人胆汁淤积肝胆酸转运蛋白OAPT-H表达降低的生物学意义及其调控机制研究

胆汁淤积常致肝损伤、肝纤维化乃至肝衰竭。目前认为胆酸转运蛋白在胆汁淤积的发生过程中起重要作用。胆酸摄取泵OATP-H对毒性胆酸有较高摄取率，我们首次发现OATP-H在胆汁淤积肝脏中明显低表达：提示其低表达可能具有肝脏保护作用。目前其生物学意义及调控机制未见报道。预实验后发现:TNFa能够下调OATP-H表达、且可能激活mTOR信号通路，OATP-H启动子区存在AP1/ASCL1结合位点，文献报道，mTOR信号通路参与调控AP1/ASCL1。故提出假设：胆汁淤积下血浆TNFa水平增高可能激活mTOR信号通路，通过AP1/ASCL1下调OATP-H的表达，从而降低毒性胆酸摄取，达到保护肝脏的目的。本课题拟运用运用基因敲除、原代肝细胞等技术，明确胆汁淤积下OATP-H表达下调对肝脏的保护作用及其调控的分子机制。这将为胆汁淤积临床治疗提供新的线索和理论支持。

Cholestasis often causes liver damage, liver fibrosis and even liver failure. It is currently believed that bile acid transporter plays an important role in the development of cholestasis. The bile acid uptake pump OATP-H has a higher uptake rate for toxic bile acid. We have found for the first time that OATP-H is significantly lower in cholestasis liver: suggesting that its low expression may have liver protective effects. At present, its biological significance and regulatory mechanism have not been reported. Early preliminary experiments found that TNFa can down-regulate OATP-H expression and may activate the mTOR signaling pathway. There is an AP1/ASCL1 binding site in the OATP-H promoter region. Therefore, we hypothesized that increased plasma TNFa levels under cholestasis may activate the mTOR signaling pathway and down-regulate OATP-H expression through AP1/ASCL1, thereby reducing toxic bile acid uptake, reducing hepatocyte damage, and protecting the liver. This project intends to use gene knockout, Chip, in vitro transcription and other technologies to clarify the protective effect of OATP-H downregulation on the liver under cholestasis and the molecular mechanism of its regulation. This will provide new clues and theoretical support for the clinical treatment of cholestasis.