RAR-Related Orphan Receptor Gamma (ROR-γ) Mediates Epithelial-Mesenchymal Transition Of Hepatocytes During Hepatic Fibrosis

Kim, Sung Min; Choi, Jung Eun; Hur, Wonhee; Kim, Jung-Hee; Hong, Sung Woo; Lee, Eun Byul; Lee, Woo Jung; Li, Tian Zhu; Sung, Pil Soo; Yoon, Seung Kew

doi:10.1002/jcb.25776

Cited by 19 publications

(13 citation statements)

References 48 publications

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“…Hepatocytes isolated from rats with carbon tetrachloride-induced liver fibrosis show mesenchymal markers (Nitta, Kim, Mohuczy, & Behrns, 2008). Furthermore, TGF-β1-driven EMT is accompanied with the up-regulation of Ecadherin transcription repressors in both primary murine hepatocytes and cultured murine hepatocyte cells (Kaimori et al, 2007;Kim et al, 2017;Kojima et al, 2008;Zeisberg et al, 2007). In this study, fructose caused hepatocytes to undergo the EMT, and then to lose E-cadherin, but gain FSP1 and vimentin.…”

Section: Discussionmentioning

confidence: 58%

Pterostilbene prevents hepatocyte epithelial‐mesenchymal transition in fructose‐induced liver fibrosis through suppressing miR‐34a/Sirt1/p53 and TGF‐β1/Smads signalling

Song

Chen

Zhao

et al. 2019

British J Pharmacology

103

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Background and Purpose: Excessive fructose consumption is a risk factor for liver fibrosis. Pterostilbene protects against liver fibrosis. Here, we investigated the potential role and the mechanisms underlying the hepatocyte epithelial-mesenchymal transition (EMT) in fructose-induced liver fibrosis and protection by pterostilbene. Experimental Approach: Characteristic features of liver fibrosis in 10% fructosefed rats and EMT in 5 mM fructose-exposed BRL-3A cells with or without pterostilbene and the change of miR-34a/Sirt1/p53 and transforming growth factor-β1 (TGF-β1)/Smads signalling were examined. MiR-34a inhibitor, miR-34a minic, or p53 siRNA were used to explore the role of miR-34a/Sirt1/p53 signalling in fructose-induced EMT and the action of pterostilbene. Key Results: Pterostilbene prevented fructose-induced liver injury with fibrosis in rats. Fructose caused hepatocyte undergoing EMT, gaining fibroblast-specific protein 1 and vimentin, and losing E-cadherin, effects attenuated by pterostilbene. Moreover, fructose induced miR-34a overexpression in hepatocytes with down-regulated Sirt1, increased p53 and ac-p53, and activated TGF-β1/Smads signalling, whereas these disturbances were suppressed by miR-34a inhibitor. Additionally, miR-34a inhibitor and p53 siRNA prevented TGF-β1-driven hepatocyte EMT under fructose exposure. Pterostilbene down-regulated miR-34a, up-regulated Sirt1, and suppressed p53 activation and TGF-β1/Smads signalling in fructose-stimulated animals and cells but showed no additional effects with miR-34a inhibitor on miR-34a/Sirt1/p53 signalling in fructose-exposed hepatocytes. Conclusions and Implications: These results strongly suggest that activation of miR-34a/Sirt1/p53 signalling is required for fructose-induced hepatocyte EMT mediated by TGF-β1/Smads signalling, contributing to liver fibrosis in rats. Pterostilbene exhibits a protective effect against liver fibrosis at least partly through inhibiting miR-34a/Sirt1/p53 signalling activation.

