Hepatocyte Nuclear Factor 4α, a Key Factor for Homeostasis, Cell Architecture, and Barrier Function of the Adult Intestinal Epithelium
Hepatocyte Nuclear Factor 4α, a Key Factor for Homeostasis, Cell Architecture, and Barrier Function of the Adult Intestinal Epithelium
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DOI：
10.1128/mcb.00939-09
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发表时间：
2009-12-01
影响因子：
5.3
通讯作者：
Ribeiro, Agnes
中科院分区：
文献类型：
--
作者：
Cattin, Anne-Laure;Le Beyec, Johanne;Ribeiro, Agnes
肝细胞核因子4α（HNF - 4α）是一种转录因子，在从十二指肠到结肠以及从隐窝到绒毛的肠上皮中高度表达。这种不断更新的上皮的内稳态依赖于对增殖、分化和凋亡的综合控制，以及上皮细胞的功能结构。为了确定成年肠上皮中HNF - 4α缺失的后果，我们使用他莫昔芬诱导的Cre - loxP系统使Hnf - 4a基因失活。在成年小鼠的肠道中，HNF - 4α的缺失导致隐窝中增殖增加，以及受Wnt/β - 连环蛋白系统控制的几个基因的表达增加。HNF - 4α对Wnt/β - 连环蛋白信号通路的这种控制在体外得到了证实。细胞谱系受到影响，表现为杯状细胞数量增加以及肠上皮细胞和肠内分泌细胞成熟受损。在没有HNF - 4α的情况下，细胞 - 细胞连接不稳定，细胞旁肠道通透性增加。我们的结果表明，HNF - 4α调节Wnt/β - 连环蛋白信号传导，并控制肠上皮内稳态、细胞功能和细胞结构。这项研究表明，HNF - 4α调节增殖和分化之间的肠道平衡，并且我们假设它可能作为一种肿瘤抑制因子发挥作用。
Hepatocyte nuclear factor 4 alpha (HNF-4 alpha) is a transcription factor which is highly expressed in the intestinal epithelium from duodenum to colon and from crypt to villus. The homeostasis of this constantly renewing epithelium relies on an integrated control of proliferation, differentiation, and apoptosis, as well as on the functional architecture of the epithelial cells. In order to determine the consequences of HNF-4 alpha loss in the adult intestinal epithelium, we used a tamoxifen-inducible Cre-loxP system to inactivate the Hnf-4a gene. In the intestines of adult mice, loss of HNF-4 alpha led to an increased proliferation in crypts and to an increased expression of several genes controlled by the Wnt/beta-catenin system. This control of the Wnt/beta-catenin signaling pathway by HNF-4 alpha was confirmed in vitro. Cell lineage was affected, as indicated by an increased number of goblet cells and an impairment of enterocyte and enteroendocrine cell maturation. In the absence of HNF-4 alpha, cell-cell junctions were destabilized and paracellular intestinal permeability increased. Our results showed that HNF-4 alpha modulates Wnt/beta-catenin signaling and controls intestinal epithelium homeostasis, cell function, and cell architecture. This study indicates that HNF-4 alpha regulates the intestinal balance between proliferation and differentiation, and we hypothesize that it might act as a tumor suppressor.