sEHi通过抑制EET降解促进雌激素减轻肝硬化的机制研究

It was found that liver cirrhosis is related to estrogen levels. Considering the low concentration of NO in the intrahepatic environment, and that estrogen has many limitations of clinical application, it is of great significance to explore the molecules with protective effects against cirrhosis and their mechanisms at the downstream of estrogen signaling. Our previous study found that soluble epoxy compound hydrolase inhibitors (sEHis) could inhibit EET hydrolysis and reduce the portal vein pressure. Its mechanism might be as follow: under NO-deficiency, estrogen may rely on its downstream effector EET to protect the liver. We hypothesize that sEHi can maintain the EET expression, which enhances the antioxidant capacity of liver cells on the one hand; and inhibits the hepatic stellate cells (HSC) activity through PPAR-γ on the other hand. Therefore, sEHis adjust the ratio balance of normal liver cells and HSC, and ultimately attenuate liver cirrhosis. This project aims to study the protective effects and mechanisms of sEHis on liver cirrhosis through blood, tissue, cell and animal levels, and to develop new therapeutic methods for cirrhosis patients.

已有研究发现肝硬化和雌激素水平相关，雌激素水平高者肝硬化的程度较轻，发病率也较少。但是目前单纯使用雌激素治疗或者其下游一氧化氮（NO）相关药物干预副作用大。而我们前期研究发现水溶性环氧化合物水解酶抑制剂（sEHi）可抑制环氧二十碳三烯酸（EET）水解，可降低大鼠门静脉压力，改善肝硬化，其原因可能在肝硬化肝内NO缺乏时，雌激素水平可依赖其下游物质EET稳定并保护肝环境。而sEHi是EET的水解酶抑制剂，因此我们推测sEHi可维持EET水平，一方面增强肝细胞的抗氧化能力，保持肝细胞活性；另一方面通过PPAR-γ抑制肝星状细胞（HSC）活性，调整正常肝细胞与HSC的数量平衡，从而降低肝硬化时肝内纤维化水平。本项目拟通过血液、组织、细胞及动物水平，研究sEHi对肝硬化的保护作用和机制，为肝硬化的治疗提供实际和理论依据。

已有研究发现肝硬化和雌激素水平相关，雌激素水平高者肝硬化的程度较轻，发病率也较少。但是目前单纯使用雌激素治疗或者其下游一氧化氮（NO）相关药物干预副作用大。而我们本项目通过血液、组织、细胞及动物水平，研究sEHi对肝硬化时肝脏的保护作用和机制，本实验发现肝内环境水溶性环氧化合物水解酶抑制剂（sEHi）可抑制环氧二十碳三烯酸（EET）水解，可降低大鼠门静脉压力，改善肝硬化，具体机制为一方面sEHi能够抑制肝细胞炎症及肝纤维化及减少肝细胞凋亡促进肝细胞增殖，减少氧化应激水平，另一方面通过PPAR-γ降低肝硬化时肝内纤维化水平。本实验为肝硬化的治疗提供实际和理论依据。