Guangxi Medical University, Nanning, Guangxi, 530021, PR China.
Guangxi Medical University, Nanning, Guangxi, 530021, PR China.
Phytomedicine. 2024 Dec;135:156016. doi: 10.1016/j.phymed.2024.156016. Epub 2024 Sep 8.
Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases accompanied by lipid and glucose metabolism disorder. Didymin has been reported to have various hepatoprotective effects, however, its potential effects and mechanisms on NAFLD remain unclear from the perspective of the whole.
To investigate the underlying mechanism of didymin against NAFLD using multi-omics technologies.
Rats were fed with a high-fat diet (HFD) for 8 weeks to induce NAFLD, followed by didymin treatment for 8 weeks. Next, biochemical analysis and histopathological examinations were performed to evaluate the effects of didymin. The key regulating pathways were predicted using transcriptomics, metabolomics and proteomics, and the target pathways were then verified by detecting the key genes/proteins using various experiments.
Didymin markedly mitigated liver injury and excessive lipid droplet accretion. An integrative multi-omics analysis suggested that the PPAR signaling cascade and insulin signaling pathway might serve as pivotal mechanisms underlying the modulation of lipid and glucose homeostasis by didymin. Further dissection identified five pivotal genes (PPARα, PPARβ, FABP4, ANGPTL4, and PLIN2) and four genes (HK1, HK3, GCK, and PTPN1) as potential hubs within these pathways. Subsequent validation experiments, including qPCR and Western blot, demonstrated upregulated expression of PPARα and PPARβ, indicating the activation of the PPAR pathway by didymin. Concurrently, didymin appeared to modulate the insulin signaling pathway, as evidenced by the upregulated expression of HK1 and downregulated expression of PTPN1. Notably, the manipulation of PPARα, PPARβ, and PTPN1 expression in LO2 cells through silence or overexpression confirmed that didymin significantly reduced lipid accumulation, with its molecular targets likely being the PPAR and insulin pathways.
Our findings demonstrate that didymin has a protective effect on NAFLD, and its underlying mechanism may be associated with the regulation of the PPAR and insulin signaling pathways.
非酒精性脂肪性肝病（NAFLD）是最常见的肝脏疾病之一，常伴有脂质和糖代谢紊乱。水飞蓟宾具有多种保肝作用，但其对 NAFLD 的潜在作用和机制尚不清楚。
采用多组学技术研究水飞蓟宾防治 NAFLD 的作用机制。
用高脂肪饮食（HFD）喂养大鼠 8 周诱导 NAFLD，然后用水飞蓟宾治疗 8 周。然后进行生化分析和组织病理学检查，以评估水飞蓟宾的作用。通过转录组学、代谢组学和蛋白质组学预测关键调控途径，然后通过各种实验检测关键基因/蛋白来验证靶途径。
水飞蓟宾显著减轻了肝损伤和过量脂质滴的积聚。整合的多组学分析表明，PPAR 信号级联和胰岛素信号通路可能是水飞蓟宾调节脂质和葡萄糖稳态的关键机制。进一步分析确定了五个关键基因（PPARα、PPARβ、FABP4、ANGPTL4 和 PLIN2）和四个基因（HK1、HK3、GCK 和 PTPN1）作为这些途径中的潜在枢纽。随后的验证实验，包括 qPCR 和 Western blot，表明 PPARα 和 PPARβ 的表达上调，表明水飞蓟宾激活了 PPAR 途径。同时，水飞蓟宾似乎调节了胰岛素信号通路，表现为 HK1 的表达上调和 PTPN1 的表达下调。值得注意的是，通过沉默或过表达 LO2 细胞中的 PPARα、PPARβ 和 PTPN1 来操纵其表达，证实了水飞蓟宾可显著减少脂质积累，其分子靶点可能是 PPAR 和胰岛素通路。
本研究表明水飞蓟宾对 NAFLD 具有保护作用，其作用机制可能与调节 PPAR 和胰岛素信号通路有关。
