AGT/AT1R通路激活是非酒精性脂肪性肝病（NAFLD）发病关键，AGTRAP蛋白可抑制该通路，维生素B12缺乏与NAFLD密切相关，但其机制未明。本室前期发现，B12缺乏可诱导大鼠NAFLD的发生并伴AGTRAP蛋白低表达和AGT/AT1R通路激活，体外实验发现B12缺乏可致RNA结合蛋白HuR定位发生胞核滞留，筛选发现AGTRAP mRNA与HuR有结合位点。综合文献和预实验可推测:B12缺乏导致HuR翻译后改变，使其携带AGTRAP mRNA出核能力降低，下调AGTRAP蛋白表达，从而弱化了该蛋白拮抗AT1R的促NAFLD作用。本项目拟先在肝组织和肝细胞水平证实B12缺乏可导致HuR亚细胞定位障碍和AGTRAP低表达，再利用细胞实验反证补充B12可以促进HuR携带AGTRAP mRNA出核增加。这将使我们充分认识B12在NAFLD中的重要地位及其调控机制，为探索其治疗提供新的靶点。

The activation of AGT/AT1R pathway is essential to the pathogenesis of nonalcoholic fatty liver disease (NAFLD), the AGTRAP protein inhibits this pathway. Vitamin B12 deficiency is closely associated with non-alcoholic fatty liver disease (NAFLD), but there are few studies in its mechanism. Unpublished data of our laboratory found that vitamin B12 deficiency can induce NAFLD in high-fat diet rats and that was associated with AGTRAP down-regulation and AGT/AT1R pathway activation. In vitro experiments we found that vitamin B12 deficiency can induce the RNA binding protein HuR subcellular mislocalization (retention in nucleus), and the screening revealed that the AGTRAP mRNA has a binding site with the HuR, The comprehensive literature review and our unpublished data suggest that the posttranscriptional modification of HuR after vitamin B12 deficiency results in the decrease of nuclear export ability of AGTRAP mRNA and the down-regulation of AGTRAP protein, which weakens the antagonistic effect of AGTRAP on AT1R. This project intends to confirm that vitamin B12 deficiency can lead to impaired subcellular localization of HuR and down-regulation of AGTRAP in liver tissue and cell line level. Then using implication of cell experiments to confirm that vitamin B12 supplementation can promote HuR/AGTRAP mRNA nuclear export increase. This will give us a full understanding of the important role of vitamin B12 in the process of NAFLD and its regulatory mechanism, which will provide new targets for exploring NAFLD treatment.