title: The role of FoxO4 in the relationship between alcohol-induced intestinal             barrier dysfunction and liver injury.
abstract: Forkhead box 'Other' (FoxO) proteins, a subgroup of the Forkhead transcription             factor family, play an important role in mediating the effects of insulin and             growth factors on diverse physiological functions. In this study, we investigated             the role of FoxO4 in the relationship between alcohol liver disease and intestinal             barrier dysfunction using an animal model. Six to eight-week-old male WT rats             were divided into eight groups. They were separately administered corn starch             dissolved in PBS; 40% alcohol (5 g/kg body weight) through stomach feeding every             12 h/time, three times in total; tumor necrosis factor α (TNFα) (10 µg/kg) injected             intraperitoneally 30 min before alcohol administration; wortmannin (1.4 mg/kg)             30 min before alcohol administration; IGF-1 (0.2 mg/kg) 30 min before alcohol             administration; anti-TNFα (5 mg/kg) injected intravenously 30 min before alcohol             administration. In addition, two placebo groups were treated with PBS either intraperitoneally             or intravenously prior to alcohol administration. TNFα and endotoxin in plasma             were measured by ELISA and Tachypleus Amebocye Lysate assays. Immunohistochemistry             and western blotting were used to identify the mechanisms of FoxO4 action in regulating             epithelial permeability. Furthermore, electron microscopy, reverse transcription-polymerase             chain reaction and western blotting were used to examine the expression of tight             junction 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 was             in high levels lost the ability to suppress NF-κB. Therefore, the expression of             NF-κB was increased and it downregulated tight junction protein (including ZO-1             and occludin) expression, and increased epithelial permeability. As a result,             intestinal bacteria grew excessively, endotoxin was released into the portal circulation             and liver injury deteriorated. These results indicate that a complex network of             mechanisms is involved in the beneficial effects of FoxO4 in epithelial barrier             dysfunction. TNFα can upregulate phosphorylation of FoxO4. FoxO4 which is located             in the nucleus is limited into the cytoplasm and inactivated; it loses the ability             to suppress NF-κB activity, it downregulates the expression of tight junction             proteins and increases epithelial permeability. Disruption of the intestinal barrier             allows endotoxin and other bacterial products in the gut lumen to pass into the             portal circulation and cause hepatic inflammation. At the same time, the changes             of liver injury deteriorate.
authors.affiliation: Department of Gastroenterology, The First Afﬁliated Hospital of China Medical University, Shenyang, Liaoning 110001, PR China.
authors.forename: Bing
authors.initials: B
authors.lastname: Chang
authors.forename: Lixuan
authors.initials: L
authors.lastname: Sang
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Jing
authors.initials: J
authors.lastname: Tong
authors.forename: Bingyuan
authors.initials: B
authors.lastname: Wang
mesh_terms: D000428:Alcohol Drinking; D019973:Alcohol-Related Disorders; D000730:Androstadienes / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D015536:Down-Regulation; D000431:Ethanol / Q000008:administration & dosage / Q000494:pharmacology*; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000008:administration & dosage / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D007422:Intestines / Q000473:pathology; D008108:Liver Diseases, Alcoholic / Q000473:pathology*; D008297:Male; D016328:NF-kappa B / Q000096:biosynthesis; D010766:Phosphorylation; D051381:Rats; D062725:Tight Junction Proteins / Q000096:biosynthesis*; D019108:Tight Junctions / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D000911:Antibodies, Monoclonal; C524737:FOXO4 protein, rat; D051858:Forkhead Transcription Factors; D016328:NF-kappa B; D062725:Tight Junction Proteins; D014409:Tumor Necrosis Factor-alpha; D000431:Ethanol; D007334:Insulin-Like Growth Factor I; D000077191:Wortmannin