Correction for Chen et al., Intestinal NCoR1, a regulator of epithelial cell maturation, controls neonatal hyperbilirubinemia.
Correction for Chen et al., Intestinal NCoR1, a regulator of epithelial cell maturation, controls neonatal hyperbilirubinemia.
复制标题
更正 Chen 等人的观点，肠 NCoR1 是上皮细胞成熟的调节因子，可控制新生儿高胆红素血症。
DOI：
10.1073/pnas.1705671114
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发表时间：
2017
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
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作者：
严重的新生儿高胆红素血症（SNH）和胆红素脑病和核黄疸的发生部分是由于UDP-葡萄糖醛酸转移酶1A 1（UGT 1A 1）表达延迟和胆红素代谢障碍所致。虽然对出生后导致血清胆红素快速升高的早期事件有了很好的了解，但在发育过程中控制UGT 1A 1延迟表达的事件仍然是一个谜。人源化UGT 1（hUGT 1）小鼠自发地发展SNH，这与肝脏和肠道UGT 1A 1的抑制有关。在这项研究中，我们报告了肠核受体辅阻遏物1（NCoR 1）的缺失完全减少了hUGT 1A 1新生儿的高胆红素血症，这是因为hUGT 1A 1基因的去阻遏。转录组学研究和免疫组织化学分析表明，NCoR 1在抑制肠道发育成熟中起着重要作用。去抑制的特征是代谢和氧化磷酸化加速、药物代谢、脂肪酸代谢和肠道成熟，这些事件主要由H3 K27乙酰化控制。NCoR 1功能和去阻遏的控制与IKKβ功能相关，在靶向缺失肠道IKKβ的hUGT 1小鼠中得到验证。新生儿发育过程中的生理事件，靶向激活肠上皮细胞中的IKKβ/NCoR 1环，导致参与肠成熟和胆红素解毒的基因去抑制。这些发现提供了NCoR 1在发育过程中肠道内稳态的机制，并提供了控制UGT 1A 1和高胆红素血症发育抑制的事件的关键联系。
Severe neonatal hyperbilirubinemia (SNH) and the onset of bilirubin encephalopathy and kernicterus result in part from delayed expression of UDP-glucuronosyltransferase 1A1 (UGT1A1) and the inability to metabolize bilirubin. Although there is a good understanding of the early events after birth that lead to the rapid increase in serum bilirubin, the events that control delayed expression of UGT1A1 during development remain a mystery. HumanizedUGT1(hUGT1) mice develop SNH spontaneously, which is linked to repression of both liver and intestinal UGT1A1. In this study, we report that deletion of intestinal nuclear receptor corepressor 1 (NCoR1) completely diminishes hyperbilirubinemia inhUGT1neonates because of intestinalUGT1A1gene derepression. Transcriptomic studies and immunohistochemistry analysis demonstrate that NCoR1 plays a major role in repressing developmental maturation of the intestines. Derepression is marked by accelerated metabolic and oxidative phosphorylation, drug metabolism, fatty acid metabolism, and intestinal maturation, events that are controlled predominantly by H3K27 acetylation. The control of NCoR1 function and derepression is linked to IKKβ function, as validated inhUGT1mice with targeted deletion of intestinal IKKβ. Physiological events during neonatal development that target activation of an IKKβ/NCoR1 loop in intestinal epithelial cells lead to derepression of genes involved in intestinal maturation and bilirubin detoxification. These findings provide a mechanism of NCoR1 in intestinal homeostasis during development and provide a key link to those events that control developmental repression of UGT1A1 and hyperbilirubinemia.