Abstract
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.
Highlights
Liver fibrosis is a pathological consequence of repeated inflammation and repair mechanisms resulting from various causes, such as viral infections, obesity, alcohol consumption, or drugs
Liver fibrosis is characterized by an excessive accumulation of extracellular matrix (ECM) proteins, including collagen, which deform the hepatic architecture by forming a fibrous scar
Western blotting analysis showed that Daxx expression was dramatically decreased in the liver of TAA-induced fibrotic mice, with high expression of the fibrosis marker, α-smooth muscle actin (α-SMA) compared to normal mice liver
Summary
Liver fibrosis is a pathological consequence of repeated inflammation and repair mechanisms resulting from various causes, such as viral infections, obesity, alcohol consumption, or drugs. The burden of liver cirrhosis, which causes portal hypertension, hepatocellular carcinoma and eventual hepatic failure, has consistently increased over the past thirty years, rising from 676,000 related deaths in 1980 to over one million related deaths in 2010; despite this rise in cases, an antifibrotic agent for the treatment of liver fibrosis has not yet been developed [1,2]. Myofibroblasts are the major ECM-producing cells and are normally derived from hepatic stellate cells (HSCs) in the liver [3]. It has been reported that damaged hepatocytes can be converted into myofibroblast-like cells via epithelial–mesenchymal transition (EMT) [4,5]. EMT has been observed in physiological processes, such as development and wound healing, but it is associated with pathological processes, such as fibrotic diseases and cancer metastasis [6,7,8]
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