核基质结合蛋白SATB1在乙型肝炎后肝纤维化发生中的作用及机制研究

It is well known that HBV chronic infection is one of the most common causes of liver fibrosis, but clearance of virus is considerably difficult. Hence, understanding the molecular mechanism of liver fibrosis development during the process of HBV chronic infection is of significant importance. A recent study showed that HBx can induce rat and human HSCs activation, and anti-TGFβ1 can interrupt this effect. Our study also confirmed that in the seven HBV-encoded proteins, HBx can upregulate TGFβ1 expression in liver cells and promote HSCs activation. However the special mechanism is still unclear. At the moment, TGFβ1 appears to be a key factor in liver fibrosis with diverse biological functions, which is not an ideal intervention target, thus a more specific intervention target in HBV-related pathogenesis is needed. Our further studies suggested that HBV induced SATB1 expression through HBx, and SATB1 participated in the HBx regulation of TGFβ1 and activation of HSCs, but the molecular mechanism by which HBV regulates and activates HSCs via the HBx-SATB1-TGFβ1 axis remains unknown. Therefore, we decided to investigate the role of SATB1 in the upregulation of TGFβ1 and the promotion of liver fibrosis by HBx in order to clarify the special mechanism of Hepatitis B-related liver fibrosis development.

HBV慢性感染是公认的导致肝纤维化的主要病因之一，明确HBV导致肝纤维化的分子机制是肝病研究的重大课题。新的研究发现，HBV能诱导人及大鼠HSCs活化。我们的预实验也证实，在七个HBV编码蛋白中，HBx能上调肝细胞中TGFβ1的表达并激活HSCs。但TGFβ1具有的广泛生物学效应，以它作为干预靶点并不理想，需要寻找更合适有效的干预靶点，探索更具有针对性的HBV相关的主要调控因子。本项目前期研究显示，HBV通过HBx上调SATB1。那么，在HBx存在的条件下，SATB1与TGFβ1之间有何联系？进一步预实验表明，SATB1参与了HBx对TGFβ1及HSCs活化的调控。但HBV通过HBx-SATB1-TGFβ1调控并活化HSC的分子机制不明。因此，本课题组拟在前期研究基础上，深入探讨SATB1在HBx上调TGFβ1及促肝纤维化形成中的意义，阐明HBV相关性肝纤维化发生的相关机制。

慢性乙型肝炎病毒（HBV）感染是肝硬化的主要病因之一。明确HBV导致肝纤维化的分子机制是肝病研究的重大课题。近年来研究发现，HBV能诱导人和大鼠肝星状细胞（HSCs）活化。我们的研究证实SATB1与HBV相关性肝纤维化病理相关，并发现HBx通过活化ERK/c-jun和JNK/c-jun信号通路上调SATB1表达。另一方面，我们阐明HBx通过SATB1诱导肝细胞表达促纤维化细胞因子IL-6、PDGF-AA、CTGF，从而激活HSCs活化和增殖的作用和机制。此外，我们在HBV转基因小鼠体内证实SATB1参与HBx促肝纤维化形成作用。本研究首次探索SATB1在乙肝相关性肝纤维化中的作用及分子机制，创新性证实肝细胞SATB1可通过分泌细胞因子促进HSCs活化和增殖这一现象，补充对慢性HBV感染在肝纤维化发病机制研究新的认识。