通过 NF-κB 失活导致人源化 UGT1 小鼠肠道中 UGT1A1 表达减少，从而导致高胆红素血症。
Reduced expression of UGT1A1 in intestines of humanized UGT1 mice via inactivation of NF-κB leads to hyperbilirubinemia.
机构信息
Laboratory of Environmental Toxicology, Department of Chemistry & Biochemistry, University of California San Diego, La Jolla, California, USA.
出版信息
Gastroenterology. 2012 Jan;142(1):109-118.e2. doi: 10.1053/j.gastro.2011.09.045. Epub 2011 Oct 6.
BACKGROUND & AIMS: Bilirubin is a natural and potent antioxidant that accumulates in the blood of newborn children and leads to physiological jaundice. Breastfed infants have higher serum levels of bilirubin than formula-fed infants and are at risk for bilirubin-induced neurological dysfunction (BIND). Clearance of bilirubin requires the expression of uridine diphosphate glucuronosyltransferase (UGT) 1A1; we investigated its role in the association between breast feeding with jaundice in mice.
METHODS
We studied mice in which the original Ugt1 locus was disrupted and replaced with the human UGT1 locus (hUGT1 mice); these mice spontaneously develop neonatal hyperbilirubinemia and BIND. We fed human breast milk or formula to neonatal hUGT1 mice and examined activation of the intestinal xenobiotic receptors pregnane X receptor and constitutive androstane receptor. We also examined inflammatory signaling pathways in mice with disruptions in IκB-kinase-α and IκB kinase-β in the intestinal epithelium.
RESULTS
hUGT1 mice that were fed breast milk developed severe hyperbilirubinemia because of suppression of UGT1A1 in the gastrointestinal tract. Formula-fed hUGT1 mice had lower serum levels of bilirubin, which resulted from induction of UGT1A1 in the gastrointestinal tract. hUGT1/Pxr-null mice did not develop severe hyperbilirubinemia, whereas hUGT1/Car-null mice were susceptible to BIND when they were fed breast milk. Breast milk appeared to suppress intestinal IκB kinase α and β, resulting in inactivation of nuclear factor-κB and loss of expression of UGT1A1, leading to hyperbilirubinemia.
CONCLUSIONS
Breast milk reduces expression of intestinal UGT1A1, which leads to hyperbilirubinemia and BIND; suppression of this gene appears to involve inactivation of nuclear factor-κB. Hyperbilirubinemia can be reduced by activation of pregnane X receptor, constitutive androstane receptor, or nuclear factor-κB.
背景与目的
胆红素是一种天然且强效的抗氧化剂，在新生儿血液中蓄积，导致生理性黄疸。母乳喂养的婴儿血清胆红素水平高于配方奶喂养的婴儿，有发生胆红素诱导的神经功能障碍（BIND）的风险。胆红素的清除需要表达尿苷二磷酸葡萄糖醛酸转移酶（UGT）1A1；我们研究了其在母乳喂养与小鼠黄疸之间的关联中的作用。
方法
我们研究了 Ugt1 基因座被破坏并被人 UGT1 基因座取代的小鼠（hUGT1 小鼠）；这些小鼠会自发出现新生儿高胆红素血症和 BIND。我们给新生 hUGT1 小鼠喂食人母乳或配方奶，并检测肠道外源性物质受体孕烷 X 受体和组成型雄烷受体的激活情况。我们还研究了肠道上皮细胞中 IκB-激酶-α和 IκB 激酶-β缺失的小鼠中的炎症信号通路。
结果
喂食母乳的 hUGT1 小鼠由于胃肠道中 UGT1A1 的抑制而出现严重的高胆红素血症。喂食配方奶的 hUGT1 小鼠血清胆红素水平较低，这是由于胃肠道中 UGT1A1 的诱导所致。hUGT1/Pxr 基因敲除小鼠不会出现严重的高胆红素血症，而 hUGT1/Car 基因敲除小鼠在母乳喂养时易发生 BIND。母乳似乎抑制了肠道 IκB 激酶 α 和 β，导致核因子-κB 失活和 UGT1A1 表达缺失，导致高胆红素血症。
结论
母乳减少了肠道 UGT1A1 的表达，导致高胆红素血症和 BIND；该基因的抑制似乎涉及核因子-κB 的失活。通过激活孕烷 X 受体、组成型雄烷受体或核因子-κB 可以降低高胆红素血症。
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