School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China.
Department of Science and Education, Tianjin Union Medical Center, Tianjin, China.
Front Immunol. 2022 Jul 28;13:959495. doi: 10.3389/fimmu.2022.959495. eCollection 2022.
Macrophages are involved in hepatocyte steatosis and necroinflammation and play an important role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Impaired autophagy function (decreased autophagy or blocked autophagic flow) leads to cell damage and death and promotes NAFLD progression. The experimental and clinical research of glycyrrhetinic acid (GA) in the treatment of NAFLD has gradually attracted attention with clear pharmacological activities such as immune regulation, antiviral, antitumor, antioxidant, liver protection, and anti-inflammatory. However, the effects of GA on the STAT3-HIF-1α pathway and autophagy in macrophages are still unclear, and its mechanism of action in the treatment of NAFLD remains to be further elucidated. We constructed a NAFLD mouse model through a high-fat and high-sugar diet to investigate the therapeutic effects of GA. The results showed that GA reduced weight, improved the pathological changes and hepatic lipid deposition of liver, and abnormally elevated the levels of serum biochemical (AST, ALT, TG, T-CHO, LDL-C, and HDL-C) and inflammatory indexes (IL-1β, IL-4, IL-6, MCP-1, and TNF-α) in NAFLD mice. Further examination revealed that GA ameliorates excessive hepatic macrophage infiltration and hepatocyte apoptosis. The results of the cell experiments further elaborated that GA modulated the PA-induced macrophage STAT3-HIF-1α pathway and ameliorated impaired autophagic flux (blockade of autophagosome-lysosome fusion) and overactivation of inflammation. Excessive hepatocyte apoptosis caused by the uncontrolled release of inflammatory cytokines was also suppressed by GA.
This study demonstrated that GA could regulate the STAT3-HIF-1α pathway of macrophages, ameliorate the impaired autophagy flux, and reduce the excessive production of inflammatory cytokines to improve the excessive apoptosis of liver cells, thus playing a therapeutic role on NAFLD.
巨噬细胞参与肝细胞脂肪变性和坏死炎症，并在非酒精性脂肪性肝病（NAFLD）的发病机制中发挥重要作用。自噬功能受损（自噬减少或自噬流受阻）导致细胞损伤和死亡，并促进 NAFLD 的进展。甘草酸（GA）在治疗 NAFLD 方面的实验和临床研究逐渐受到关注，其具有免疫调节、抗病毒、抗肿瘤、抗氧化、肝脏保护和抗炎等明确的药理作用。然而，GA 对巨噬细胞中 STAT3-HIF-1α通路和自噬的影响尚不清楚，其在治疗 NAFLD 中的作用机制仍有待进一步阐明。我们通过高脂肪高糖饮食构建了 NAFLD 小鼠模型，以研究 GA 的治疗效果。结果表明，GA 可减轻体重，改善肝脏的病理变化和肝内脂质沉积，并异常升高 NAFLD 小鼠血清生化（AST、ALT、TG、T-CHO、LDL-C 和 HDL-C）和炎症指标（IL-1β、IL-4、IL-6、MCP-1 和 TNF-α）水平。进一步检查显示，GA 可改善肝内巨噬细胞过度浸润和肝细胞凋亡。细胞实验结果进一步表明，GA 调节 PA 诱导的巨噬细胞 STAT3-HIF-1α通路，并改善受损的自噬流（自噬体-溶酶体融合受阻）和炎症过度激活。GA 还抑制了由炎症细胞因子失控释放引起的肝细胞过度凋亡。
本研究表明，GA 可调节巨噬细胞的 STAT3-HIF-1α通路，改善受损的自噬流，并减少炎症细胞因子的过度产生，从而减少肝细胞的过度凋亡，从而对 NAFLD 发挥治疗作用。
