Effect of modulation of PPAR-γ activity on Kupffer cells M1/M2 polarization in the development of non-alcoholic fatty liver disease.
Effect of modulation of PPAR-γ activity on Kupffer cells M1/M2 polarization in the development of non-alcoholic fatty liver disease.
复制标题
PPAR-γ 活性调节对非酒精性脂肪肝发展中库普弗细胞 M1/M2 极化的影响
DOI：
10.1038/srep44612
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发表时间：
2017-03-16
影响因子：
4.6
通讯作者：
Hua J
中科院分区：
文献类型：
--
作者：
Luo W;Xu Q;Wang Q;Wu H;Hua J
脂质介导的肝脏炎症免疫功能异常和慢性低度炎症在非酒精性脂肪性肝病（NAFLD）的发病机制中起重要作用。巨噬细胞极化是调节炎症反应的重要机制。由于PPAR-γ是巨噬细胞极化的主要调节因子，本研究旨在研究脂质诱导的巨噬细胞/枯否细胞（M1/M2）极化，并探讨其与巨噬细胞M1/M2极化漂移的关系。在这里，我们发现，长期高脂饮食增加了库普弗细胞的含量与M1占主导地位的表型和促炎细胞因子的产生增加。饱和脂肪酸使Kupffer细胞/巨噬细胞向M1型分化，n-3 PUFA使Kupffer细胞/巨噬细胞向M2型分化，这分别与NF-κB信号通路和PPAR-γ的激活有关。此外，过氧化物酶体增殖物激活物受体-γ的上调使脂质诱导的巨噬细胞极化从M1为主表型转变为M2表型。巨噬细胞极化开关与PPAR-γ和NF-κ Bp 65信号通路的相互作用有关。罗格列酮可恢复高脂饮食诱导的枯否细胞M1/M2极化，减轻肝脂肪变性以及局部促炎反应。这些发现表明，操纵PPAR-γ活性有可能平衡脂质诱导的M1/M2巨噬细胞/枯否细胞极化，从而防止NAFLD的发展。
Abnormal lipid-mediated hepatic inflammatory-immune dysfunction and chronic low grade inflammation play an important role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Macrophage polarization is an important mechanism for the regulation of inflammatory response. Since PPAR-γ has emerged as a master regulator of macrophage polarization, we aimed to investigate the lipid-induced macrophage/Kupffer cell polarizationin vivoandin vitro, and explore the association between PPAR-γ activity and macrophages M1/M2 polarization shifting. Here we showed that long-term high-fat diet increased Kupffer cells content with M1-predominant phenotype and increasing production of pro-inflammatory cytokines. Saturated fatty acids polarized Kupffer cells/macrophages to an M1-predominant phenotype while n-3 PUFA polarized Kupffer cells/macrophages to an M2 phenotype, which was associated with activation of NF-κB signal pathway and PPAR-γ respectively. Furthermore, up-regulation of PPAR-γ shifted lipid-induced macrophages polarization from M1-predominant phenotype to M2 phenotype. Macrophages polarization switch was associated with the interaction between PPAR-γ and NF-κBp65 signal pathway. Rosiglitazone restored high-fat diet-induced imblance of Kupffer cells M1/M2 polarization and alleviated hepatic steatosis as well as local pro-inflammatory response. These findings suggest that manipulation of PPAR-γ activity has the potential to balance lipid-induced M1/M2 macrophage/Kupffer cell polarization, and leading to prevent the development of NAFLD.