文献类型：期刊文献

中文题名：美他多辛通过MAPK增强线粒体功能降低酒精性肝病脂质蓄积

英文题名：Metadoxine enhances mitochondrial function and relieves lipid accumulation in alcoholic liver disease by phosphorylation of MAPK

作者：王咏枝[1];李芸[1];郭伊菲[1];周园奇[1];李洪林[1];张健[1]

机构：[1]华东理工大学药学院,上海市新药设计重点实验室,上海200237

年份：2026

卷号：61

期号：4

起止页码：1246

中文期刊名：药学学报

外文期刊名：Acta Pharmaceutica Sinica

收录：;北大核心:【北大核心2023】；

基金：国家自然科学基金资助项目(82370068).

语种：中文

中文关键词：美他多辛;线粒体损伤;脂质集聚;酒精液体饲料饮食;酒精性肝病

外文关键词：metadoxine;mitochondrial damage;lipid accumulation;Lieber-DeCarli liquid diet;alcoholic steatosis

摘要：为探究美他多辛在酒精性肝病中抑制肝脏细胞脂肪变性的作用机制,本研究采用美他多辛灌胃治疗高脂高乙醇饮食诱导的酒精性肝病小鼠,通过肝脏组织的转录组测序(RNA sequencing,RNA-Seq)分析药物作用的通路;利用乙醇损伤诱导的HepG2细胞线粒体损伤模型探究美他多辛对线粒体功能的影响,从而探究美他多辛改善脂代谢的作用机制。本研究动物实验遵循合肥工业大学科学研究伦理委员会的规定并通过动物实验伦理审查(批号:HUFT20210615002)。实验结果表明,酒精性肝病饮食喂养的小鼠出现了肝脏脂质蓄积。体内实验发现,美他多辛给药后的小鼠血脂水平与模型组相比下降(P<0.05),肝功能损伤减少(P<0.05),肝细胞炎性浸润和脂肪变性显著性减少(P<0.01)。体外实验发现,美他多辛显著逆转了乙醇处理引起的肝细胞线粒体呼吸功能损伤,并增加了线粒体膜电位。通过肝脏组织的RNA-Seq分析发现丝裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)通路明显富集。通过对肝组织的MAPK磷酸化水平的测定,发现美他多辛处理可显著降低p38 MAPK的磷酸化水平(P<0.01)。而p38-MAPK抑制剂和美他多辛共处理后,美他多辛的作用抵消。而p38-MAPK激活剂和美他多辛共处理的情况下,可逆转美他多辛对p38-MAPK磷酸化的抑制作用。美他多辛促进p38 MAPK磷酸化并增强线粒体呼吸功能,减少肝细胞的脂质积累,减少肝脏炎症,从而改善酒精性肝病。
The aim of this study is to elucidate the mechanism of metadoxine through which it attenuates alcoholic liver disease-associated hepatic steatosis.In this study,the effect of metadoxine on alcoholic liver disease was evaluated in mouse model of alcoholic liver disease induced by high alcohol and high fat diets.In addition,RNA sequencing(RNA-Seq)of the liver tissues was applied to determine the dominant signaling pathways in response to metadoxine treatment.The mechanism of metadoxine on metabolic was investigated by mitochondrial function in HepG2 cells.The animal experiments in this study were conducted in accordance with the guidelines of the Ethics Committee for Scientific Research of Hefei University of Technology and were approved by the Animal Experiment Ethics Committee(approval No.:HUFT20210615002).When mice were fed a diet designed to induce alcoholic liver disease,hepatic lipid accumulation resulted.In this study,the level of serum biomarkers of liver injury,such as alanine aminotransferase(ALT)and aspartate aminotransferase(AST),was substantially decreased in mice treated with metadoxine compared to the model group(P<0.05).Meanwhile,the inflammatory infiltration and steatosis in liver were alleviated by the administration of metadoxine compared to the model group(P<0.01).In vitro,metadoxine significantly reversed ethanol overload-induced impairment of mitochondrial respiratory function and increased mitochondrial membrane potential in hepatocytes.Transcriptomic sequencing(RNA-Seq)analysis of liver tissue identified significant enrichment of the mitogen-activated protein kinase(MAPK)signaling pathway.Measurement of MAPK phosphorylation levels in liver tissue showed that metadoxine treatment significantly reduced MAPK phosphorylation(P<0.01).Furthermore,the protective effects of metadoxine were abolished upon co-treatment with a p38-MAPK inhibitor.Conversely,co-treatment with a p38-MAPK activator reversed the inhibitory effect of metadoxine on p38-MAPK phosphorylation.This study investigated the mechanism of metadoxine in alcoholic liver disease and found that metadoxine enhanced mitochondrial function by the phosphorylation of MAPK and reduced the lipid accumulation and inflammation in alcoholic liver disease.