Relevance of reactive oxygen species in liver disease observed in transgenic mice expressing the hepatitis B virus X protein

Dae-Yeul Yu

doi:10.1186/s42826-020-00037-1

Abstract

The hepatitis B virus (HBV) infects approximately 240 million people worldwide, causing chronic liver disease (CLD) and liver cancer. Although numerous studies have been performed to date, unfortunately there is no conclusive drug or treatment for HBV induced liver disease. The hepatitis B virus X (HBx) is considered a key player in inducing CLD and hepatocellular carcinoma (HCC). We generated transgenic (Tg) mice expressing HBx protein, inducing HCC at the age of 11–18 months. The incidence of histological phenotype, including liver tumor, differed depending on the genetic background of HBx Tg mice. Fatty change and tumor generation were observed much earlier in livers of HBx Tg hybrid (C57BL/6 and CBA) (HBx-Tg hybrid) mice than in HBx Tg C57BL/6 (HBx-Tg B6) mice. Inflammation was also enhanced in the HBx-Tg B6 mice as compared to HBx-Tg hybrid mice. HBx may be involved in inducing and promoting hepatic steatosis, glycemia, hepatic fibrosis, and liver cancer. Reactive oxygen species (ROS) generation was remarkably increased in livers of HBx Tg young mice compared to young wild type control mice. Previous studies on HBx Tg mice indicate that the HBx-induced ROS plays a role in inducing and promoting CLD and HCC.

Highlights

The hepatitis B virus (HBV) infection is prevalent worldwide, causing liver disease and liver cancer
Ahodantin et al [55] examined whether HBV X (HBx) promotes liver fibrosis in full length (FL)-HBx Tg mice treated with Carbon tetrachloride (CCl4), and observed that FL-HBx expression alters hepatocyte proliferation and potentiates CCl4-induced liver fibrosis, with increasing expression of inflammatory cytokines (TNFα, TGF-β) and proteins (Collagen1a, α-Sma, PdgfR-β, MMP-13) involved in the epithelial mesenchymal transition (EMT), and severity of liver disease
HBx Tg mice inducing hepatocellular carcinoma (HCC) were generated by microinjecting the X-gene construct with the HBV-X gene under authentic promoter

Summary

Introduction

The hepatitis B virus (HBV) infection is prevalent worldwide, causing liver disease and liver cancer. The HBV X (HBx) gene encodes a 16.5-kd protein (HBxAg) having multiple functions, including signal transduction, transcriptional activation, DNA repair, cell cycle control, and inhibition of protein degradation [3–6]. High levels of HBV replication are suggested to be correlated with the progression of chronic liver disease (CLD) to hepatocellular carcinoma (HCC) [7]. Fragments of HBV DNA, mostly encoding the HBx, become integrated at multiple sites within the host DNA [8] These integration events result in enhancing the intrahepatic expression levels of HBx that alter patterns of host gene expression. The relationship of HBx expression to disease severity is consistent with the idea that when the liver regenerates, fragments of HBV DNA encoding the HBx region increasingly integrate into multiple regions of the host genome during normal host DNA replication, resulting in increasing accumulation of intrahepatic HBx with CLD progression [26]. Persistent inflammation in a chronically damaged liver may result in the development of HCC, despite low levels or undetectable levels of virus replication [26]

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