肝脏和内脏脂肪巨噬细胞（Mφ）是决定非酒精性脂肪肝（NAFLD）进展的关键细胞亚群。然而，二者的相互关系和调控机制尚不完全清楚。我们在以往发现Notch信号调控Mφ迁移与活化的基础上，近期又通过腹腔移植GFP肥胖小鼠的内脏脂肪组织观察到脂肪肝小鼠的腹腔和肝脏出现了GFP+脂肪Mφ。这提示内脏脂肪Mφ可向肝归巢，并与肝Mφ协同参与NAFLD进展。本课题拟采用GFP转基因和Mφ特异激活/阻断Notch信号小鼠建立NAFLD模型，结合临床样本、小鼠脂肪Mφ移植/清除实验，以及细胞和分子生物学研究手段，明确NAFLD进展中内脏脂肪Mφ肝向归巢的特征；阐明Notch信号参与调控脂肪Mφ肝向归巢的分子机制；揭示内脏脂肪来源Mφ与肝Mφ协同参与NAFLD进展的作用和机制。本研究有望揭示脂肪Mφ调控NAFLD进展的新途径以及调控脂肪/肝Mφ协同作用的关键分子，为靶向Mφ干预NAFLD提供新策略和靶点。

Macrophage derived from visceral adipose tissue and liver are key players in nonalcoholic fatty liver disease (NAFLD) pathogenesis. However, the detailed interaction and regulation mechanism between these two subsets of tissue macrophages in NAFLD development remained unclear. Our previous studies have shown that Notch signaling pathway can regulate macrophage migration, polarization and function under inflammatory status. Recently, using high-fat diet-fed mice, we found that GFP+ adipose macrophage was observed in liver tissue of obese recipient mice after adipose tissue transplantation that was isolated from GFP+ obese donor mice, suggesting that adipose tissue macrophages might migrate into liver during the development of NAFLD, and then coordinately promote NAFLD progression with hepatic macrophage or Kupffer cells. In the current project, we intend to clarify the homing of adipose tissue macrophages to liver by GFP transgenic mice and NAFLD mice model combined with adipose tissue macrophage transfer/deletion experiments, and then verify this phenomenon using clinical samples from bariatric surgery patients; We will also reveal the function of Notch signaling pathway in the regulation of adipose tissue macrophage homing and contribution for hepatic macrophages pool in NAFLD progression using a macrophage-specific Notch activated/blockade mouse; Furthermore, with advanced cellular immunology and molecular biology methods, we will explore the molecular mechanisms of Notch-mediated macrophage activation and function including adipose tissue-derived macrophages and hepatic macrophages in liver during NAFLD progression. These studies are expected to uncover the new mechanism of adipsoe tissue macrophage contribution to NAFLD pathogenesis and the key molecular regulating two subsets of macrophage activation to promote NAFLD pathogenesis. These results will provide new strategies and targets to intervene macrophage-originated from different tissues for NAFLD treatment, therefore it should have important theoretical significance and potential application value.