脂肪性肝病发生的关键因素是以单核巨噬细胞M1和M2亚型比例失调、极化紊乱为特征的炎症反应失控，而其细胞分子机制尚不清。我们前期研究发现，具有免疫调节活性的间充质干细胞、具有抑炎功能的15d-PGJ2、具有促炎功能的S1P以不同方式参与肝脏炎症反应，但具体到脂肪性肝病时调节单核巨噬细胞极化的机制尚不详。本项目拟以蛋氨酸胆碱缺失+高脂饮食制成的小鼠脂肪性肝病模型、小鼠单核巨噬细胞（肝脏或骨髓来源）、间充质干细胞为研究对象，以15d-PGJ2或S1P为靶分子，应用骨髓细胞为EGFP+的嵌合体小鼠、S1P受体2/3 基因敲除小鼠、流式细胞分析、RNAi等技术，探讨15d-PGJ2或S1P对小鼠单核巨噬细胞或间充质干细胞向脂肪性肝病肝脏浸润、极化及相互之间作用的机制；再用适宜的细胞或分子干预脂肪性肝病小鼠，确认15d-PGJ2或S1P的作用机理，为阐明脂肪性肝病发生发展及转归机制提供理论和实验依据。

The key factor in the occurrence of non-alcoholic fatty liver disease (NAFLD) is uncontrolled inflammatory response which characterized by the monocyte /macrophages M1 and M2 subtype imbalance, or polarization disorder. Our previous study found that mesenchymal stem cells (MSC) with immuno-modulatory activity, 15d-PGJ2 with function of suppressing inflammation, and S1P with pro-inflammatory function, participated in liver inflammation by different ways. However, little is known about the cellular and molecular mechanisms that MSC, 15d-PGJ2, and S1P control the polarization disorder of monocyte/macrophages M1 and M2 subtype during NAFLD. In the project, we will prepare a NAFLD mouse model by feeding a methionine- and choline-deficient + high-fat diet (MCDHF), perform bone marrow transplantation to produce chimera mice of all bone marrow cells or MSCs lebelling with EGFP, and use the receptors (S1PR2 or S1PR3) gene knockout mice, flow cytometry analysis, cell co-culture, immunofluorescence, RNAi technology, to explore the functions and mechanisms of 15d-PGJ2 or S1P on infiltration and polarization of monocyte/macrophages (including Kupffer cells and bone marrow-derived monocyte/macrophages) and MSCs, and the interaction between each other in the liver of NAFLD mice. Based on the above research works, we will select the appropriate polarized monocyte/macrophages or MSCs (for cell therapy), choose the molecules which play an important role in key 15d-PGJ2 or S1P signaling pathway (e.g. enzyme or receptor agonist , blocker), intervene NAFLD in mice, and determine its outcome results. Accordingly, we will further confirm the roles of monocyte/macrophages, MSCs, 15d-PGJ2 or S1P during NAFLD in mice. The knowledge will help to represent novel therapeutic targets in NAFLD.