TGF-β1- CD147正反馈环路调控肝星状细胞糖代谢的分子机制研究

The activation of hepatic stellate cells (HSCs) is the core event of liver fibrosis. The hepatic fibrosis microenvironment always leads to hypoxia of the HSCs around the sinusoids. Simultaneously, the HSCs show a strong ability to activate and proliferate, which requires sufficient energy. Cellular aberrant glucose metabolism might be a novel aspect in the pathogenesis study of liver fibrosis. Recent research proved that CD147 enhanced cell proliferation ability by promoting glycolysis. TGF-β1 is closely related to hedgehog pathway, which is vital in glycolysis regulation. Our preliminary study showed that TGF-β1 regulated CD147 transcriptional expression through Smads signaling, and CD147 activated HSC. CD147 over-expression significantly promoted the HSC glycolysis. Thus, this project is aimed to investigate the molecular mechanism of CD147 promoting glycolysis in HSC activation by conducting the following: (1) the expression and function of CD147 in HSC activation, (2) the molecular mechanisms of TGF-β1-CD147 positive feedback loop, (3) whether or not the TGF-β1-CD147 positive feedback loop promotes HSC glycolysis through hedgehog pathway. This project will provide a strong basis for novel molecular mechanisms of HSC activation and put forward novel targets for the development of new analgesics in clinical treatment of liver fibrosis.

肝星状细胞（HSC）活化是肝纤维化发病的核心事件。肝纤维化时HSC处于缺氧缺能供的微环境，但又需要充足能量维持其活化及高增殖状态，因此糖代谢异常改变成为研究HSC活化的新视角。近期研究证实，CD147通过促进糖酵解增强细胞增殖能力，Hedghog通路对糖代谢具有关键调控作用，而TGF-β1与Hedghog通路密切相关。我们的预实验结果显示：CD147可以促进HSC活化；TGF-β1通过Smad调控CD147的转录表达；过表达CD147促进HSC糖酵解。因此，本项目拟聚焦于CD147促进HSC糖代谢从而导致其活化的分子机制，研究：①CD147在HSC活化中的表达和作用；②TGF-β1-CD147正反馈环路的分子机制；③TGF-β1-CD147正反馈环路是否通过Hedghog途径调控HSC糖代谢。本项目将为揭示HSC活化机制开辟新思路，并为研发临床抗纤维化新药提供科学依据。

肝纤维化是一种严重影响患者生存质量及生命安全的慢性疾病。肝星状细胞（HSC）活化是肝纤维化发生发展的中心环节。在以往的研究中CD147在肝纤维化的病理过程中发挥了重要作用，但具体分子机制尚未阐明。本项目聚焦于CD147促进HSC糖代谢从而导致其活化的分子机制，通过体外体内实验证实了：①CD147在HSC中高表达并促进了HSC的活化； ②CD147通过有氧糖酵解介导HSC活化；③CD147通过调控Hedgehog信号通路介导糖酵解，从而促进HSC活化。本项目丰富了HSC活化的机制，并为研发临床抗纤维化新药提供新的思路及实验数据。