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Proc Natl Acad Sci U S A. 2017 Feb 21;114(8):E1432-E1440. doi: 10.1073/pnas.1700232114. Epub 2017 Feb 6.

Intestinal NCoR1, a regulator of epithelial cell maturation, controls neonatal hyperbilirubinemia.

Author information

1
Laboratory of Environmental Toxicology, Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093; mkarin@ucsd.edu s18chen@ucsd.edu.
2
Laboratory of Environmental Toxicology, Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093.
3
Laboratory of Integrative and Systems Physiology, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
4
Gene Expression Laboratory, Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, CA 92037.
5
Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093.
6
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.

Abstract

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. Humanized UGT1 (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 in hUGT1 neonates because of intestinal UGT1A1 gene 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 in hUGT1 mice 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.

KEYWORDS:

IKKβ; UDP-glucuronosyltransferase 1A1; encephalopathy; humanized UGT1 mice; kernicterus

PMID:
28167773
PMCID:
PMC5338369
DOI:
10.1073/pnas.1700232114
[Indexed for MEDLINE]
Free PMC Article

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