ATF3通过髓系抑制性细胞参与脂肪肝发生的机制研究

Studies have indicated that dysregulation of hepatic immunity plays an important role in fatty liver, the mechanisms of which, however, remain to be understood. In our preliminary study, we found that: both the levels and the suppressive activity of myeloid-derived suppressor cells (MDSCs) in mice with fatty liver were significantly higher than the control normal mice, MDSC depletion clearly alleviated the hepatic steatosis; Expression of ATF3 was down-regulated in fatty liver-derived MDSCs; Mice with ATF3 deficiency displayed much higher lipid levels in both liver and serum; as well as MDSCs accumulation and upregulation of S100A9 expression in MDSCs; silencing of S100A9 abrogated the steatosis in ATF3-KO mice. We therefore propose that: ATF3 suppression induced by high-fat diet lead to MDSC expansion and activation in liver, which secret pro-inflammatory molecule S100A9 and promote fatty liver disease. Aim to test this hypothesis, we will: demonstrate the enhancement of hepatic steatosis by MDSCs; elucidate the regulation of MDSCs development and activation by ATF3; uncover the mechanism underlying ATF3-mediated MDSCs expansion in promoting fatty liver; determine the pathological significance of this project in clinical samples from fatty liver patients. The implementation of this study will reveal a novel mechanism of fatty liver, also will provide potential thereapeutic strategy and target for lipid metabolic disorder.

研究表明：肝脏局部的免疫调节紊乱是脂肪肝发生的重要机制，然而其细胞及分子机制尚待阐明。我们前期发现：脂肪肝小鼠肝脏中髓系抑制性细胞（MDSC）的水平及功能显著高于正常对照小鼠，清除MDSC可缓解肝脏脂质沉积；脂肪肝来源的MDSC中ATF3表达水平显著下调；ATF3-KO小鼠的肝脏脂质含量显著高于WT小鼠，伴随MDSC扩增及炎症分子S100A9表达上调；沉默S100A9可缓解ATF3-KO小鼠的脂肪肝症状。据此提出假说：高脂饮食通过抑制ATF3，导致肝脏中MDSC聚集与活化，并分泌S100A9而促进肝脏炎症及脂肪肝发生。为验证此假说，拟首先确定MDSC对脂肪肝的促进作用，进而研究ATF3对肝脏MDSC的调控作用，及其参与脂肪肝发生的分子机制，最后利用脂肪肝患者样品对其临床病理意义进行研究。本项目的实施将从细胞及分子水平揭示脂肪肝发生的机制，并为其免疫干预治疗提供新策略和新靶点。

研究表明：肝脏局部的免疫调节紊乱是脂肪肝发生的重要机制，然而其细胞及分子机制尚待阐明。我们发现：脂肪肝小鼠肝脏中髓系抑制性细胞（Myeloid-derived Suppressor Cells, MDSC）的水平及功能显著高于正常对照小鼠，清除MDSC可缓解肝脏脂质沉积；脂肪肝来源的MDSC中ATF3表达水平显著下调；ATF3基因缺失的小鼠肝脏脂质含量显著增加，伴随MDSC的扩增与活化。进一步炎症因子S100A9介导了ATF3对肝脏中MDSC的调控。研究成果揭示了ATF3在调控肝脏MDSC中的作用及其在脂肪肝中的意义，为脂肪肝的免疫干预提供了新策略和新靶点。 同时，对包括新生儿肠道及肺脏在内的区域免疫特性进行了探索，并取得突破性的研究成果。