Xue Lijuan, Liu Keanqi, Yan Caixia, Dun Junling, Xu Yexin, Wu Linlin, Yang Huizhu, Liu Huafang, Xie Lin, Wang Guangji, Liang Yan
Key Lab of Drug Metabolism & Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
Zhejiang Provincial Key Laboratory for Drug Evaluation and Clinical Research, Department of Clinical Pharmacy, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
Acta Pharm Sin B. 2023 Aug;13(8):3545-3560. doi: 10.1016/j.apsb.2023.04.009. Epub 2023 Apr 23.
Nonalcoholic steatohepatitis (NASH) is a spectrum of chronic liver disease characterized by hepatic lipid metabolism disorder. Recent reports emphasized the contribution of triglyceride and diglyceride accumulation to NASH, while the other lipids associated with the NASH pathogenesis remained unexplored. The specific purpose of our study was to explore a novel pathogenesis and treatment strategy of NASH profiling the metabolic characteristics of lipids. Herein, multi-omics techniques based on LC-Q-TOF/MS, LC-MS/MS and MS imaging were developed and used to screen the action targets related to NASH progress and treatment. A methionine and choline deficient (MCD) diet-induced mouse model of NASH was then constructed, and lignans extract (SLE) was applied to alleviate hepatic damage by regulating the lipid metabolism-related enzymes CES2A and CYP4A14. Hepatic lipidomics indicated that MCD-diet led to aberrant accumulation of phosphatidylethanolamines (PEs), and SLE could significantly reduce the accumulation of intrahepatic PEs. Notably, exogenous PE (18:0/18:1) was proved to significantly aggravate the mitochondrial damage and hepatocyte apoptosis. Supplementing PE (18:0/18:1) also deteriorated the NASH progress by up regulating intrahepatic proinflammatory and fibrotic factors, while PE synthase inhibitor exerted a prominent hepatoprotective role. The current work provides new insights into the relationship between PE metabolism and the pathogenesis of NASH.
非酒精性脂肪性肝炎（NASH）是一种以肝脏脂质代谢紊乱为特征的慢性肝病谱。最近的报道强调了甘油三酯和甘油二酯积累对NASH的作用，而与NASH发病机制相关的其他脂质仍未被探索。我们研究的具体目的是通过分析脂质的代谢特征来探索NASH的新发病机制和治疗策略。在此，基于液相色谱-四极杆飞行时间质谱（LC-Q-TOF/MS）、液相色谱-串联质谱（LC-MS/MS）和质谱成像的多组学技术被开发并用于筛选与NASH进展和治疗相关的作用靶点。然后构建了蛋氨酸和胆碱缺乏（MCD）饮食诱导的NASH小鼠模型，并应用木脂素提取物（SLE）通过调节脂质代谢相关酶CES2A和CYP4A14来减轻肝脏损伤。肝脏脂质组学表明，MCD饮食导致磷脂酰乙醇胺（PEs）异常积累，而SLE可显著减少肝内PEs的积累。值得注意的是，外源性PE（18:0/18:1）被证明可显著加重线粒体损伤和肝细胞凋亡。补充PE（18:0/18:1）还通过上调肝内促炎和纤维化因子而使NASH进展恶化，而PE合酶抑制剂发挥了显著的肝脏保护作用。目前的工作为PE代谢与NASH发病机制之间的关系提供了新的见解。
