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ROR? decreases oxidative stress through the induction of SOD2 and GPx1 expression and thereby protects against nonalcoholic steatohepatitis in mice.

ABSTRACT:

Aims

Increased hepatic oxidative stress and inflammation is the main cause of exacerbating nonalcoholic steatohepatitis (NASH). Retinoic acid-related orphan receptor ? (ROR?) 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? in regulating hepatic oxidative stress and inflammation.

Results

First, cholesterol sulfate (CS), an agonist of ROR?, lowered oxidative stress that was induced by 1.5?mM oleic acid in the primary cultures of hepatocytes. Second, exogenously introduced ROR? or CS treatment induced the mRNA level of antioxidant enzymes, superoxide dismutase 2 (SOD2) and glutathione peroxidase 1 (GPx1), through the ROR? response elements located in the upstream promoters of Sod2 and Gpx1. Third, ROR? significantly decreased reactive oxygen species levels and mRNA levels of tumor necrosis factor ? (TNF?) and interleukin-1? that were induced by lipopolysaccharide or TNF? 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? and its ligands protect NASH in mice by reducing hepatic oxidative stress and inflammation. Further, the molecular mechanism of the protective function of ROR? against oxidative stress in the liver was revealed. These findings may offer a rationale for developing therapeutic strategies against NASH using ROR? ligands.

SUBMITTER: Han YH

PROVIDER: S-EPMC4215383 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Publications

RORα decreases oxidative stress through the induction of SOD2 and GPx1 expression and thereby protects against nonalcoholic steatohepatitis in mice.

Han Yong-Hyun YH Kim Hyeon-Ji HJ Kim Eun-Jin EJ Kim Kyu-Seo KS Hong Suckchang S Park Hyeung-Geun HG Lee Mi-Ock MO

Antioxidants & redox signaling 20140410 15

<h4>Aims</h4>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.<h4>Results</h4>First, cholesterol sulfate (CS), an agonist of RORα, lowered oxidative st ...[more]

PMID: 24597775

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