title: Phosphatidylethanol accumulation promotes intestinal hyperplasia by inducing ZONAB-mediated cell density increase in response to chronic ethanol exposure.
abstract: Chronic alcohol consumption is associated with increased risk of gastrointestinal cancer. High concentrations of ethanol trigger mucosal hyperregeneration, disrupt cell adhesion, and increase the sensitivity to carcinogens. Most of these effects are thought to be mediated by acetaldehyde, a genotoxic metabolite produced from ethanol by alcohol dehydrogenases. Here, we studied the role of low ethanol concentrations, more likely to mimic those found in the intestine in vivo, and used intestinal cells lacking alcohol dehydrogenase to identify the acetaldehyde-independent biological effects of ethanol. Under these conditions, ethanol did not stimulate the proliferation of nonconfluent cells, but significantly increased maximal cell density. Incorporation of phosphatidylethanol, produced from ethanol by phospholipase D, was instrumental to this effect. Phosphatidylethanol accumulation induced claudin-1 endocytosis and disrupted the claudin-1/ZO-1 association. The resulting nuclear translocation of ZONAB was shown to mediate the cell density increase in ethanol-treated cells. In vivo, incorporation of phosphatidylethanol and nuclear translocation of ZONAB correlated with increased proliferation in the colonic epithelium of ethanol-fed mice and in adenomas of chronic alcoholics. Our results show that phosphatidylethanol accumulation after chronic ethanol exposure disrupts signals that normally restrict proliferation in highly confluent intestinal cells, thus facilitating abnormal intestinal cell proliferation.
authors.affiliation: Laboratoire de Biochimie, Faculté de Pharmacie, Institut de Génomique Fonctionnelle, Bâtiment E, 15 Avenue Charles Flahault, 34093 Montpellier Cedex 5, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Pannequin
authors.forename: Nathalie
authors.initials: N
authors.lastname: Delaunay
authors.forename: Charbel
authors.initials: C
authors.lastname: Darido
authors.forename: Tangui
authors.initials: T
authors.lastname: Maurice
authors.forename: Philippe
authors.initials: P
authors.lastname: Crespy
authors.forename: Michael A
authors.initials: MA
authors.lastname: Frohman
authors.forename: Maria S
authors.initials: MS
authors.lastname: Balda
authors.forename: Karl
authors.initials: K
authors.lastname: Matter
authors.forename: Dominique
authors.initials: D
authors.lastname: Joubert
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Bourgaux
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Bali
authors.forename: Frédéric
authors.initials: F
authors.lastname: Hollande
mesh_terms: D000230:Adenocarcinoma / Q000139:chemically induced* / Q000378:metabolism; D000426:Alcohol Dehydrogenase / Q000172:deficiency / Q000235:genetics; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D018938:Caco-2 Cells; D002452:Cell Count; D062445:Claudin-1; D003110:Colonic Neoplasms / Q000139:chemically induced* / Q000378:metabolism; D004705:Endocytosis; D000431:Ethanol / Q000633:toxicity*; D020404:Glycerophospholipids / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006965:Hyperplasia / Q000139:chemically induced; D007422:Intestines / Q000187:drug effects* / Q000473:pathology*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D010739:Phospholipase D / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D062826:Zonula Occludens-1 Protein
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; C568108:CLDN1 protein, human; D062445:Claudin-1; C568113:Cldn1 protein, mouse; D020404:Glycerophospholipids; D006360:Heat-Shock Proteins; D008565:Membrane Proteins; D010750:Phosphoproteins; C569042:TJP1 protein, human; C569043:Tjp1 protein, mouse; C094867:YBX3 protein, human; D062826:Zonula Occludens-1 Protein; C051521:phosphatidylethanol; D000431:Ethanol; D000426:Alcohol Dehydrogenase; D010739:Phospholipase D