Hypoxic gene expression in chronic hepatitis B virus infected patients is not observed in state-of-the-art in vitro and mouse infection models

Sci Rep. 2020 Aug 24;10(1):14101. doi: 10.1038/s41598-020-70865-7.

Abstract

Hepatitis B virus (HBV) is the leading cause of hepatocellular carcinoma (HCC) worldwide. The prolyl hydroxylase domain (PHD)-hypoxia inducible factor (HIF) pathway is a key mammalian oxygen sensing pathway and is frequently perturbed by pathological states including infection and inflammation. We discovered a significant upregulation of hypoxia regulated gene transcripts in patients with chronic hepatitis B (CHB) in the absence of liver cirrhosis. We used state-of-the-art in vitro and in vivo HBV infection models to evaluate a role for HBV infection and the viral regulatory protein HBx to drive HIF-signalling. HBx had no significant impact on HIF expression or associated transcriptional activity under normoxic or hypoxic conditions. Furthermore, we found no evidence of hypoxia gene expression in HBV de novo infection, HBV infected human liver chimeric mice or transgenic mice with integrated HBV genome. Collectively, our data show clear evidence of hypoxia gene induction in CHB that is not recapitulated in existing models for acute HBV infection, suggesting a role for inflammatory mediators in promoting hypoxia gene expression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Cell Hypoxia / genetics*
  • Cell Hypoxia / physiology
  • Cell Line, Tumor
  • Disease Models, Animal
  • Female
  • Hep G2 Cells
  • Hepatitis B, Chronic / pathology*
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Hypoxia-Inducible Factor-Proline Dioxygenases / metabolism*
  • Liver / metabolism
  • Liver Cirrhosis / pathology
  • Liver Cirrhosis / virology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Oxidative Stress / physiology
  • Oxygen / metabolism
  • Trans-Activators / metabolism*
  • Viral Regulatory and Accessory Proteins / metabolism*

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Trans-Activators
  • Viral Regulatory and Accessory Proteins
  • hepatitis B virus X protein
  • endothelial PAS domain-containing protein 1
  • EGLN1 protein, human
  • Hypoxia-Inducible Factor-Proline Dioxygenases
  • Oxygen