PDF(Pubmed)
Abstract：
Background and aims: 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. Methods: 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. Results: 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. Conclusion: 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.
摘要：
背景和目的：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,目前没有批准的治疗NASH的药物.我们的研究旨在评估银杏素对NASH的影响及其相关机制。方法:高脂饮食24周构建NASH小鼠模型。通过组织学研究评估银杏素对NASH的影响。蛋白质印迹,和生化分析。RNA测序(RNA-Seq)分析用于研究在主体和单细胞水平上的基因表达和信号传导途径的改变。结果：服用银杏素导致肝脏脂质积累的显着改善，炎症,和NASH模型中的纤维化。这些结果得到了大量RNA-Seq分析的支持，其中相关的信号通路和基因表达显著下调。此外，单细胞RNA-Seq（scRNA-Seq）分析显示，银杏素对NASH的影响与巨噬细胞的重编程有关，肝星状细胞，和内皮细胞。尤其是,银杏素诱导NASH小鼠巨噬细胞的显著减少和从促炎表型到抗炎表型的转变。和NASH相关巨噬细胞（NAMs），在NASH期间出现，银杏素也显著下调。结论：银杏素对改善NASH具有有益作用，由批量和单细胞RNA-Seq支持。我们的研究可以促进NASH的药物治疗，提高对NASH的认识。
