PDF(Pubmed)
Abstract：
Hepatitis C virus (HCV) is an oncogenic virus that causes chronic liver disease in more than 80% of patients. During the last decade, efficient direct-acting antivirals were introduced into clinical practice. However, clearance of the virus does not reduce the risk of end-stage liver diseases to the level observed in patients who have never been infected. So, investigation of HCV pathogenesis is still warranted. Virus-induced changes in cell metabolism contribute to the development of HCV-associated liver pathologies. Here, we studied the impact of the virus on the metabolism of polyamines and proline as well as on the urea cycle, which plays a crucial role in liver function. It was found that HCV strongly suppresses the expression of arginase, a key enzyme of the urea cycle, leading to the accumulation of arginine, and up-regulates proline oxidase with a concomitant decrease in proline concentrations. The addition of exogenous proline moderately suppressed viral replication. HCV up-regulated transcription but suppressed protein levels of polyamine-metabolizing enzymes. This resulted in a decrease in polyamine content in infected cells. Finally, compounds targeting polyamine metabolism demonstrated pronounced antiviral activity, pointing to spermine and spermidine as compounds affecting HCV replication. These data expand our understanding of HCV\'s imprint on cell metabolism.
摘要：
丙型肝炎病毒（HCV）是一种致癌病毒，在80％以上的患者中引起慢性肝病。在过去的十年里，有效的直接作用抗病毒药物被引入临床实践.然而,清除病毒不会将终末期肝病的风险降低到从未感染过的患者的水平。所以,HCV发病机制的研究仍有必要。病毒诱导的细胞代谢变化有助于HCV相关肝脏病变的发展。这里,我们研究了病毒对多胺和脯氨酸代谢以及尿素循环的影响，这对肝功能起着至关重要的作用。发现HCV强烈抑制精氨酸酶的表达，尿素循环的关键酶，导致精氨酸的积累，并上调脯氨酸氧化酶，同时脯氨酸浓度降低。外源脯氨酸的添加适度地抑制了病毒复制。HCV上调转录，但抑制多胺代谢酶的蛋白质水平。这导致感染细胞中多胺含量降低。最后,靶向多胺代谢的化合物表现出明显的抗病毒活性，指出精胺和亚精胺是影响HCV复制的化合物。这些数据扩大了我们对HCV对细胞代谢的影响的理解。
