巨噬细胞M2型活化在肝脏细胞孤核受体TR4调控肝纤维化中的作用和分子机制研究

Liver fibrosis is an imbalance process in hepatic fibrosis and degradation caused by liver injury, resulting in excessive collagen deposition in the liver. Severe fibrosis leads to upper gastrointestinal bleeding, hepatic encephalopathy, cancer and other serious diseases. The process of hepatic fibrosis is controlled by a complex network regulation system. It is of important clinical significance to improve its mechanism and seek more effective treatment. The role of the orphan nuclear receptor TR4 in hepatobiliary diseases is a long-term project of our group; TR4 is highly expressed in the liver and is closely related to liver diseases. The incidence of non-alcoholic fatty liver disease (NAFLD) in TR4-specific knockout mice is reduced, and NAFLD is a closely related disease to liver fibrosis, but the direct role of TR4 in liver fibrosis has not been studied. We previously found that liver fibrosis was positively correlated with the expression of TR4 by immunohistochemical staining of clinical specimens. TR4 receptor was specifically knocked out in liver cells by constructing Crisper-Cas9 system and it was confirmed that liver cell nuclear receptor TR4 promoted hepatic fibrosis formation. Further studies showed that TR4 may promote the progression of hepatic fibrosis by regulating the activation of macrophage M2. However, its regulatory mechanism is not yet clear, pending further study of this issue.

肝纤维化是肝脏损伤致肝内纤维生成与降解失衡,致使过多胶原在肝内沉积的过程。严重肝纤维化可并发上消化道出血、肝性脑病、癌变等严重疾病。肝纤维化的过程受复杂的网状调控系统控制，完善其机制研究，寻求更有效的治疗手段具有重要的临床意义。孤核受体TR4在肝胆疾病中的作用是本课题组长期研究的内容；TR4在肝脏中呈高表达，与肝脏疾病密切相关。TR4特异性敲除小鼠的非酒精性脂肪肝病（NAFLD）发生率降低，NAFLD是与肝纤维化密切相关的疾病，但TR4在肝纤维化中的直接作用尚未研究。我们前期通过临床标本免疫组化发现肝纤维化与TR4表达量正相关，通过构建Crisper-Cas9体系特异性敲除肝细胞内的TR4受体，证实肝细胞孤核受体TR4促进了肝纤维化形成。进一步的研究发现肝细胞孤核受体TR4可能通过调控巨噬细胞M2型活化促进肝纤维化进展。但其调控机制尚不明确，有待本课题进一步研究。

肝纤维化是在大多数类型的慢性肝病中发生的细胞外基质蛋白（包括胶原蛋白和 α 平滑肌动蛋白）的过度积累。 晚期肝纤维化导致肝硬化、肝功能衰竭和门静脉高压症，通常需要肝移植。 活化的肝星状细胞、门静脉成纤维细胞和骨髓来源的肌成纤维细胞已被确定为受损肝脏中主要的胶原蛋白生成细胞。 先前的研究表明，TR4-/- 小鼠保护它们免受可能发展为肝纤维化的肝脂肪变性。 在本研究中，我们研究了TR4在肝纤维化中的作用，特别是在肝星状细胞（HSCs）功能中的作用。TR4通过转录上调促进HSCs的COL1A1合成促进肝纤维化的进展。 TR4 还通过增强 TR4-CSF1 信号通路促进 M2 巨噬细胞极化和募集。 从而促进肝纤维化的发展。

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