Hepatocyte nuclear factor 4alpha in the intestinal epithelial cells protects against inflammatory bowel disease.
Hepatocyte nuclear factor 4alpha in the intestinal epithelial cells protects against inflammatory bowel disease.
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DOI：
10.1002/ibd.20413
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发表时间：
2008-07
影响因子：
4.9
通讯作者：
Inoue, Yusuke
中科院分区：
文献类型：
--
作者：
Ahn, Sung-Hoon;Shah, Yatrik M.;Inoue, Junko;Morimura, Keiichirou;Kim, Insook;Yim, SunHee;Lambert, Gilles;Kurotani, Reiko;Nagashima, Kunio;Gonzalez, Frank J.;Inoue, Yusuke
肝细胞核因子4α(HNF4α；NR2A1)是在肝脏和肠道表达的核受体超家族中的孤儿成员。虽然HNF4α的表达对肝功能至关重要，但它在肠道和炎症性肠病发病机制中的作用尚不清楚。检测了正常对照和炎症性肠病患者的肠道组织中编码HNF4α和其他核受体的mRNAs的表达。利用HNF4FLOXD等位基因和α-Cre转基因，建立了肠道特异的HNF4Cre缺失小鼠品系(HNF4αΔIEpC)。这些小鼠和它们的对照小鼠(HNF4αF/F)接受了葡聚糖硫酸钠(DSS)诱导的IBD结肠炎方案，并测定了它们的临床症状和基因表达模式。在人类肠道活检组织中，克隆氏病和溃疡性结肠炎患者的肠道组织中HNF4α显著减少。DSS处理的小鼠肠道中hNF4α的表达也受到抑制。在HNF4αΔIEpC小鼠中，HNF4α的表达在整个肠道上皮细胞中被破坏。在DSS诱导的结肠炎模型中，与Hnf4αΔF/F小鼠相比，Hnf4αIEpC小鼠在与IBD相关的临床症状和病理改变方面明显更严重，包括体重减轻、结肠长度和组织学形态。此外，HNF4αΔIEpC小鼠表现出粘蛋白相关基因的显著改变和肠道通透性的增加，这可能在炎症性侮辱后增加急性结肠炎的易感性中起重要作用。虽然HNF4α在肠道的正常功能中不起主要作用，但它可以保护肠道免受DSS诱导的结肠炎的影响。
Hepatocyte nuclear factor 4α (HNF4α; NR2A1) is an orphan member of the nuclear receptor superfamily expressed in liver and intestine. While HNF4α expression is critical for liver function, its role in the gut and in the pathogenesis of inflammatory bowel disease (IBD) is unknown. Human intestinal biopsies from control and IBD patients were examined for expression of mRNAs encoding HNF4α and other nuclear receptors. An intestine-specific HNF4α null mouse line (Hnf4αΔIEpC) was generated using an Hnf4α-floxed allele and villin-Cre transgene. These mice and their control floxed counterparts (Hnf4αF/F), were subjected to a dextran sulfate sodium (DSS)-induced IBD colitis protocol and their clinical symptoms and gene expression patterns determined. In human intestinal biopsies, HNF4α was significantly decreased in intestinal tissues from Crohn’s disease and ulcerative colitis patients. HNF4α expression was also suppressed in the intestine of DSS-treated mice. In Hnf4αΔIEpC mice, disruption of HNF4α expression was observed in the epithelial cells throughout intestine. In the DSS-induced colitis model, Hnf4αΔIEpC mice showed markedly more severe changes in clinical symptoms and pathologies associated with IBD including loss of body weight, colon length, and histological morphology, as compared with Hnf4αF/F mice. Furthermore the Hnf4αΔIEpC mice demonstrate a significant alteration of mucin associated genes and increase intestinal permeability, which may play an important role in the increased susceptibility to acute colitis following an inflammatory insult. While HNF4α does not have a major role in normal function of the intestine, it protects the gut against DSS-induced colitis.
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