title: Preventing Gut Leakiness and Endotoxemia Contributes to the Protective Effect of Zinc on Alcohol-Induced Steatohepatitis in Rats.
abstract: BACKGROUND
  Zinc deficiency has been well documented in alcoholic liver disease.
  
  
  OBJECTIVE
  This study was undertaken to determine whether dietary zinc supplementation provides beneficial effects in treating alcohol-induced gut leakiness and endotoxemia.
  
  
  METHODS
  Male Sprague Dawley rats were divided into 3 groups and pair-fed (PF) Lieber-DeCarli liquid diet for 8 wk: 1) control (PF); 2) alcohol-fed (AF; 5.00-5.42% wt:vol ethanol); and 3) AF with zinc supplementation (AF/Zn) at 220 ppm zinc sulfate heptahydrate. The PF and AF/Zn groups were pair-fed with the AF group. Hepatic inflammation and endotoxin signaling were determined by immunofluorescence and quantitative polymerase chain reaction (qPCR). Alterations in intestinal tight junctions and aldehyde dehydrogenases were assessed by qPCR and Western blot analysis.
  
  
  RESULTS
  The AF rats had greater macrophage activation and cytokine production (P < 0.05) in the liver compared with the PF rats, whereas the AF/Zn rats showed no significant differences (P > 0.05). Plasma endotoxin concentrations of the AF rats were 136% greater than those of the PF rats, whereas the AF/Zn rats did not differ from the PF rats. Ileal permeability was 255% greater in the AF rats and 19% greater in the AF/Zn rats than in the PF rats. The AF group had reduced intestinal claudin-1, occludin, and zona occludens-1 (ZO-1) expression, and the AF/Zn group had upregulated claudin-1 and ZO-1 expression (P < 0.05) compared with the PF group. The intestinal epithelial expression and activity of aldehyde dehydrogenases were elevated (P < 0.05) in the AF/Zn rats compared with those of the AF rats. Furthermore, the ileal expression and function of hepatocyte nuclear factor 4α, which was impaired in the AF group, was significantly elevated in the AF/Zn group compared with the PF group.
  
  
  CONCLUSIONS
  The results demonstrate that attenuating hepatic endotoxin signaling by preserving the intestinal barrier contributes to the protective effect of zinc on alcohol-induced steatohepatitis in rats.
authors.affiliation: Center for Translational Biomedical Research and.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhong
authors.affiliation: Center for Translational Biomedical Research and.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Li
authors.affiliation: Center for Translational Biomedical Research and Department of Nutrition, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC; and.
authors.forename: Qian
authors.initials: Q
authors.lastname: Sun
authors.affiliation: Center for Translational Biomedical Research and.
authors.forename: Wenliang
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Chemistry, University of Louisville, Louisville, KY.
authors.forename: Jiayang
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Center for Translational Biomedical Research and.
authors.forename: Xinguo
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department of Chemistry, University of Louisville, Louisville, KY.
authors.forename: Xinmin
authors.initials: X
authors.lastname: Yin
authors.affiliation: Department of Chemistry, University of Louisville, Louisville, KY.
authors.forename: Xiang
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Center for Translational Biomedical Research and Department of Nutrition, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC; and z_zhou@uncg.edu.
authors.forename: Zhanxiang
authors.initials: Z
authors.lastname: Zhou
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000818:Animals; D062445:Claudin-1 / Q000032:analysis; D016207:Cytokines / Q000096:biosynthesis; D019587:Dietary Supplements; D019446:Endotoxemia / Q000517:prevention & control*; D004731:Endotoxins / Q000032:analysis; D000431:Ethanol / Q000009:adverse effects; D005235:Fatty Liver, Alcoholic / Q000503:physiopathology / Q000517:prevention & control*; D007410:Intestinal Diseases / Q000139:chemically induced / Q000517:prevention & control*; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000737:chemistry / Q000201:enzymology; D008099:Liver / Q000473:pathology / Q000503:physiopathology; D008262:Macrophage Activation; D008297:Male; D062793:Occludin / Q000032:analysis; D010539:Permeability / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D062725:Tight Junction Proteins / Q000032:analysis; D015032:Zinc / Q000008:administration & dosage* / Q000172:deficiency; D062826:Zonula Occludens-1 Protein / Q000032:analysis
chemical_list: D062445:Claudin-1; D016207:Cytokines; D004731:Endotoxins; D062793:Occludin; D062725:Tight Junction Proteins; D062826:Zonula Occludens-1 Protein; D000431:Ethanol; D000444:Aldehyde Dehydrogenase; D015032:Zinc
keywords: HNF-4α; alcohol; alcoholic liver disease; aldehyde dehydrogenase; endotoxemia; intestinal barrier; zinc