Abstract

Given the important role of angiogenesis in liver pathology, the current study investigated the role of Runt-related transcription factor 1 (RUNX1), a regulator of developmental angiogenesis, in the pathogenesis of non-alcoholic steatohepatitis (NASH). Quantitative RT-PCRs and a transcription factor analysis of angiogenesis-associated differentially expressed genes in liver tissues of healthy controls, patients with steatosis and NASH, indicated a potential role of RUNX1 in NASH. The gene expression of RUNX1 was correlated with histopathological attributes of patients. The protein expression of RUNX1 in liver was studied by immunohistochemistry. To explore the underlying mechanisms, in vitro studies using RUNX1 siRNA and overexpression plasmids were performed in endothelial cells (ECs). RUNX1 expression was significantly correlated with inflammation, fibrosis and NASH activity score in NASH patients. Its expression was conspicuous in liver non-parenchymal cells. In vitro, factors from steatotic hepatocytes and/or VEGF or TGF-β significantly induced the expression of RUNX1 in ECs. RUNX1 regulated the expression of angiogenic and adhesion molecules in ECs, including CCL2, PECAM1 and VCAM1, which was shown by silencing or over-expression of RUNX1. Furthermore, RUNX1 increased the angiogenic activity of ECs. This study reports that steatosis-induced RUNX1 augmented the expression of adhesion and angiogenic molecules and properties in ECs and may be involved in enhancing inflammation and disease severity in NASH.

Highlights

  • Non-alcoholic fatty liver disease (NAFLD) includes a wide compass of liver pathologies, ranging from simple steatosis, usually a mild, benign and non-progressive condition, to non-alcoholic steatohepatitis (NASH), which may progress to liver cirrhosis and hepatocellular carcinomaCells 2019, 8, 1277; doi:10.3390/cells8101277 www.mdpi.com/journal/cells (HCC)

  • Among the confirmed DEGs, we found transcription factor RUNX1, quite recently described to regulate stellate cell activation in NASH [14], and known targets of RUNX1 comprised of CCL2, NOS3, PI3KCA and PRKCE

  • Hypothesizing the role of RUNX1 in endothelial cell mediated inflammation and leukocyte infiltration, we evaluated the expression of adhesion molecules and chemotactic factor CCL2 in human umbilical vein endothelial cells (HUVECs)

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Summary

Introduction

Non-alcoholic fatty liver disease (NAFLD) includes a wide compass of liver pathologies, ranging from simple steatosis, usually a mild, benign and non-progressive condition, to non-alcoholic steatohepatitis (NASH), which may progress to liver cirrhosis and hepatocellular carcinomaCells 2019, 8, 1277; doi:10.3390/cells8101277 www.mdpi.com/journal/cells (HCC). Non-alcoholic fatty liver disease (NAFLD) includes a wide compass of liver pathologies, ranging from simple steatosis, usually a mild, benign and non-progressive condition, to non-alcoholic steatohepatitis (NASH), which may progress to liver cirrhosis and hepatocellular carcinoma. Several cellular and molecular events conspire and collaborate to transform simple steatosis to NASH to HCC. Some of the newly emerging concepts include iron overload, inflammation, dysregulated fat metabolism, oxidative stress, gut microbiota and angiogenesis [2]. Angiogenesis or new blood vessel formation is a crucial aspect of inflammation and a critical step in tissue damage, healing, and vascular remodeling. Changes in liver vascular architecture have been linked to the progression of fibrosis, cirrhosis and HCC in chronic liver diseases (CLD) [3,4]

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