Wu Jingyi, Jia Shu, Xu Benhong, Yao Xiaokun, Shao Jingping, Yao Jianzuo, Cen Danwei, Yao Xiaomin
Faculty of Pharmacy, Zhejiang Pharmaceutical University, Ningbo, China.
Shenzhen Key Laboratory of Modern Toxicology, Shenzhen Medical Key Discipline of Health Toxicology, Shenzhen Center for Disease Control and Prevention, Shengzhen, Guangdong, China.
Front Pharmacol. 2023 Mar 17;14:1157200. doi: 10.3389/fphar.2023.1157200. eCollection 2023.
The pathological progression of non-alcoholic fatty liver disease (NAFLD) is driven by multiple factors, and non-alcoholic steatohepatitis (NASH) represents its progressive form. In our previous studies, we found that bicyclol had beneficial effects on NAFLD/ NASH. Here we aim to investigate the underlying molecular mechanisms of the bicyclol effect on NAFLD/NASH induced by high-fat diet (HFD) feeding. A mice model of NAFLD/NASH induced by HFD-feeding for 8 weeks was used. As a pretreatment, bicyclol (200 mg/kg) was given to mice by oral gavage twice daily. Hematoxylin and eosin (H&E) stains were processed to evaluate hepatic steatosis, and hepatic fibrous hyperplasia was assessed by Masson staining. Biochemistry analyses were used to measure serum aminotransferase, serum lipids, and lipids in liver tissues. Proteomics and bioinformatics analyses were performed to identify the signaling pathways and target proteins. Data are available Proteome X change with identifier PXD040233. The real-time RT-PCR and Western blot analyses were performed to verify the proteomics data. Bicyclol had a markedly protective effect against NAFLD/NASH by suppressing the increase of serum aminotransferase, hepatic lipid accumulation and alleviating histopathological changes in liver tissues. Proteomics analyses showed that bicyclol remarkably restored major pathways related to immunological responses and metabolic processes altered by HFD feeding. Consistent with our previous results, bicyclol significantly inhibited inflammation and oxidative stress pathway related indexes (SAA1, GSTM1 and GSTA1). Furthermore, the beneficial effects of bicyclol were closely associated with the signaling pathways of bile acid metabolism (NPC1, SLCOLA4 and UGT1A1), cytochrome P450-mediated metabolism (CYP2C54, CYP3A11 and CYP3A25), biological processes such as metal ion metabolism (Ceruloplasmin and Metallothionein-1), angiogenesis (ALDH1A1) and immunological responses (IFI204 and IFIT3). These findings suggested that bicyclol is a potential preventive agent for NAFLD/NASH by targeting multiple mechanisms in future clinical investigations.
非酒精性脂肪性肝病（NAFLD）的病理进展由多种因素驱动，非酒精性脂肪性肝炎（NASH）是其进展形式。在我们之前的研究中，我们发现双环醇对NAFLD/NASH有有益作用。在此，我们旨在研究双环醇对高脂饮食（HFD）诱导的NAFLD/NASH作用的潜在分子机制。使用通过8周高脂饮食喂养诱导的NAFLD/NASH小鼠模型。作为预处理，双环醇（200mg/kg）通过每日两次口服灌胃给予小鼠。进行苏木精和伊红（H&E）染色以评估肝脂肪变性，并通过Masson染色评估肝纤维增生。生化分析用于测量血清转氨酶、血脂和肝组织中的脂质。进行蛋白质组学和生物信息学分析以鉴定信号通路和靶蛋白。数据可在Proteome X change上获取，标识符为PXD040233。进行实时RT-PCR和蛋白质印迹分析以验证蛋白质组学数据。双环醇通过抑制血清转氨酶升高、肝脂质积累并减轻肝组织中的组织病理学变化，对NAFLD/NASH具有显著的保护作用。蛋白质组学分析表明，双环醇显著恢复了与高脂饮食喂养改变的免疫反应和代谢过程相关的主要途径。与我们之前的结果一致，双环醇显著抑制炎症和氧化应激途径相关指标（SAA1、GSTM1和GSTA1）。此外，双环醇的有益作用与胆汁酸代谢（NPC1、SLCOLA4和UGT1A1）、细胞色素P450介导的代谢（CYP2C54、CYP3A11和CYP3A25）、金属离子代谢（铜蓝蛋白和金属硫蛋白-1）、血管生成（ALDH1A1）和免疫反应（IFI204和IFIT3）等生物学过程的信号通路密切相关。这些发现表明，在未来的临床研究中，双环醇通过靶向多种机制可能是一种潜在的NAFLD/NASH预防药物。
