Reduced expression of UGT1A1 in intestines of humanized UGT1 mice via inactivation of NF-κB leads to hyperbilirubinemia

Gastroenterology. 2012 Jan;142(1):109-118.e2. doi: 10.1053/j.gastro.2011.09.045. Epub 2011 Oct 6.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Video-Audio Media

MeSH terms

  • Animals
  • Animals, Newborn
  • Bilirubin / blood*
  • Biomarkers / blood
  • Disease Models, Animal
  • Down-Regulation
  • Glucuronosyltransferase / genetics
  • Glucuronosyltransferase / metabolism*
  • Humans
  • Hyperbilirubinemia, Neonatal / enzymology*
  • Hyperbilirubinemia, Neonatal / genetics
  • Hyperbilirubinemia, Neonatal / prevention & control
  • I-kappa B Kinase / genetics
  • I-kappa B Kinase / metabolism
  • Infant Formula / administration & dosage
  • Infant, Newborn
  • Intestines / enzymology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Milk, Human / metabolism*
  • NF-kappa B / metabolism*
  • Pregnane X Receptor
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Receptors, Steroid / genetics
  • Receptors, Steroid / metabolism
  • Signal Transduction
  • Time Factors

Substances

  • Biomarkers
  • NF-kappa B
  • Pregnane X Receptor
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Steroid
  • constitutive androstane receptor
  • UGT1A1 enzyme
  • Glucuronosyltransferase
  • Chuk protein, mouse
  • I-kappa B Kinase
  • Ikbkb protein, mouse
  • Bilirubin