Phosphatidylethanol accumulation promotes intestinal hyperplasia by inducing ZONAB-mediated cell density increase in response to chronic ethanol exposure.
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.
Pannequin
Julie
J
Laboratoire de Biochimie, Faculté de Pharmacie, Institut de Génomique Fonctionnelle, Bâtiment E, 15 Avenue Charles Flahault, 34093 Montpellier Cedex 5, France.
Delaunay
Nathalie
N
Darido
Charbel
C
Maurice
Tangui
T
Crespy
Philippe
P
Frohman
Michael A
MA
Balda
Maria S
MS
Matter
Karl
K
Joubert
Dominique
D
Bourgaux
Jean-François
JF
Bali
Jean-Pierre
JP
Hollande
Frédéric
F
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
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