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Forkhead box 'Other' (FoxO) proteins, a subgroup of the Forkhead transcriptionfactor family, play an important role in mediating the effects of insulin andgrowth factors on diverse physiological functions. In this study, we investigatedthe role of FoxO4 in the relationship between alcohol liver disease and intestinalbarrier dysfunction using an animal model. Six to eight-week-old male WT ratswere divided into eight groups. They were separately administered corn starchdissolved in PBS; 40% alcohol (5 g/kg body weight) through stomach feeding every12 h/time, three times in total; tumor necrosis factor α (TNFα) (10 µg/kg) injectedintraperitoneally 30 min before alcohol administration; wortmannin (1.4 mg/kg)30 min before alcohol administration; IGF-1 (0.2 mg/kg) 30 min before alcoholadministration; anti-TNFα (5 mg/kg) injected intravenously 30 min before alcoholadministration. In addition, two placebo groups were treated with PBS either intraperitoneallyor intravenously prior to alcohol administration. TNFα and endotoxin in plasmawere measured by ELISA and Tachypleus Amebocye Lysate assays. Immunohistochemistryand western blotting were used to identify the mechanisms of FoxO4 action in regulatingepithelial permeability. Furthermore, electron microscopy, reverse transcription-polymerasechain reaction and western blotting were used to examine the expression of tightjunction proteins and nuclear factor-κB (NF-κB). Compared with the control group,TNFα in the alcohol group was significantly higher. TNFα could induce FoxO4 phosphorylation;p-FoxO4 was limited into the cytoplasm and inactivated; inactive FoxO4 which wasin high levels lost the ability to suppress NF-κB. Therefore, the expression ofNF-κB was increased and it downregulated tight junction protein (including ZO-1and occludin) expression, and increased epithelial permeability. As a result,intestinal bacteria grew excessively, endotoxin was released into the portal circulationand liver injury deteriorated. These results indicate that a complex network ofmechanisms is involved in the beneficial effects of FoxO4 in epithelial barrierdysfunction. TNFα can upregulate phosphorylation of FoxO4. FoxO4 which is locatedin the nucleus is limited into the cytoplasm and inactivated; it loses the abilityto suppress NF-κB activity, it downregulates the expression of tight junctionproteins and increases epithelial permeability. Disruption of the intestinal barrierallows endotoxin and other bacterial products in the gut lumen to pass into theportal circulation and cause hepatic inflammation. At the same time, the changesof liver injury deteriorate.

The role of FoxO4 in the relationship between alcohol-induced intestinal barrier dysfunction and liver injury