高盐摄入引起的炎症反应在心血管及代谢性疾病发生中有重要作用。肝脏不仅是重要代谢器官，也是炎症因子产生的主要场所。我们前期工作发现高盐介导的肝脏炎症反应和线粒体功能异常在撤盐后持续存在，并伴随线粒体蛋白SIRT3基因启动子组蛋白3乙酰化H3K27ac异常；二甲双胍能抑制高盐介导的肝脏持续性炎症，阻碍SIRT3启动子H3K27ac增加并促进NRF2结合, 但高盐导致H3K27ac增加的调控因素及NRF2依赖的促SIRT3转录机制不甚清楚。为此，我们提出假设：高盐通过增加SIRT3启动子的H3K27ac水平减少NRF2的结合抑制SIRT3，而无NRF2结合的炎症因子则表达增加；激活AMPK抑制H3K27ac，增加NRF2的结合，促进SIRT3表达并抑制持续性炎症。本研究拟采用三种基因敲除小鼠，结合细胞实验阐明高盐导致肝脏持续性炎症的分子机制，为拮抗高盐所致心血管代谢性疾病提供新的干预靶点。

The inflammatory response evoked by high salt intake plays a critical role in the development of cardiovascular and metabolic diseases. In addition to be a crucial metabolic organ, liver also acts as the main source of inflammatory cytokines. We have observed that the hepatic inflammation and mitochondrial dysfunction induced by high salt diet persist even after changing to normal diet, accompanied by increase of the acetylation level of histone 3 (H3K27ac) on the promoter of mitochondrial protein SIRT3 gene and lowered its expression. Treatment with metformin significantly suppressed high salt-induced hepatic continuous inflammation, inhibited the increase of H3K27ac on the promoter of SIRT3 and promoted NRF2 binding on it. However, the possible regulatory factors involved in the high salt-increased H3K27ac level and the mechanism of NRF2-dependent SIRT3 transcription remain unclear. Therefore, we hypothesized that high salt intake would reduce the binding of NRF2 on SIRT3 promoter to decrease its expression by augmenting the H3K27ac level, whereas the expression of those inflammatory factors without NRF2 binding continuously increase. Metformin might enhance the binding of NRF2 on SIRT3 promoter to increase its expression and inhibit the continuous inflammation through AMPK-mediated decrease of H3K27ac level. We plan to use three specific gene-knockout mice, accompanied with cellular experiments, to elucidate the molecular mechanism of high salt-induced hepatic continuous inflammation. This project would provide new theoretical knowledge and intervention targets to prevention and cure of the cardiovascular and metabolic diseases caused by high salt intake.