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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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Project description:Nonalcoholic fatty liver disease (NAFLD) is the most frequent histological finding in individuals with abnormal liver-function tests in the Western countries. In previous studies, we have shown that oxidative phosphorylation (OXPHOS) is decreased in individuals with NAFLD, but the cause of this mitochondrial dysfunction remains uncertain. The aims of this study were to determine whether feeding mice a high-fat diet (HFD) induces any change in the activity of OXPHOS, and to investigate the mechanisms involved in the pathogenesis of this defect. To that end, 30 mice were distributed between five groups: control mice fed a standard diet, and mice on a HFD and treated with saline solution, melatonin (an antioxidant), MnTBAP (a superoxide dismutase analog) or uric acid (a scavenger of peroxynitrite) for 28 weeks intraperitoneously. In the liver of these mice, we studied histology, activity and assembly of OXPHOS complexes, levels of subunits of these complexes, gene expression of these subunits, oxidative and nitrosative stress, and oxidative DNA damage. In HFD-fed mice, we found nonalcoholic steatohepatitis, increased gene expression of TNFα, IFNγ, MCP-1, caspase-3, TGFβ1 and collagen α1(I), and increased levels of 3-tyrosine nitrated proteins. The activity and assembly of all OXPHOS complexes was decreased to about 50-60%. The amount of all studied OXPHOS subunits was markedly decreased, particularly the mitochondrial-DNA-encoded subunits. Gene expression of mitochondrial-DNA-encoded subunits was decreased to about 60% of control. There was oxidative damage to mitochondrial DNA but not to genomic DNA. Treatment of HFD-fed mice with melatonin, MnTBAP or uric acid prevented all changes observed in untreated HFD-fed mice. We conclude that a HFD decreased OXPHOS enzymatic activity owing to a decreased amount of fully assembled complexes caused by a reduced synthesis of their subunits. Antioxidants and antiperoxynitrites prevented all of these changes, suggesting that nitro-oxidative stress played a key role in the pathogenesis of these alterations. Treatment with these agents might prevent the development of NAFLD in humans.