Abstract
Bromodomain-containing protein 4 (BRD4) has been implicated to play a regulatory role in fibrogenic gene expression in animal models of liver fibrosis. The potential role of BRD4 in liver fibrosis in humans remains unclear. We sought to investigate the expression and cellular localization of BRD4 in fibrotic liver tissues. Human liver tissues were collected from healthy individuals and patients with liver fibrosis of various etiologies. RNA-seq showed that hepatic BRD4 mRNA was elevated in patients with liver fibrosis compared with that in healthy controls. Subsequent multiple manipulations such as western blotting, real-time quantitative polymerase chain reaction, and dual immunofluorescence analysis confirmed the abnormal elevation of the BRD4 expression in liver fibrosis of various etiologies compared to healthy controls. BRD4 expression was positively correlated with the severity of liver fibrosis, and also correlated with the serum levels of aspartate aminotransferase and total bilirubin. Moreover, the expression of C-X-C motif chemokine ligand 6 (CXCL6), a factor interplayed with BRD4, was increased in hepatic tissues of the patients with liver fibrosis. Its expression level was positively correlated with BRD4 level. BRD4 is up-regulated in liver fibrosis, regardless of etiology, and its increased expression is positively correlated with higher degrees of liver fibrosis. Our data indicate that BRD4 play a critical role in the progress of liver fibrosis, and it holds promise as a potential target for intervention of liver fibrosis.
Highlights
Hepatic fibrosis is a pathological process involving persistent injury to the liver and subsequent wound-healing responses that induce the production and deposition of extracellular matrix (ECM) proteins
It was recently reported that hepatic C-X-C Motif Chemokine Ligand 6 (CXCL6) expression is up-regulated in liver fibrosis and can promote the interaction of Bromodomain-containing protein 4 (BRD4) with other transcriptional factors [19]
Considering that fresh liver samples were limited to liver fibrosis/cirrhosis samples in the vicinity of liver cancer, we examined the hepatic BRD4 expression pattern using pathologic specimens from patients with liver fibrosis/cirrhosis with a variety of etiologies, including hepatitisBRD4 and Liver FibrosisB virus (HBV), hepatitis C virus (HCV), autoimmune hepatitis (AIH), primary sclerosing cholangitis (PBC), non-alcoholic steatohepatitis (NASH), cholestasis, and overlap syndrome
Summary
Hepatic fibrosis is a pathological process involving persistent injury to the liver and subsequent wound-healing responses that induce the production and deposition of extracellular matrix (ECM) proteins. Chronic inflammation in response to liver injury and excessive accumulation of ECM proteins can result in the progressive substitution of liver parenchyma by scar tissue. The exact mechanisms underlying the development and progression of hepatic fibrosis remain elusive. It has been documented that the activation of hepatic stellate cells (HSCs) through various inflammatory and fibrogenic pathways plays a pivotal role in liver fibrosis [4, 5]. Rapid progress has been made in the basic research on experimental liver fibrosis, accurate non-invasive biomarkers and effective anti-fibrotic drugs are not available in clinical practice. Better understanding of the molecular mechanisms underlying liver fibrosis may provide new therapeutic and diagnostic targets, and in turn may accelerate the development of treatment and diagnosis for liver fibrosis
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