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

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.