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Section: Discussionmentioning

confidence: 58%

Pterostilbene prevents hepatocyte epithelial‐mesenchymal transition in fructose‐induced liver fibrosis through suppressing miR‐34a/Sirt1/p53 and TGF‐β1/Smads signalling

Song

Chen

Zhao

et al. 2019

British J Pharmacology

103

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“…Th17 response was mutually modulated by STAT3 (Atarashi et al, 2015). Retinoid-related orphan receptor (ROR)c, an orphan nuclear receptor, induces Th17 and Th1 differentiation (Chen et al, 2003;Kim et al, 2017;Nakanishi et al, 2018). In the chronic colitis model, cytokines including IL-17, TNF-a, IL-6 and IL-23, as well as the percentage and absolute number of Th1 and Th17 cells, were significantly decreased in LP of mice treated with CM compared with mice treated with DDW.…”

Section: Discussionmentioning

confidence: 99%

Camel milk regulates T‐cell proliferation to alleviate dextran sodium sulphate‐induced colitis in mice

Cui

Yue

et al. 2019

Int J of Food Sci Tech

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Summary The incidence of inflammatory bowel disease (IBD) is increasing in China. Current clinical methods of treatment for IBD are accompanied by side effects, and thus, the search for effective therapeutic drugs with minimal adverse effects is necessary. In the present study, the effects of camel milk (CM) on dextran sodium sulphate (DSS)‐induced acute and chronic colitis in a mouse model were investigated. The results showed CM effectively alleviated the injury induced by DSS to the colon mucosa and imbalance of immune cells in mice. However, treatment with CM significantly increased the body weight of mice and decreased the disease activity index (DAI), histopathological score, proliferation of Th17 cells and concentration of inflammatory cytokine IL‐17. The results from the present study indicate CM possesses intestinal protective effects.

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“…To detect the expression of mRNAs, complementary DNA (cDNA) was synthesized as previously described [ 20 ]. PCR was performed using specific primers.…”

Section: Methodsmentioning

confidence: 99%

Death-Associated Protein 6 (Daxx) Alleviates Liver Fibrosis by Modulating Smad2 Acetylation

Kim

Hur

Kang

et al. 2021

Cells

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Transforming growth factor-β (TGF-β) has been identified as an inducer of hepatocyte epithelial–mesenchymal transition (EMT), which triggers liver fibrosis. Death-associated protein 6 (Daxx) is known to be associated with the TGF-β-induced apoptotic pathway, but the function of Daxx in liver fibrosis remains unknown. This study aimed to elucidate the role of Daxx in liver fibrosis. We used liver fibrosis tissues from humans and mice to assess Daxx expression. EMT properties and TGF-β signaling pathway activation were investigated in the Daxx-overexpressing FL83B cell line. The therapeutic effect of Daxx was investigated in a mouse model of liver fibrosis by the hydrodynamic injection of plasmids. The expression of Daxx was markedly decreased in hepatocytes from fibrotic human and mouse livers, as well as in hepatocytes treated with TGF-β in vitro. The overexpression of Daxx inhibited the EMT process by interfering with the TGF-β-induced phosphorylation of Smad2. Coimmunoprecipitation analysis confirmed that Daxx reduced the transcriptional activity of Smad2 by binding to its MH1 domain and interfering with Smad2 acetylation. In addition, the therapeutic delivery of Daxx alleviated liver fibrosis in a thioacetamide-induced fibrosis mouse model. Overall, our results indicate that Daxx could be a potential therapeutic target to modulate fibrogenesis, as well as a useful biomarker for liver fibrosis.

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RAR-Related Orphan Receptor Gamma (ROR-γ) Mediates Epithelial-Mesenchymal Transition Of Hepatocytes During Hepatic Fibrosis

Cited by 19 publications

References 48 publications

Pterostilbene prevents hepatocyte epithelial‐mesenchymal transition in fructose‐induced liver fibrosis through suppressing miR‐34a/Sirt1/p53 and TGF‐β1/Smads signalling

Pterostilbene prevents hepatocyte epithelial‐mesenchymal transition in fructose‐induced liver fibrosis through suppressing miR‐34a/Sirt1/p53 and TGF‐β1/Smads signalling

Camel milk regulates T‐cell proliferation to alleviate dextran sodium sulphate‐induced colitis in mice

Death-Associated Protein 6 (Daxx) Alleviates Liver Fibrosis by Modulating Smad2 Acetylation

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