Phosphatidylethanol accumulation promotes intestinal hyperplasia by inducing ZONAB-mediated cell density increase in response to chronic ethanol exposure
Phosphatidylethanol accumulation promotes intestinal hyperplasia by inducing ZONAB-mediated cell density increase in response to chronic ethanol exposure
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DOI：
10.1158/1541-7786.mcr-07-0198
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发表时间：
2007-11-01
影响因子：
5.2
通讯作者：
Hollande, Frederic
中科院分区：
文献类型：
--
作者：
Pannequin, Julie;Delaunay, Nathalie;Hollande, Frederic
长期饮酒与胃肠癌风险增加有关。高浓度的乙醇会引发粘膜过度再生，破坏细胞粘附，并增加对致癌物的敏感性。大多数这些影响被认为是由乙醛介导的，乙醛是一种由乙醇脱氢酶产生的遗传毒性代谢物。在这里，我们研究了低乙醇浓度的作用，更可能模拟体内肠道中发现的乙醇浓度，并使用缺乏乙醇脱氢酶的肠道细胞来鉴定乙醇的不依赖于乙醛的生物效应。在这些条件下，乙醇不会刺激未汇合细胞的增殖，但显着增加了最大细胞密度。磷脂酶 D 由乙醇产生的磷脂酰乙醇的掺入有助于实现这一效果。磷脂酰乙醇积累诱导claudin-1内吞作用并破坏claudin-1/ZO-1结合。结果表明，ZONAB 的核转位可介导乙醇处理细胞中细胞密度的增加。在体内，磷脂酰乙醇的掺入和 ZONAB 的核转位与乙醇喂养小鼠的结肠上皮和慢性酗酒者的腺瘤的增殖增加相关。我们的结果表明，慢性乙醇暴露后磷脂酰乙醇的积累破坏了通常限制高度汇合肠道细胞增殖的信号，从而促进异常肠道细胞增殖。
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.