Basic Study
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jun 14, 2015; 21(22): 6872-6883
Published online Jun 14, 2015. doi: 10.3748/wjg.v21.i22.6872
Induction of endoplasmic reticulum-derived oxidative stress by an occult infection related S surface antigen variant
In-Kyung Lee, Seoung-Ae Lee, Hong Kim, You-Sub Won, Bum-Joon Kim
In-Kyung Lee, Seoung-Ae Lee, Hong Kim, You-Sub Won, Bum-Joon Kim, Department of Microbiology and Immunology, Liver Research Institute, Cancer Research Institute and SNUMRC, College of Medicine, Seoul National University, Seoul 110-799, South Korea
Author contributions: Kim BJ conceived this research and participated in its design and coordination; Lee IK and Lee SA performed the experiments; Kim H, Lee SA, and Won YS analyzed and interpreted the data; Lee SA, Kim H, and Won YS contributed the reagents, materials, and analysis tools; Lee IK, Lee SA and Kim BJ wrote and reviewed the manuscript; Lee IK and Lee SA equally contributed to this research; all authors approved the final manuscript.
Supported by National Research Foundation of Korea grant funded by the Korea government (MEST), No. 2013-005810.
Conflict-of-interest: No conflict-of-interest.
Data sharing: 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: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Bum-Joon Kim, Professor, Department of Microbiology and Immunology, Liver Research Institute, Cancer Research Institute and SNUMRC, College of Medicine, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 110-799, South Korea. kbumjoon@snu.ac.kr
Telephone: +82-2-7408316 Fax: +82-2-7430881
Received: December 19, 2014
Peer-review started: December 21, 2014
First decision: January 8, 2015
Revised: January 28, 2015
Accepted: February 12, 2015
Article in press: February 13, 2015
Published online: June 14, 2015
Processing time: 181 Days and 3.6 Hours
Abstract

AIM: To investigate the mechanism of endoplasmic reticulum (ER) stress induction by an occult infection related hepatitis B virus S surface antigen (HBsAg) variant.

METHODS: We used an HBsAg variant with lower secretion capacity, which was a KD variant from a Korean subject who was occultly infected with the genotype C. We compared the expression profiles of ER stress-related proteins between HuH-7 cells transfected with HBsAg plasmids of a wild-type and a KD variant using Western blot.

RESULTS: Confocal microscopy indicated that the KD variant had higher levels of co-localization with ER than the wild-type HBsAg. The KD variant up-regulated ER stress-related proteins and induced reactive oxygen species (ROS) compared to the wild-type via an increase in calcium. The KD variant also down-regulated anti-oxidant proteins (HO-1, catalase and SOD) compared to the wild-type, which indicates positive amplification loops of the ER-ROS axis. The KD variant also induced apoptotic cell death via the up-regulation of caspase proteins (caspase 6, 9 and 12). Furthermore, the KD variant induced a higher level of nitric oxide than wild-type HBsAg via the up-regulation of the iNOS protein.

CONCLUSION: Our data indicate that occult infection related HBsAg variants can lead to ER-derived oxidative stress and liver cell death in HuH-7 cells.

Keywords: Endoplasmic reticulum oxidative stress; Hepatitis B virus; KD variant; Colocalization; Reactive oxidative species; Apoptotic cell death

Core tip: The molecular mechanisms underlying the relationships between occult hepatitis B virus infection and liver disease progression remain a mystery. The present study demonstrated that the HBsAg variant KD, which exhibits a secretion defective phenotype, universally induced endoplasmic reticulum (ER) stress pathways in hepatocytes. This induction of ER stress may evoke ER stress-mediated biological actions that induce liver damaging processes, including ROS production, nitric oxide production, and apoptosis induction. In conclusion, occult infection related to hepatitis B virus S surface antigen variants may play a very pivotal role in the progression of liver diseases primarily via ER-derived oxidative stress and apoptosis in hepatocytes.