戊型肝炎病毒感染引起的肝纤维化中Agap2的表达变化

Changes in Agap2 expression in hepatic fibrosis induced by hepatitis E virus infection

摘要:

目的 探究戊型肝炎病毒(hepatitis E virus, HEV)感染后肝脏纤维化进程中具有GTP结合蛋白样结构域、锚蛋白重复序列和PH结构域2的Arf GAP (ArfGAP with GTPase domain, ankyrin repeat and PH domain 2, Agap2)的表达变化，并初步探究HEV慢性化感染与Agap2表达之间的关联。方法 通过尾静脉接种HEV构建HEV感染的BALB/c小鼠模型，并进行全转录组测序。利用免疫组化、免疫荧光和实时荧光定量PCR方法检测感染HEV的BALB/c小鼠肝脏中HEV感染情况及Agap2表达情况。结果 研究发现HEV感染后Agap2表达显著上升(24 hpi感染组P=0.000 3，48 hpi感染组P=0.001 9)。HEV慢性化感染会导致小鼠肝纤维化发生，且经检测发现小鼠肝脏中Agap2的表达与HEV病毒载量呈正相关(r=0.797 4，P<0.000 1)。通过体外实验同样发现，Agap2在HEV感染的Huh 7.5.1 (r=0.968 3，P=0.002 4)和LX-2 (r=0.683 5，P=0.006 5)细胞系中表达呈上调趋势，与HEV病毒载量呈正相关。结论 本研究表明，在HEV慢性化感染后肝脏纤维化进程中Agap2的表达与HEV病毒载量呈正相关，Agap2可能是治疗HEV感染中肝纤维化的潜在新分子靶标。

Abstract:

Objective To investigate changes in ArfGAP with GTPase domain, ankyrin repeat and PH domain 2 (Agap2) expression during hepatic fibrosis progression following hepatitis E virus (HEV) infection and preliminarily explore the association between chronic HEV infection and Agap2 expression.Methods A BALB/c mouse model of HEV infection was established through inoculation in tail vein and subjected to RNA sequencing. HEV infection and Agap2 expression in the liver tissue were detected via immunohistochemistry, immunofluorescence assay, and real-time qPCR.Results Agap2 expression was upregulated following HEV infection (24 hpi group: P=0.000 3, 48 hip group: P=0.001 9). Chronic HEV infection induced hepatic fibrosis in mice, and Agap2 expression in the mouse liver was positively correlated with HEV load (r=0.797 4, P<0.000 1). Similarly, in vitro experiments demonstrated that Agap2 expression was upregulated in HEV-infected Huh 7.5.1 cells (r=0.968 3, P=0.002 4) and LX-2 cells (r=0.683 5, P=0.006 5), showing a positive correlation with HEV load.Conclusion The results demonstrate that Agap2 expression is positively correlated with HEV load during hepatic fibrosis progression after chronic HEV infection. Agap2 may serve as a potential molecular target for the treatment of HEV-associated hepatic fibrosis.