Dicer deletion in hepatocytes promotes macrophages M1 polarization through dysregulated miR-192-3p/IGF2 in non-alcoholic steatohepatitis and hepatocellular carcinoma
Dicer deletion in hepatocytes promotes macrophages M1 polarization through dysregulated miR-192-3p/IGF2 in non-alcoholic steatohepatitis and hepatocellular carcinoma
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DOI：
10.1038/s41417-022-00432-x
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发表时间：
2022-02
影响因子：
6.4
通讯作者：
Caihong Hu;X. Li;Yiqun Sui;Yongyu Chen;Ying Zhao;Yan Yang;Qun Zhou;Hengli Ni;Lina Sun;Wenjuan Gan;Jianming Li;Yao Liu
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文献类型：
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作者：
Caihong Hu;X. Li;Yiqun Sui;Yongyu Chen;Ying Zhao;Yan Yang;Qun Zhou;Hengli Ni;Lina Sun;Wenjuan Gan;Jianming Li;Yao Liu
巨噬细胞在非酒精性脂肪性肝炎（NASH）和肝细胞癌（HCC）的发展中起着至关重要的作用，但巨噬细胞的极化在以前的报道中并不一致，肝细胞对巨噬细胞极化的贡献尚不清楚。在这里，我们发现在临床NASH和HCC样本中，受损的Dicer活性是常见的，并且与M1样巨噬细胞增加相关。肝细胞Dicer基因缺失的小鼠在高脂饮食诱导NASH和DEN治疗后肝癌的发生过程中均可诱导巨噬细胞M1极化。在肝细胞中，Dicer缺失提供了不同的脂质谱并增加了脂质氧化。在机制上，Dicer缺失导致肝细胞中miR-192- 3 p下降和IGF 2增加。恢复miR-192- 3 p可抑制IGF 2和巨噬细胞在肝组织中的浸润，并减少脂质的从头合成和过氧化。总之，我们的数据突出了Dicer相关的miR-192- 3 p在NASH和HCC中巨噬细胞M1极化的发病机制中的核心作用。
Macrophages plays a vital role in the development of non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC), but the polarization of macrophages was not consistent in previous reports and the contribution of hepatocytes to macrophage polarization is not clear. Here, we show that in clinical NASH and HCC samples, impaired Dicer activity was common and correlated with increased M1-like macrophages. Mice with Dicer deletion in hepatocytes could induce macrophages M1 polarization either in the development of NASH under high fat diet feeding, or in the carcinogenesis of HCC after DEN treatment. In hepatic cells, Dicer deletion delivered distinct lipid profile and increased lipid oxidation. Mechanically, Dicer deletion caused declined miR-192-3p and increased IGF2 in hepatocytes. Restoring miR-192-3p could suppress IGF2 and inhibit macrophage infiltration in the liver tissue, as well as reduce the lipid de novo synthesis and peroxidation. Overall, our data highlights the central role of Dicer-associated miR-192-3p in the etiopathogenesis of macrophage M1 polarization in NASH and HCC.