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携带有 W4P 突变的 preS1 区的完整乙肝病毒基因组的转基因小鼠中病毒载量、炎症和肝损伤的性别差异。

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.

机构信息

Department of Microbiology and Immunology, Biomedical Sciences, Liver Research Institute and Cancer Research Institute, Seoul National University, College of Medicine, Seoul 110799, South Korea.

出版信息

World J Gastroenterol. 2018 Mar 14;24(10):1084-1092. doi: 10.3748/wjg.v24.i10.1084.

DOI:10.3748/wjg.v24.i10.1084
PMID:29563753
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5850128/
Abstract

AIM

To study sex disparity in susceptibility to hepatocellular carcinoma (HCC), we created a transgenic mouse model that expressed the full hepatitis B virus (HBV) genome with the W4P mutation.

METHODS

Transgenic 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), interleukin (IL)-6, and the liver enzymes alanine aminotransferase (ALT) and aspartate transaminase (AST), as well as liver histopathological features in male and female transgenic (W4P TG) mice and in nontransgenic littermates of 10 mo of age.

RESULTS

W4P TG males exhibited more pronounced hepatomegaly, significantly increased granule generation in liver tissue, elevated HBsAg expression in the liver and serum, and higher serum ALT and IL-6 levels compared to W4P TG females or littermate control groups.

CONCLUSION

Together, our data indicate that the W4P mutation in preS1 may contribute to sex disparity in susceptibility to HCC by causing increased HBV virion replication and enhanced IL-6-mediated inflammation in male individuals. Additionally, our transgenic mouse model that expresses full HBV genome with the W4P mutation in preS1 could be effectively used for the studies of the progression of liver diseases, including HCC.

摘要

目的

为了研究乙型肝炎病毒（HBV）全基因组 W4P 突变型转基因小鼠模型在易感性方面的性别差异，我们构建了该模型。

方法

通过将 pHY92-1.1x-HBV-full 基因组质粒（基因型 A2）转入 C57Bl/6N 小鼠，得到转基因小鼠。我们比较了 10 月龄雄性和雌性转基因（W4P TG）小鼠及其同窝非转基因对照小鼠的血清乙型肝炎表面抗原（HBsAg）、白细胞介素（IL）-6、丙氨酸转氨酶（ALT）和天冬氨酸转氨酶（AST）水平，以及肝组织病理学特征。

结果

与 W4P TG 雌性小鼠或同窝非转基因对照组相比，W4P TG 雄性小鼠表现出更为显著的肝肿大，肝组织中颗粒生成显著增加，肝和血清中 HBsAg 表达升高，血清 ALT 和 IL-6 水平升高。

结论

综上所述，我们的数据表明，前 S1 区 W4P 突变可能通过增加 HBV 病毒粒子复制和增强雄性个体中 IL-6 介导的炎症，导致 HCC 易感性的性别差异。此外，我们构建的表达前 S1 区 W4P 突变的 HBV 全基因组的转基因小鼠模型可有效用于研究包括 HCC 在内的肝脏疾病的进展。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3fbe/5850128/044c46f91054/WJG-24-1084-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3fbe/5850128/faa9f238c099/WJG-24-1084-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3fbe/5850128/e1c3a42b3143/WJG-24-1084-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3fbe/5850128/5a29f9262bb8/WJG-24-1084-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3fbe/5850128/f0a65d3e389d/WJG-24-1084-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3fbe/5850128/94df52306733/WJG-24-1084-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3fbe/5850128/044c46f91054/WJG-24-1084-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3fbe/5850128/faa9f238c099/WJG-24-1084-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3fbe/5850128/e1c3a42b3143/WJG-24-1084-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3fbe/5850128/5a29f9262bb8/WJG-24-1084-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3fbe/5850128/f0a65d3e389d/WJG-24-1084-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3fbe/5850128/94df52306733/WJG-24-1084-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3fbe/5850128/044c46f91054/WJG-24-1084-g006.jpg

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