymes, superoxide dismutase 2 (SOD2) and glutathione peroxidase 1 (GPx1), through the ROR alpha response elements located in the upstream promoters of Sod2 and Gpx1. Third, ROR alpha significantly decreased reactive oxygen species levels and mRNA levels of tumor necrosis factor alpha (TNF alpha) and interleukin-1 beta that were induced by lipopolysaccharide or TNF alpha 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. Innovation and Conclusion: We showed for the first time that ROR alpha and its ligands protect NASH in mice by reducing hepatic oxidative stress and inflammation. Further, the molecular mechanism of the protective function of ROR alpha against oxidative stress in the liver was revealed. These findings may offer a rationale for developing therapeutic strategies against NASH using ROR alpha ligands. Antioxid. Redox Signal. 21, 2083-2094.