Wang Chaoyang, Bai Yaowei, Li Tongqiang, Liu Jiacheng, Wang Yingliang, Ju Shuguang, Yao Wei, Xiong Bin, Zhou Guofeng
Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Interventional Radiology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
Front Pharmacol. 2023 Oct 4;14:1267445. doi: 10.3389/fphar.2023.1267445. eCollection 2023.
Nonalcoholic steatohepatitis (NASH) has become one of the major causes of cirrhosis and liver failure. However, there are currently no approved medications for managing NASH. Our study was designed to assess the effects of ginkgetin on NASH and the involved mechanisms. We constructed a mouse model of NASH by high-fat diet for 24 weeks. The effects of ginkgetin on NASH were evaluated by histological study, Western blot, and biochemical analysis. RNA Sequencing (RNA-Seq) analysis was used to investigate the alteration in gene expression and signaling pathways at bulk and single-cell levels. Administration of ginkgetin resulted in a marked improvement in hepatic lipid accumulation, inflammation, and fibrosis in the NASH model. And these results were supported by bulk RNA-Seq analysis, in which the related signaling pathways and gene expression were markedly downregulated. Furthermore, single-cell RNA-Seq (scRNA-Seq) analysis revealed that the effects of ginkgetin on NASH were associated with the reprogramming of macrophages, hepatic stellate cells, and endothelial cells. Especially, ginkgetin induced a marked decrease in macrophages and a shift from pro-inflammatory to anti-inflammatory phenotype in NASH mice. And the NASH-associated macrophages (NAMs), which emerge during NASH, were also significantly downregulated by ginkgetin. Ginkgetin exhibits beneficial effects on improving NASH, supported by bulk and single-cell RNA-Seq. Our study may promote pharmacological therapy for NASH and raise the existent understanding of NASH.
非酒精性脂肪性肝炎（NASH）已成为肝硬化和肝衰竭的主要原因之一。然而，目前尚无获批用于治疗NASH的药物。我们的研究旨在评估白果素对NASH的影响及其相关机制。我们通过高脂饮食24周构建了NASH小鼠模型。通过组织学研究、蛋白质印迹法和生化分析评估白果素对NASH的影响。RNA测序（RNA-Seq）分析用于研究整体和单细胞水平上基因表达和信号通路的变化。在NASH模型中，给予白果素可显著改善肝脏脂质蓄积、炎症和纤维化。这些结果得到了整体RNA-Seq分析的支持，其中相关信号通路和基因表达明显下调。此外，单细胞RNA测序（scRNA-Seq）分析显示，白果素对NASH的影响与巨噬细胞、肝星状细胞和内皮细胞的重编程有关。特别是，白果素可使NASH小鼠的巨噬细胞显著减少，并使其从促炎表型转变为抗炎表型。而且，在NASH期间出现的NASH相关巨噬细胞（NAMs）也被白果素显著下调。在整体和单细胞RNA-Seq的支持下，白果素对改善NASH具有有益作用。我们的研究可能会促进NASH的药物治疗，并加深对NASH的现有认识。
