Basic Study
Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Nov 21, 2016; 22(43): 9534-9543
Published online Nov 21, 2016. doi: 10.3748/wjg.v22.i43.9534
Hepatitis B virus upregulates host expression of α-1,2-mannosidases via the PPARα pathway
Song Hu, Li-Bin Jiang, Xiao-Jing Zou, Wei Yi, De-Ying Tian
Song Hu, Li-Bin Jiang, Xiao-Jing Zou, Wei Yi, De-Ying Tian, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
Author contributions: Hu S and Tian DY designed the research; Hu S, Jiang LB, Zou XJ and Yi W performed the research; Tian DY contributed new reagents/analytic tools; Hu S, Jiang LB and Tian DY analyzed the data; Hu S and Tian DY wrote the paper.
Supported by the National Natural Science Foundation of China, No. 81171559.
Institutional review board statement: The study was reviewed and approved by the Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Institutional Review Board.
Conflict-of-interest statement: All authors declare that they have 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: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: De-Ying Tian, PhD, Professor, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1037 Luoyu Road, Wuhan 430030, Hubei Province, China. dytian@tjh.tjmu.edu.cn
Telephone: +86-130-18047239 Fax: +86-21-64085875
Received: August 24, 2016
Peer-review started: August 24, 2016
First decision: September 6, 2016
Revised: September 20, 2016
Accepted: October 19, 2016
Article in press: October 19, 2016
Published online: November 21, 2016
Processing time: 86 Days and 5.8 Hours
Abstract
AIM

To assess the effects of hepatitis B virus (HBV) on the expression of host α-1,2-mannosidases and determine the underlying mechanisms.

METHODS

We measured the expression levels of MAN1A1, MAN1A2, MAN1B1, and MAN1C1 in cell lines HepG2.2.15, HepN10, HepAD38 and HepG2 by Western blot. Viral antigens (HBsAg and HBeAg) in the culture medium were measured using the chemiluminescence method. HBV DNA quantification assays were performed using a commercial real-time PCR kit. Protein levels of human liver tissue α-1,2-mannosidases were also evaluated by Western blot. Plasmids containing seven individual viral genes of HBV (PTT22-HBx, PTT22-HBs, PTT22-preS2, PTT22-preS1, PTT22-HBc, PTT22-HBe, and PTT22-HBp) or control plasmids (PTT22-vector) were transfected into HepG2 cells. MK886 (PPARα) and GW9662 (PPARγ) inhibitors were used to explore the effects of HBV on α-1,2-mannosidase expression after the PPARα and PPARγ pathways were blocked.

RESULTS

We showed that the expression of α-1,2-mannosidases was higher in stably transfected HBV cells than in controls. The expression levels of α-1,2-mannosidase were higher in AD38 cells than those in ND10 cells, which were in turn greater than those in G2.2.15 cells, and positively correlated with the expression of HBsAg in all the cell lines. Levels of α-1,2-mannosidase in non-tumorous liver tissues of HBV-related HCC patients were also higher than in the tissues from non-HBV-related HCC patients. Moreover, transfecting HepG2 cells with a component of the HBV viral envelope also increased the expression of α-1,2-mannosidases. However, this envelope protein component could not induce MAN1C1 expression in the presence of a PPARα inhibitor, MK886. We also found that MK886 did not affect the expression of MAN1C1 in AD38 cells without tetracycline in the culture medium. This phenomenon was not observed in the case of GW9662.

CONCLUSION

Our results indicate that HBV increases the expression of α-mannosidases both in vitro and in vivo via activation of the PPARα pathway by its envelope protein.

Keywords: Hepatitis B; Pattern recognition receptors; α-Mannosidase; Glycosylation; Dendritic cells

Core tip: To date, few studies have investigated whether hepatitis B virus (HBV) hijacks the host hepatocyte’s demannosylation system to trim the mannose oligosaccharides found on its viral envelope, thereby evading DC-SIGN recognition. Our study showed that HBV could increase the expression of α-mannosidase I both in vitro and in vivo. Moreover, the HBV envelope protein increases the expression of α-mannosidase I via the PPARα pathway. Therefore, α-mannosidase I may be a novel drug target to inhibit the demannosylation of HBV, and prevent viral escape.