The Role Of IRF6 In Non-alcoholic Fatty Liver Disease

Aims Nonalcoholic fatty liver disease(NAFLD)has now become a global epidemic disease.With the increasing incidence and prevalence,the mechanism of disease development and treatment needs have stimulated a lot of research in this field.In this study,we found that interferon regulatory factor 6(IRF6)was suppressed in mouse fatty liver induced by a high-fat diet by combining genomic data published in the Gene Expression Omnibus database with samples from rodents with NAFLD,indicating that IRF6 gene in hepatocytes might be a protective factor in hepatic steatosis.Therefore,we hypothesized that IRF6-dependent mechanism might possess an important role in NAFLD.Methods First,the expression of IRF6 protein in the liver samples of NAFLD mice and patients was examined to see if there was a correlation between IRF6 and lipid metabolism abnormalities.Secondly,the Irf6 knock-out L02 cell line was constructed in vitro,and the lipid accumulation of liver cells was induced by PA/OA stimulation for 24 hours to observe whether IRF6 had an effect on liver lipid accumulation.Finally,by constructing an IRF6 liver-specific transgenic mouse model,a fatty liver model was established through high-fat feeding,through pathological staining and various metabolic indicators(serum insulin,serum glucose content,insulin homeostasis model,insulin tolerance test,glucose tolerance test,alanine aminotransferase,aspartate aminotransferase)to evaluate the effect of IRF6 overexpression on hepatic lipid metabolism.Results After high-fat feeding,NAFLD mice showed a decrease in the expression of hepatic IRF6.The pathological immunohistochemical examination of liver tissue in patients with NAFLD also showed a decrease in the expression of IRF6.In vitro studies revealed that IRF6 was down-regulated in the in vitro palmitic acid/oleic acid-induced model,and Irf6 knockout hepatocytes were further established,and hepatocyte lipid accumulation was found to be aggravated.IRF6 liver-specific overexpression(IRF6-HTG)mice are resistant to obesity,insulin resistance,and lipid deposition caused by high-fat diet feeding.Conclusion In this study,we concluded that the transcription factor IRF6 in hepatocytes is a key protector against NAFLD.Overexpression of IRF6 in hepatocytes attenuates HFD-induced liver lipid accumulation.