Iron-rich Kupffer cells exhibit phenotypic changes during the development of liver fibrosis in NASH.
Iron-rich Kupffer cells exhibit phenotypic changes during the development of liver fibrosis in NASH.
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DOI：
10.1016/j.isci.2020.102032
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发表时间：
2021-02-19
期刊：
影响因子：
5.8
通讯作者：
Suganami T
中科院分区：
文献类型：
--
作者：
Kanamori Y;Tanaka M;Itoh M;Ochi K;Ito A;Hidaka I;Sakaida I;Ogawa Y;Suganami T
尽管最近的证据表明铁蓄积参与了非酒精性脂肪性肝炎(NASH)的发病，但其潜在的机制仍然知之甚少。以前，我们报道了一种独特的组织结构，称为“冠状结构(CLS)”，在这种结构中，驻肝巨噬细胞(Kupffer细胞)包围死亡的肝细胞，清除它们的碎片，并在NASH中诱导炎症和纤维化。在这项研究中，我们使用磁柱分离，我们发现富含铁的枯否细胞在NASH的发展过程中表现出促炎症和促纤维化的表型变化，至少部分是通过激活MIT/TFE转录因子来实现的。在Kupffer细胞中观察到MIT/TFE转录因子的激活，形成了小鼠和人NASH的CLSS。铁螯合有效减轻小鼠NASH模型中的肝纤维化。这项研究对铁在NASH中的病理生理作用提供了深入的了解。我们的数据还揭示了一种独特的、富含铁的巨噬细胞亚群，它有助于CLS的形成，并作为肝纤维化的驱动因素。在Nash模型中，Kupffer细胞被磁性地分为Fe-hi和Fe-lo组分。Fe-hi Kupffer细胞在Nash模型中发挥促炎和促纤维化的作用MIT/TFE转录因子介导铁诱导的Kupffer细胞表型变化在小鼠和人类Nash生物科学；生物化学；细胞生物学中Kupffer细胞激活MIT/TFE转录因子
Although recent evidence suggests the involvement of iron accumulation in the pathogenesis of nonalcoholic steatohepatitis (NASH), the underlying mechanisms remain poorly understood. Previously, we reported a unique histological structure termed “crown-like structure (CLS),” where liver-resident macrophages (Kupffer cells) surround dead hepatocytes, scavenge their debris, and induce inflammation and fibrosis in NASH. In this study, using magnetic column separation, we show that iron-rich Kupffer cells exhibit proinflammatory and profibrotic phenotypic changes during the development of NASH, at least partly, through activation of MiT/TFE transcription factors. Activation of MiT/TFE transcription factors is observed in Kupffer cells forming CLSs in murine and human NASH. Iron chelation effectively attenuates liver fibrosis in a murine NASH model. This study provides insight into the pathophysiologic role of iron in NASH. Our data also shed light on a unique macrophage subset rich in iron that contributes to CLS formation and serves as a driver of liver fibrosis. Kupffer cells are magnetically divided into Fe-hi and Fe-lo fractions in a NASH model Fe-hi Kupffer cells exert proinflammatory and profibrotic properties in NASH MiT/TFE transcription factors mediate iron-induced Kupffer cells' phenotypic changes MiT/TFE transcription factors are activated in Kupffer cells in murine and human NASH Biological Sciences; Biochemistry; Cell Biology
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影响因子：
6.5
作者：
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影响因子：
13.5
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