Expression of hepatic stellate cell activation-related genes in HBV-, HCV-, and nonalcoholic fatty liver disease-associated fibrosis

Abstract

Liver fibrosis is a manifestation of chronic liver injury. It leads to hepatic dysfunction and is a critical element in the pathogenesis of cirrhosis and hepatocellular carcinoma. The activation of hepatic stellate cells (HSC) plays a central role in liver fibrogenesis of different etiologies. To elucidate the molecular mechanism of this phenomenon, it is important to analyze the changes in gene expression that accompany the HSC activation process. In this study, we isolated quiescent and activated HSCs from control mice and mice with CCl 4-induced liver fibrosis, respectively, and performed RNA sequencing to compare the differences in gene expression patterns between the two types of HSCs. We also reanalyzed public gene expression data for fibrotic liver tissues isolated from patients with HBV infection, HCV infection, and nonalcoholic fatty liver disease to investigate the gene expression changes during liver fibrosis of these three etiologies. We detected 146 upregulated and 18 downregulated genes in activated HSCs, which were implicated in liver fibrosis as well. Among the overlapping genes, seven transcription factor-encoding genes, ARID5B, GATA6, MITF, PBX1, PLAGL1, SOX4, and SOX9, were upregulated, while one, RXRA, was downregulated. These genes were suggested to play a critical role in HSC activation, and subsequently, in the promotion of liver fibrosis. We undertook the RNA sequencing of quiescent and activated HSCs and analyzed the expression profiles of genes associated with HSC activation in liver fibrotic tissues from different liver diseases, and also aimed to elucidate the changes in gene expression patterns associated with HSC activation and liver fibrosis.

Super-enhancer signature reveals key mechanisms associated with resistance to non-alcoholic steatohepatitis in humans with obesity

“…In another example, we linked an NP-enhancer hotspot to tyrosine kinase SYK , the hepatic expression of which positively correlates with fibrosis stage in human tissues(85). NP-specific enhancer associated genes that were previously reported in cell/animal models but reported in our study for the first time in humans include: ARID5B (hepatic stellate cell activation(86)), ARRB2 (fibrosis(87)), FMNL1 (macrophage migration(88)), and PANX1 (apoptosis and fibrosis(89–91)). We also uncovered novel genes that had not been previously linked to NASH progression in humans or animal models.…”

microRNA-186 in extracellular vesicles from bone marrow mesenchymal stem cells alleviates idiopathic pulmonary fibrosis via interaction with SOX4 and DKK1

“…In a preceding study, SOX4 upregulation was suggested to be associated with the progression of IPF [ 38 ]. Known as a fibrogenic gene, SOX4 potentially contributes to activation of hepatic stellate cells and promotion of PF pathology [ 39 ]. Furthermore, the interaction between miR-186 and SOX4 and their functional mechanisms in IPF have been addressed in our study.…”

miR-139-5p sponged by LncRNA NEAT1 regulates liver fibrosis via targeting β-catenin/SOX9/TGF-β1 pathway

“…A study has indicated that SOX9 could promote HSCs activation and exacerbate liver fibrosis [ 28 ]. Nevertheless, the mechanism how SOX9 regulates HSCs activation and fibrotic liver remains unclear.…”