核受体PPAR-gamma调控Kupffer细胞M1/M2型极化转变在NAFLD防治中的作用

Kupffer cell is the key cell who regulates the hepatic innate immune system and adaptive immune system.Our recent studies have shown that inflammatory activated Kupffer cell and its related abnormality of hepatic innate immune system were involved in the development of non-alcoholic fatty liver disease. Recent studies have shown that M1/M2 phenotype polarization of macrophages is thought to contribute to the progression of inflammation and metabolism. Nuclear receptor PPARgamma played important role in body engery metabolism and inflammatory immune response,and was also implicated in macrophages polarization. In the present study, effect of high lipid environment on M1/M2 phenotype polarization of Kupffer cell was observed through in vivo animal models and in vitro cell experiments. Furthermore,we investigate the role of nuclear receptor PPARgamma in the switch of Kupffer cell M1/M2 polarization induced by lipid , and explore the mechanism of such modulation. In addition,effect of the different phenotype polarization of Kupffer cells on lipid metabolism of hepatocytes was further investigated. Based on the present study, we want to elucidate the mechanism of lipid induced Kupffer cell polarization, and design a new therapeutic strategy based on modulation of Kupffer cell polarization to provide a new theoretical basis for NAFLD prevention and treatment.

Kupffer细胞是肝内天然免疫和适应性免疫网络的关键调节细胞。在我们前期的研究中发现炎性活化的Kupffer细胞及其相关的肝内天然免疫紊乱在NAFLD发生、发展中具有重要作用。最近研究显示，巨噬细胞M1/M2型不同表型活化转变将影响机体炎症-代谢过程。已发现核受体PPARgamma在调控机体能量代谢、炎症免疫反应中具有重要地位，并参与巨噬细胞极化改变。因此，本研究拟通过动物模型及细胞实验观察体内外高脂环境对Kupffer细胞M1-M2极化的影响，并探索核受体PPARgamma在脂质诱导的Kupffer细胞M1/M2极化转变中的作用及调控机制，以及不同极化类型的Kupffer细胞对肝细胞脂质代谢的影响。从而阐明异常脂质对Kupffer细胞极化的影响,并设计基于调控Kupffer细胞极化为基础的治疗策略,为预防、治疗NAFLD提供新的理论依据和新视野。

背景：巨噬细胞/ Kupffer细胞M1/M2型极化表型转变可能影响机体炎症-代谢过程。核受体PPAR-γ在调控炎症免疫反应答中具有重要地位，并参与巨噬细胞极化。.目的：探讨体内外高脂环境对巨噬细胞/Kupffer细胞M1-M2极化的影响及相关信号通路的变化，调控核受体PPAR-γ对脂质诱导的巨噬细胞极化转变的影响。.方法：高脂饮食建立小鼠NAFLD模型，体外建立不同种类脂肪酸干预的Kupffer细胞/巨噬细胞培养系，以及巨噬细胞-肝细胞的条件液共培养体系，并以PPAR-γ激动剂和拮抗剂干预。检测Kupffer细胞/巨噬细胞M1/M2极化基因表达、NF-κB信号通路和PPAR-γ等蛋白的表达，以及肝细胞脂代谢情况。.结果：（1）长期高脂饮食增加小鼠肝内Kupffer细胞数量，主要为CD11c+的M1型Kupffer细胞，其动态变化与高脂饮食诱导的肝脏脂肪变性程度及肝内炎症反应密切相关。（2）饱和脂肪酸诱导巨噬细胞M1型极化并与NF-κB 信号通路活化密切相关，PPAR-γ在不同脂质介导的巨噬细胞M2型活化中发挥重要作用。（3）上调PPAR-γ表达使脂质诱导的巨噬细胞极化发生M2型偏倚，下调PPAR-γ表达则具有相反效应，与PPAR-γ表达改变影响NF-κB炎性信号通路活性有关。（4）饱和脂肪酸诱导的M1型巨噬细胞可增强肝细胞脂质合成代谢，抑制其脂质分解代谢，加重肝内脂质沉积，上调 PPAR-γ 表达使脂质诱导的巨噬细胞极化发生 M2 型偏倚，继而抑制肝细胞脂质合成代谢。下调巨噬细胞 PPAR-γ 表达则具有相反效应。（5）体内PPAR-γ激动剂抑制高脂饮食诱导的Kupffer细胞M1型极化并改善肝内炎症和脂质代谢紊乱。.结论：体内外高脂环境诱导巨噬细胞/Kupffer细胞M1型炎性活化在NAFLD发展中具有重要作用，通过调控核受体PPAR-γ活性改变巨噬细胞/Kupffer细胞极化表型对肝脏炎症和脂代谢具有重要影响。