PT  - JOURNAL ARTICLE
AU  - Shujuan Chen
AU  - Robert H Tukey
TI  - Humanized UGT1 mice, regulation of UGT1A1,and the role of the intestinal tract in neonatal hyperbilirubinemia and breast milk induced jaundice
AID  - 10.1124/dmd.118.083212
DP  - 2018 Jan 01
TA  - Drug Metabolism and Disposition
PG  - dmd.118.083212
4099  - http://dmd.aspetjournals.org/content/early/2018/08/08/dmd.118.083212.short
4100  - http://dmd.aspetjournals.org/content/early/2018/08/08/dmd.118.083212.full
AB  - Neonatal hyperbilirubinemia and the onset of bilirubin encephalopathy and kernicterus result in part from delayed expression of UDP-glucuronosyltransferase 1A1 (UGT1A1) and the ability to metabolize bilirubin. It is generally believed that acute neonatal forms of hyperbilirubinemia develop due to an inability of hepatic UGT1A1 to efficiently metabolize bilirubin for clearance through the hepatobiliary tract. Newly developed mouse models designed to study bilirubin metabolism have led to important advances defining the mechanisms that lead to delayed expression of UGT1A1 and the processes that facilitate its elimination. Humanization of mice with the UGT1 locus (hUGT1 mice) and the UGT1A1 gene provided a unique tool to study the onset of hyperbilirubinemia since the human UGT1A1 gene is developmentally regulated during the neonatal period in hUGT1 mice. Through genetic manipulation of nuclear receptor expression and transcriptional corepressor proteins in hUGT1 mice, an advanced model that implicates intestinal UGT1A1 expression as a key modifier of neonatal hyperbilirubinemia has emerged. Central in controlling expression of intestinal UGT1A1 is repression of the gene by nuclear receptor corepressor 1 (NCoR1). Evidence indicates that activation of intestinal reactive oxygen species (ROS), resulting in potent induction of UGT1A1 and the reduction in total serum bilirubin (TSB) levels, is linked to derepression of intestinal UGT1A1 by NCoR1. A key component of intestinal UGT1A1 expression and control of neonatal TSB levels in hUGT1 mice is the constitutive expression of IKKβ, since its deletion in intestinal epithelial cells (IEC) leads to reduced levels of UGT1A1, elevated TSB levels, and bilirubin-induced CNS toxicity. Our findings allow us to outline a new model that includes an active intestinal ROS/IKK/NCoR1 loop that can be applied to an understanding of breast milk-induced jaundice.