乙型肝炎表面抗原激活未折叠蛋白反应形成慢性乙型肝炎的

StephenW

Viruses. 2019 Apr 25;11(4). pii: E386. doi: 10.3390/v11040386.
Hepatitis B Surface Antigen Activates Unfolded Protein Response in Forming Ground Glass Hepatocytes of Chronic Hepatitis B.
Li Y1,2, Xia Y3, Cheng X4, Kleiner DE5, Hewitt SM6, Sproch J7, Li T8, Zhuang H9, Liang TJ10.
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Abstract

Ground glass hepatocytes (GGHs), a histological hallmark of chronic hepatitis B virus (HBV) infection, contain excessive hepatitis surface antigen (HBsAg) in the endoplasmic reticulum (ER), which is linked to unfolded protein response (UPR). The mechanism by which HBV activates UPR has not been fully defined. To investigate this, HepG2-NTCP cells and primary human hepatocytes (PHHs) were either infected with HBV or transduced with adenoviral vectors expressing replication-competent HBV genome or individual HBV genes. UPR markers were evaluated by qPCR, Western blotting, and immunofluorescence. Apoptosis and cell viability were measured by Caspase-3/7 and ATPlite assay respectively. We found that UPR markers were induced by the overexpression of HBsAg in HepG2-NTCP cells and PHHs. Elevation of UPR-induced genes showed a dose-dependent correlation with HBsAg levels. In HBV-infected livers, GGHs also demonstrated excessive accumulation of HBsAg associated with increased BIP/GRP78 staining, a marker of UPR. Prolonged activation of UPR by HBsAg overexpression induced signs of apoptosis. Overexpression of HBsAg can induce ER stress through protein kinase RNA-like endoplasmic reticulum kinase (PERK) pathway in vitro, and may be linked to the appearance of GGHs. The activation of UPR by HBsAg may sensitize hepatocytes to cell death and result in possible subsequent cellular changes leading to a premalignant phenotype.
KEYWORDS:

apoptosis; chronic hepatitis B; endoplasmic reticulum stress; ground glass hepatocyte; hepatocellular carcinoma; liver disease

PMID:
    31027244
DOI:
    10.3390/v110403

StephenW

病毒。 2019年4月25日; 11（4）。 pii：E386。 doi：10.3390 / v11040386。
乙型肝炎表面抗原激活未折叠蛋白反应形成慢性乙型肝炎的磨玻璃肝细胞。
Li Y1,2，Xia Y3，Cheng X4，Kleiner DE5，Hewitt SM6，Sproch J7，Li T8，庄H9，梁TJ10。
作者信息
抽象

地面玻璃肝细胞（GGHs）是慢性乙型肝炎病毒（HBV）感染的组织学标志，在内质网（ER）中含有过量的肝炎表面抗原（HBsAg），其与未折叠蛋白反应（UPR）相关。 HBV激活UPR的机制尚未完全确定。为了研究这一点，HepG2-NTCP细胞和原代人肝细胞（PHH）被HBV感染或用表达复制能力的HBV基因组或个体HBV基因的腺病毒载体转导。通过qPCR，Western印迹和免疫荧光评估UPR标志物。分别通过Caspase-3/7和ATPlite测定法测量细胞凋亡和细胞活力。我们发现UPR标志物是由HepG2-NTCP细胞和PHHs中HBsAg的过表达诱导的。 UPR诱导基因的升高显示出与HBsAg水平的剂量依赖性相关性。在HBV感染的肝脏中，GGH还表现出与增加的BIP / GRP78染色相关的HBsAg过量积累，这是UPR的标志。 HBsAg过度表达导致UPR的长时间激活诱导细胞凋亡的迹象。 HBsAg的过度表达可通过体外蛋白激酶RNA样内质网激酶（PERK）途径诱导ER应激，并可能与GGH的出现有关。 HBsAg对UPR的激活可使肝细胞对细胞死亡敏感，并导致可能的后续细胞变化，导致癌前表型。
关键词：

细胞凋亡;慢性乙型肝炎;内质网应激;磨玻璃肝细胞;肝细胞癌;肝病

结论：
    31027244
DOI：
    10.3390 / v110403

StephenW

https://www.mdpi.com/1999-4915/11/4/386/pdf