Basic Study
Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Mar 14, 2018; 24(10): 1084-1092
Published online Mar 14, 2018. doi: 10.3748/wjg.v24.i10.1084
Sex disparity in viral load, inflammation and liver damage in transgenic mice carrying full hepatitis B virus genome with the W4P mutation in the preS1 region
Seoung-Ae Lee, So-Young Lee, Yu-Min Choi, Hong Kim, Bum-Joon Kim
Seoung-Ae Lee, So-Young Lee, Yu-Min Choi, Hong Kim, Bum-Joon Kim, Department of Microbiology and Immunology, Biomedical Sciences, Liver Research Institute and Cancer Research Institute, Seoul National University, College of Medicine, Seoul 110799, South Korea
Author contributions: Kim BJ conceived this research and participated in its design and coordination; Lee SA performed the experiments; Lee SY, Choi YM and Kim H analyzed and interpreted the data; Kim BJ contributed the reagents, materials and analysis tools.
Supported by the Korea Health Technology R&D Project through the Korea Health Industry Development Institute and the Ministry of Health and Welfare, South Korea, No. HI14C0955.
Conflict-of-interest statement: There was no conflict of interest.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Correspondence to: Bum-Joon Kim, PhD, Professor, Department of Biomedical Sciences, Microbiology and Immunology, and Liver Research Institute, Seoul National University College of Medicine, 103, Daehak-ro, Jongno-gu, Seoul 110799, South Korea.
Telephone: +82-2-7408316 Fax: +82-2-7430881
Received: January 11, 2018
Peer-review started: January 11, 2018
First decision: January 25, 2018
Revised: January 31, 2018
Accepted: February 9, 2018
Article in press: February 9, 2018
Published online: March 14, 2018
Research background

A remarkable global epidemiological feature of hepatocellular carcinoma (HCC) is its higher incidence in males. Recently, we identified the novel W4P substitution in the preS1 region of hepatitis B virus (HBV) related to HCC that occurs exclusively in male patients. We have also shown that the W4P mutation likely contributed to HCC development, particularly in male patients, in an interleukin (IL)-6-dependent manner.

Research motivation

Studies of sex disparity in the susceptibility to HCC in vivo have mainly utilized the chemical agent diethylnitrosamine to induce HCC in mice. However, no transgenic (TG) mouse model system expressing the full HBV genome has yet been available for the study of sex disparity in HBV-related liver diseases.

Research objectives

To gain further insight into the role of the W4P mutation in the preS1 region of HBV on sex disparity of HBV-induced liver inflammatory manifestations, we created a TG mouse that carried the full HBV genome with this mutation and evaluated HBV virion replication and IL-6-mediated inflammation in mutant and wild-type (WT) mice of both sexes.

Research methods

TG mice were generated by transferring the pHY92-1.1x-HBV-full genome plasmid (genotype A2) into C57Bl/6N mice. We compared serum levels of hepatitis B surface antigen (HBsAg), IL-6, and the liver enzymes alanine aminotransferase (ALT) and aspartate transaminase (AST), as well as liver histopathology features in male and female W4P TG mice and their WT littermates.

Research results

Our data showed significantly increased hepatomegaly, enhanced granule generation in liver tissue, higher HBsAg expression in the liver and serum, and higher serum ALT and IL-6 levels in W4P TG males compared to the values of these parameters in W4P TG females or littermate control groups.

Research conclusions

This is the first study that used TG mice to uncover the role of the W4P mutation in HBV preS1 in sex disparity of liver disease progression due to concomitantly increased HBV virion replication and greater IL-6-mediated inflammation in male individuals.

Research perspectives

The obtained results suggest that W4P TG mice developed in this study could be effectively used not only for the basic research into the mechanisms of HBV-associated liver diseases, including HCC, but also for screening antiHBV and antiinflammatory drugs.