Pathological impact of hepatitis B virus surface proteins on the liver is associated with the host genetic background.
Pathological impact of hepatitis B virus surface proteins on the liver is associated with the host genetic background.
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DOI：
10.1371/journal.pone.0090608
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Roeb E
中科院分区：
文献类型：
--
作者：
Churin Y;Roderfeld M;Stiefel J;Würger T;Schröder D;Matono T;Mollenkopf HJ;Montalbano R;Pompaiah M;Reifenberg K;Zahner D;Ocker M;Gerlich W;Glebe D;Roeb E
虽然B型肝炎病毒（HBV）感染引起的免疫发病机制已被广泛研究，但对HBV表面蛋白的直接致病作用知之甚少。在这里，我们研究了HBV表面蛋白在不同遗传背景的转基因小鼠肝脏中表达的病理细胞效应。在两种小鼠品系BALB/c和C57 BL/6中研究了HBV表面蛋白表达对肝脏的影响。组织学和羟脯氨酸测定进行了研究肝脏形态和纤维化。通过微阵列、qPCR和Western印迹分析基因表达和信号传导。HBV表面蛋白在转基因小鼠肝脏中的表达诱导蛋白激酶样内质网激酶（PERK）和真核起始因子2α（eIF 2 α）磷酸化的激活。与C57 BL/6背景的转基因小鼠相比，eIF 2 α磷酸化导致ER应激标志物葡萄糖调节蛋白（GRP）78和促凋亡C/EBP同源蛋白（CHOP）在BALB/c遗传背景的转基因小鼠中活化，导致更严重的肝损伤和纤维化。肝星状细胞是HBV转基因小鼠主要的胶原生成细胞。肝细胞增殖的关键调节因子c-Jun和STAT 3在HBV转基因小鼠中被激活。转基因小鼠的肿瘤发病率是品系和性别依赖性的。由肝HBV表面蛋白表达诱导的肝损伤、纤维化和肿瘤发展的程度在很大程度上取决于宿主的遗传背景。
While the immune pathogenesis caused by hepatitis B virus (HBV) infection has been studied extensively, little is known about direct pathogenic effects of HBV surface proteins. Here, we have investigated pathological cellular effects of HBV surface protein expression in the liver of transgenic mice with different genetic background. The impact of HBV surface protein expression on the liver was studied in two mouse strains, BALB/c and C57BL/6. Histology and hydroxyproline assays were performed to investigate liver morphology and fibrosis. Gene expression and signaling were analyzed by microarray, qPCR and Western blotting. Expression of HBV surface proteins in the liver of transgenic mice induced activation of protein kinase-like endoplasmic reticulum kinase (PERK) and eukaryotic initiation factor 2α (eIF2α) phosphorylation. Phosphorylation of eIF2α resulted in activation of the ER stress markers glucose regulated protein (GRP) 78 and pro-apoptotic C/EBP homologous protein (CHOP) in transgenic mice on BALB/c genetic background leading to stronger liver injury and fibrosis in comparison with transgenic mice on C57BL/6 background. Hepatic stellate cells represented the main collagen-producing liver cells in HBV transgenic mice. The key regulators of hepatocyte proliferation, transcription factors c-Jun and STAT3 were activated in HBV transgenic mice. Tumour incidence in transgenic mice was strain- and sex-dependent. Extent of liver injury, fibrosis, and tumour development induced by hepatic HBV surface protein expression considerably depends on host genetic background.
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影响因子：
25.7
作者：
Malhi, Harmeet;Kaufman, Randal J.
通讯作者：
Kaufman, Randal J.
影响因子：
29.4
作者：
LAU, JYN;BAIN, VG;WILLIAMS, R
通讯作者：
WILLIAMS, R
影响因子：
64.5
作者：
CHISARI, FV;KLOPCHIN, K;PALMITER, RD
通讯作者：
PALMITER, RD
影响因子：
3.2
作者：
Lee, Ursula E.;Friedman, Scott L.
通讯作者：
Friedman, Scott L.
影响因子：
21.3
作者：
Min, Lihua;Ji, Yuan;Wagner, Erwin F.
通讯作者：
Wagner, Erwin F.