Intestinal NCoR1, a regulator of epithelial cell maturation, controls neonatal hyperbilirubinemia.
Severe neonatal hyperbilirubinemia (SNH) and the onset of bilirubin encephalopathy and kernicterus result in part from delayed expression of UDP-glucuronosyltransferase 1A1 (UGT1A1) and the inability to metabolize bilirubin. Although there is a good understanding of the early events after birth that lead to the rapid increase in serum bilirubin, the events that control delayed expression of UGT1A1 during development remain a mystery. HumanizedUGT1(hUGT1) mice develop SNH spontaneously, which is linked to repression of both liver and intestinal UGT1A1. In this study, we report that deletion of intestinal nuclear receptor corepressor 1 (NCoR1) completely diminishes hyperbilirubinemia inhUGT1neonates because of intestinalUGT1A1gene derepression. Transcriptomic studies and immunohistochemistry analysis demonstrate that NCoR1 plays a major role in repressing developmental maturation of the intestines. Derepression is marked by accelerated metabolic and oxidative phosphorylation, drug metabolism, fatty acid metabolism, and intestinal maturation, events that are controlled predominantly by H3K27 acetylation. The control of NCoR1 function and derepression is linked to IKKβ function, as validated inhUGT1mice with targeted deletion of intestinal IKKβ. Physiological events during neonatal development that target activation of an IKKβ/NCoR1 loop in intestinal epithelial cells lead to derepression of genes involved in intestinal maturation and bilirubin detoxification. These findings provide a mechanism of NCoR1 in intestinal homeostasis during development and provide a key link to those events that control developmental repression of UGT1A1 and hyperbilirubinemia.
Laboratory of Environmental Toxicology, Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093; mkarin@ucsd.edu s18chen@ucsd.edu.
Shujuan
S
Chen
Laboratory of Environmental Toxicology, Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093.
Wenqi
W
Lu
Laboratory of Environmental Toxicology, Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093.
Mei-Fei
MF
Yueh
Laboratory of Environmental Toxicology, Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093.
Eva
E
Rettenmeier
Laboratory of Environmental Toxicology, Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093.
Miao
M
Liu
Miles
M
Paszek
Laboratory of Integrative and Systems Physiology, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
Johan
J
Auwerx
Gene Expression Laboratory, Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, CA 92037.
Ruth T
RT
Yu
Gene Expression Laboratory, Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, CA 92037.
Ronald M
RM
Evans
Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093.
Kepeng
K
Wang
Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093 mkarin@ucsd.edu s18chen@ucsd.edu.
Michael
M
Karin
Laboratory of Environmental Toxicology, Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093.
Robert H
RH
Tukey
D000818:Animals; D000831:Animals, Newborn / Q000378:metabolism; D001663:Bilirubin / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000378:metabolism; D006801:Humans; D051556:Hyperbilirubinemia, Neonatal / Q000378:metabolism*; D051550:I-kappa B Kinase / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D051379:Mice; D056971:Nuclear Receptor Co-Repressor 1 / Q000378:metabolism*; D000099148:UGT1A1 Enzyme
D001663:Bilirubin; D014453:Glucuronosyltransferase; D051550:I-kappa B Kinase; D056971:Nuclear Receptor Co-Repressor 1; D000099148:UGT1A1 Enzyme
IKKβ; UDP-glucuronosyltransferase 1A1; encephalopathy; humanized UGT1 mice; kernicterus