The mechanism of FOXO4 in acute alcoholic liver disease

Abstract

Objective To investigate the role of tumor necrosis factor alpha (TNFα) in a rat model of experimental acute alcoholic liver disease,and further elucidate the relationship among TNFα,forkhead box subtype O4 (FOXO4),nuclear factor κB (NF-κB),and zonula occludens-1 (ZO-1).Methods Sixty four Wister (WT) rats were divided into eight groups (8 in each group):normal group,alcohol group,alcohol + TNFα group,alcohol + wortmannin group,alcohol + insulin-like growth factor-1 (IGF-1) group,alcohol + anti-TNFo group,and two placebo groups (treated with saline).TNFα in plasma was measured by enzyme linked immunosorbent assay (ELISA).Western blot was used to identify the mechanisms of FOXO4 in regulating the epithelial permeability.Electron microscopy,reverse transcription polymerase chain reaction and western blot were used to examine the tightjunction proteins and NF-κB.Results Compared to control group,TNFα in alcohol group was obviously high.At the same time,TNFα could induce the phosphorylation of FOXO4.Phosphorylated FOXO4 was excluded into cytoplasm and was inactive.The inactive FOXO4 at a high level lose the ability to restrain NF-κB.Therefore,the expression of NF-κB was increased,then it down-regulated the expressions of tight junction proteins (including ZO-1 and occludin) and increased epithelial permeability.As a result,the intestinal bacteria were grown excessively,endotoxin was released into portal circulation and liver injury was deteriorated.Conclusions TNFα can up-regulate phosphorylation of FOXO4.Phosphorylated FOXO4 in the nucleus is excluded into cytoplasm and is inactive.The inactive FOXO4 lose the ability to restrain NF-κB activity,then down-regulate the expression of tight junction proteins and increase epithelial permeability. Key words: NF-kappa B/biosynthesis; Liver diseases, alcoholic/metabolism; Disease models, animal ; Tumor necrosis factor-alpha/blood; Acute disease