Gastroenterology · 2011
Reduced expression of UGT1A1 in intestines of humanized UGT1 mice via inactivation of NF-κB leads to hyperbilirubinemia.
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Fujiwara Ryoichi, Chen Shujuan, Karin Michael, Tukey Robert H
Аннотация
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.
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.
Предметные рубрики MeSH
AnimalsAnimals, NewbornBilirubinBiomarkersConstitutive Androstane ReceptorDisease Models, AnimalDown-RegulationGlucuronosyltransferaseHumansHyperbilirubinemia, NeonatalI-kappa B KinaseInfant FormulaInfant, NewbornIntestinesMiceMice, Inbred C57BLMice, KnockoutMice, TransgenicMilk, HumanNF-kappa BPregnane X ReceptorReceptors, Cytoplasmic and NuclearReceptors, SteroidSignal TransductionTime FactorsUGT1A1 Enzyme