Novel regulatory events that control expression of the UGT1A1 gene

人UDP-葡萄糖醛酸基转移酶1A1(UGT1A1)基因受宿主在转录水平上的调控 异源核受体包括PxR、CAR、LxRα/β、PPARα以及ah受体和 抗氧化反应因子Nrf2。暴露针对这些受体中的任何一个的特定配体将导致 UGT1A1基因的诱导。UGT1A1在许多组织中表达，但主要在肝脏和 成人的胃肠道。此外，UGT1A1基因在发育过程中受到调节，具有很大的 在新生儿发育过程中，肝脏和胃肠道的表达减少。UGT1A1基因表达下调 在发育过程中起着重要的生理作用，因为UGT1A1是唯一的葡萄糖醛酸基转移酶 负责血清胆红素的代谢。在新生儿发育过程中，UGT1A1表达减少 结果导致血清胆红素积聚，表现为中度或重度高胆红素血症。而当 通常，良性、严重的新生儿高胆红素血症(SNH)可导致急性和慢性脑病， 行为异常、反张、癫痫发作、小脑发育不良，可能与自闭症谱系有关 精神错乱。因此，我们假设，在那些胆红素诱生风险较高的儿童中 神经毒性，控制或加速胆红素代谢，降低血清总胆红素 水平将防止神经毒性。我们最近培育了人源化的UGT1(HUGT1)小鼠，其中 小鼠的UGT1基因被人的UGT1基因取代，包括人的UGT1A1基因。人类 UGT1A1基因以与其表达一致的组织特异性和发育方式进行调控 在人体组织中。重要的是，hUGT1小鼠在新生儿阶段发展成SNH，为我们提供了一个独特的 动物模型检测UGT1A1基因的调节特性。我们最近证实SNH 在hUGT1小鼠中，可导致癫痫发作、小脑发育不良，并伴有明显的髓鞘缺陷，所有这些都可以 可通过诱导肝脏或胃肠道UGT1A1基因表达而逆转。在这个背景下，有三个重要的 在过去1-2年中发现的，并将UGT1A1基因的调节与SNH联系起来的发现将是 在这份提案中进行了审查。首先，肝脏UGT1A1基因在新生儿期受到积极抑制 辅阻遏子蛋白SMRT(维甲酸和甲状腺激素受体沉默中介)。第二，口头 给新生的hUGT1小鼠注射异硫氰酸酯，这是已知的诱导氧化应激， 通过激活肝脏CAR显著诱导肝脏UGT1A1基因表达。第三，肠道的调节 UGT1A1在发育过程中的表达受辅助抑制蛋白NCoR1(核抑制蛋白)控制 辅抑制子)。我们将NCoR1a对肠道UGT1A1基因表达的抑制与IKKβ活性和 氧化应激。我们已经概述的监管事件，每一项都可以降低SNH的风险，将是 研究以揭示这些导致人类UGT1A1基因表达的新机制。

The human UDP-glucuronosyltransferase 1A1 (UGT1A1) gene is regulated at the transcriptional level by a host of xenobiotic nuclear receptors (XNRs), including PXR, CAR, LXRα/β, PPARα in addition to the Ah receptor and the antioxidant response factor Nrf2. Exposure of specific ligands that targets any of these receptors will lead to induction of the UGT1A1 gene. UGT1A1 is expressed in many tissues, but predominantly in the liver and gastrointestinal (GI) tract in adults. In addition, the UGT1A1 gene is developmentally regulated, with greatly reduced expression in the liver and GI tract during neonatal development. Reduced expression of UGT1A1 during development plays an important physiological role because UGT1A1 is the sole glucuronosyltransferase responsible for the metabolism of serum bilirubin. During neonatal development, reduced UGT1A1 expression results in a build-up of serum bilirubin that is presented as either moderate or severe hyperbilirubinemia. While usually benign, severe neonatal hyperbilirubinemia (SNH) can lead to acute and chronic encephalopathy, abnormal behavior, opisthotonus, seizures, cerebellar hypoplasia, with potential linkages to autism spectrum disorders. Thus, we hypothesize that in those children that are at heightened risk for bilirubin induced neurotoxicity, controlling or accelerating the metabolism of bilirubin and reducing total serum bilirubin (TSB) levels would prevent neurotoxicity. We have recently generated humanized UGT1 (hUGT1) mice where the murine Ugt1 locus was replaced with the human UGT1 locus, including the human UGT1A1 gene. The human UGT1A1 gene is regulated in a tissue specific and developmental fashion that is concordant with its expression in human tissues. Importantly, hUGT1 mice develop SNH during the neonatal stage, providing us with a unique animal model to examine the regulatory properties of the UGT1A1 gene. We have recently established that SNH in hUGT1 mice can lead to seizures, cerebellar hypoplasia, with significant myelination defects, all of which can be reversed by inducing either liver or GI tract UGT1A1 gene expression. With this background, three significant discoveries, all identified with in the last 1-2 years and linking regulation of the UGT1A1 gene to SNH will be examined in this proposal. First, the liver UGT1A1 gene is actively repressed during the neonatal period by the corepressor protein SMRT (silencing mediatory of retinoic acid and thyroid hormone receptor). Second, oral administration of isothiocyanates to neonatal hUGT1 mice, which are known to induce oxidative stress, dramatically induce liver UGT1A1 gene expression by activating liver CAR. Third, regulation of intestinal UGT1A1 expression during development is controlled by the corepressor protein NCoR1 (nuclear repressor corepressor). We have linked repression of intestinal UGT1A1 gene expression by NCoR1 with IKKβ activity and oxidative stress. The regulatory events that we have outlined, each of which can reduce the risk of SNH, will be examined to unravel these novel mechanisms leading to expression of the human UGT1A1 gene.