雌激素通过维生素D受体途径抗肝纤维化的机制研究

Liver fibrosis is the common course associated with all the chronic liver disease, and there are apparent sex differences in the occurrence and development of liver fibrosis. Reports from our hepatitis cohort which were followed for several years found that post-menopause women and men were more likely to get liver fibrosis while there is no liver fibrosis occurred among women of childbearing age. Our results indicate that estrogen plays an important role for anti-fibrosis. However, how estrogen made this remains unknown. Recent studies have demonstrated that Vitamin D receptor (VDR) activation in HSCs inhibits liver fibrosis. Combined with bioinformatics analysis, we believe that VDR may play an important role in estrogen receptor signaling pathway which is anti-liver fibrosis. We aim to demonstrate weather estrogen up regulate expression of VDR gene as estrogen receptors are transcription factor for VDR gene in vivo and in vitro experiment. The project also investigates that weather estrogen lead to inhibition of liver fibrosis and result in non-fibrotic tissue repair. We try to find the role of VDR in the pathway of Estrogen receptor signaling and provide a theoretical basis for the cause or consequence of differential liver fibrosis development between males and female, also shed insight onto future control and treatment strategies.

肝纤维化几乎是所有慢性肝脏疾病进展的共同过程，肝纤维化的发生发展存在显著的性别差异。在我们前期建立的前瞻性肝炎患者研究队列中发现，具有相同病程的患者，肝纤维化程度存在显著的性别差异，且女性多在绝经期之后发生肝纤维化，提示雌激素具有抗纤维化的作用，但具体机制尚不清楚。近年来研究发现维生素D受体（VDR）的激活可以抑制肝星状细胞的活化，是治疗肝纤维化的潜在靶点。结合生物信息学分析结果提示VDR可能在雌激素受体信号通路中介导了抗纤维化作用。本项目拟运用基因组学和药理学方法，通过体内和体外实验，观察雌激素与对肝星状细胞中VDR基因表达的影响，探明雌激素受体被雌激素激活后作为转录因子调控VDR基因表达的机制；同时探讨雌激素通过VDR途径逆转肝星状细胞活化过程进而逆转肝纤维化的生物学机制。为肝纤维化发生发展中出现的性别差异提供理论依据，也为肝纤维化的控制和治疗提供新的线索。

肝纤维化几乎是所有慢性肝脏疾病进展的共同过程，肝纤维化的发生发展存在显著的性别差异。本研究尝试通过体外培养LX-2细胞和体内肝纤维化鼠模型的建立，探讨雌激素激活雌激素受体后通过VDR途径抗纤维化作用的机制。在课题资助下，完成雌激素及其受体影响肝星状细胞中VDR基因的表达的体外实验和体内尝试实验，由于动物实验中未取得预期结果，将部分研究内容调整为研究人原代肝星状细胞激活前后和在肝硬化非肝硬化患者中雌激素受体的表达差异的比较，以及IL22抗肝纤维化作用的研究。研究结果提示在肝硬化发生时或HSCs被体外激活时，基因ESR1的表达水平明显下调，说明雌激素受体确实是肝纤维化过程中重要的调节环节。IL22基因上单核苷酸位点rs1179249和rs2227472的A等位基因可能是肝纤维化发生的保护因素；而rs1026788 和rs2227491的G等位基因可能是肝纤维化发生发展的危险因素。从基因组水平证实IL22参与肝纤维化过程。综上，我们的研究结果证实雌激素受体在肝纤维化进展过程中起到重要作用，但其具体机制需要进一步探索。IL22基因多态性与肝纤维化的关系提示IL22可能是肝纤维化防止的重要靶标。