Bone marrow macrophage-derived exosomal miR-143-5p contributes to insulin resistance in hepatocytes by repressing MKP5.
Bone marrow macrophage-derived exosomal miR-143-5p contributes to insulin resistance in hepatocytes by repressing MKP5.
复制标题
骨髓巨噬细胞来源的外泌体 miR-143-5p 通过抑制 MKP5 导致肝细胞胰岛素抵抗
DOI：
10.1111/cpr.13140
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发表时间：
2021-12
影响因子：
8.5
通讯作者：
Li J
中科院分区：
文献类型：
--
作者：
Li L;Zuo H;Huang X;Shen T;Tang W;Zhang X;An T;Dou L;Li J
在本研究中，我们旨在探讨骨髓巨噬细胞来源的外泌体在肝脏胰岛素抵抗中的作用，研究外泌体中调节肝脏胰岛素信号通路的物质，揭示肝脏胰岛素抵抗的具体分子机制，并进一步探讨外泌体在2型糖尿病中的作用。以高脂饮食（HFD）喂养的小鼠作为肥胖诱导的肝脏胰岛素抵抗模型，用超离心方法从高脂饮食喂养的小鼠的bmm中分离外泌体。使用microRNA阵列分析外泌体microRNA表达的光谱变化。转染miR - 143 - 5p模拟物后，检测肝细胞中胰岛素信号通路的激活和糖生成水平。荧光素酶法和western blot检测miR - 143 - 5p的靶蛋白。HFD喂养小鼠的bmm向M1极化，miR - 143 - 5p在HFD喂养小鼠的bmm外泌体中显著上调。miR - 143 - 5p在Hep1 - 6细胞中过表达导致AKT和GSK磷酸化和糖原合成降低。双荧光素酶报告基因检测和western blot结果表明，有丝分裂原激活的蛋白激酶磷酸酶- 5 （Mkp5，也称为Dusp10）是miR - 143 - 5p的靶基因。此外，MKP5的过表达可以挽救miR - 143 - 5p模拟物转染Hep1 - 6诱导的胰岛素抵抗。骨髓巨噬细胞来源的外泌体miR - 143 - 5p通过抑制MKP5诱导肝细胞胰岛素抵抗。BMM外泌体中上调的miR - 143 - 5p可以通过靶向Mkp5传递到肝细胞并破坏肝糖生成。
In this study, we aim to explore the role of bone marrow macrophage‐derived exosomes in hepatic insulin resistance, investigate the substance in exosomes that regulates hepatic insulin signalling pathways, reveal the specific molecular mechanisms involved in hepatic insulin resistance and further explore the role of exosomes in type 2 diabetes. High‐fat diet (HFD)‐fed mice were used as obesity‐induced hepatic insulin resistance model, exosomes were isolated from BMMs which were extracted from HFD‐fed mice by ultracentrifugation. Exosomes were analysed the spectral changes of microRNA expression using a microRNA array. The activation of the insulin signalling pathway and the level of glycogenesis were examined in hepatocytes after transfected with miR‐143‐5p mimics. Luciferase assay and western blot were used to assess the target of miR‐143‐5p. BMMs from HFD‐fed mice were polarized towards M1, and miR‐143‐5p was significantly upregulated in exosomes of BMMs from HFD‐fed mice. Overexpression of miR‐143‐5p in Hep1‐6 cells led to decreased phosphorylation of AKT and GSK and glycogen synthesis. Dual‐luciferase reporter assay and western blot demonstrated that mitogen‐activated protein kinase phosphatase‐5 (Mkp5, also known as Dusp10) was the target gene of miR‐143‐5p. Moreover, the overexpression of MKP5 could rescue the insulin resistance induced by transfection miR‐143‐5p mimics in Hep1‐6. Bone marrow macrophage‐derived exosomal miR‐143‐5p induces insulin resistance in hepatocytes through repressing MKP5. Up‐regulated miR‐143‐5p in BMM exosomes could be passed to hepatocytes and impaired hepatic glycogenesis by targeting Mkp5.
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