Zhong Li, Huang Lu, Xue Qian, Liu Chang, Xu Keshu, Shen Wei, Deng Liang
Department of Gastroenterology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Department of Gastroenterology and Hepatology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
J Cell Biochem. 2019 Jul;120(7):11761-11774. doi: 10.1002/jcb.28456. Epub 2019 Feb 11.
We have demonstrated runt-related transcription factor 2 (Runx2) plays important role in atherosclerosis. It has been indicated that atherosclerosis shares the similar histopathology with nonalcoholic steatohepatitis (NASH), a progressive stage of nonalcoholic fatty liver disease (NAFLD), on macrophages infiltration. However, the function of Runx2 in NAFLD is completely unknown. Here, we investigated the underlying mechanism of Runx2 triggering macrophages infiltration in the development of NAFLD.
Mice were fed with high-fat diet (HFD) for a long time. Histopathologic features, macrophages infiltration, expression of monocyte chemotactic protein 1 (MCP-1), and Runx2 were, respectively, analyzed in vivo. Lentivirus or short interfering RNA were transfected in murine hepatic stellate cells (HSCs) and the transwell assay was performed to verify the contribution of Runx2 for macrophages migration in vitro.
Long-term treatment with HFD induced the progression of NAFLD, and NASH was initiated from 8 months on diet. HFD increased the expression of F4/80 upon HFD feeding, indicated HFD promotes hepatic infiltration of macrophages in NAFLD. In addition, HFD upregulated the expression of MCP-1 and Runx2 during NAFLD development. Unexpectedly, Runx2 upregulation is cell-type depended in NAFLD, and only abundantly elevated in activated HSCs. Furthermore, we found that Runx2 could increase or decrease the expression of MCP-1 in HSCs, and regulate macrophages migration by influencing MCP-1 production in vitro.
Our results give evidence that the upregulation of Runx2 specific in activated HSCs promotes hepatic infiltration of macrophages by increasing MCP-1 expression in NAFLD, which reveals a novel mechanism and provides a cell-specific therapeutic target for NAFLD.
我们已证明 runt 相关转录因子 2（Runx2）在动脉粥样硬化中起重要作用。有研究表明，在巨噬细胞浸润方面，动脉粥样硬化与非酒精性脂肪性肝病（NAFLD）的进展期非酒精性脂肪性肝炎（NASH）具有相似的组织病理学特征。然而，Runx2 在 NAFLD 中的功能完全未知。在此，我们研究了 Runx2 在 NAFLD 发展过程中引发巨噬细胞浸润的潜在机制。
长期给小鼠喂食高脂饮食（HFD）。分别在体内分析组织病理学特征、巨噬细胞浸润、单核细胞趋化蛋白 1（MCP - 1）的表达以及 Runx2 的表达。将慢病毒或小干扰 RNA 转染至小鼠肝星状细胞（HSCs）中，并进行 Transwell 实验以在体外验证 Runx2 对巨噬细胞迁移的作用。
长期 HFD 处理诱导了 NAFLD 的进展，从饮食 8 个月开始出现 NASH。喂食 HFD 后，HFD 增加了 F4/80 的表达，表明 HFD 促进了 NAFLD 中巨噬细胞的肝脏浸润。此外，在 NAFLD 发展过程中，HFD 上调了 MCP - 1 和 Runx2 的表达。出乎意料的是，Runx2 的上调在 NAFLD 中具有细胞类型依赖性，仅在活化的 HSCs 中大量升高。此外，我们发现 Runx2 可增加或降低 HSCs 中 MCP - 1 的表达，并通过影响体外 MCP - 1 的产生来调节巨噬细胞迁移。
我们的结果表明，活化的 HSCs 中特异性上调的 Runx2 通过增加 NAFLD 中 MCP - 1 的表达促进巨噬细胞的肝脏浸润，这揭示了一种新机制，并为 NAFLD 提供了细胞特异性治疗靶点。
