Role of extrahepatic UDP-glucuronosyltransferase 1A1: Advances in understanding breast milk-induced neonatal hyperbilirubinemia

Abstract

Newborns commonly develop physiological hyperbilirubinemia (also known as jaundice). With increased bilirubin levels being observed in breast-fed infants, breast-feeding has been recognized as a contributing factor for the development of neonatal hyperbilirubinemia. Bilirubin undergoes selective metabolism by UDP-glucuronosyltransferase (UGT) 1A1 and becomes a water soluble glucuronide. Although several factors such as gestational age, dehydration and weight loss, and increased enterohepatic circulation have been associated with breast milk-induced jaundice (BMJ), deficiency in UGT1A1 expression is a known cause of BMJ. It is currently believed that unconjugated bilirubin is metabolized mainly in the liver. However, recent findings support the concept that extrahepatic tissues, such as small intestine and skin, contribute to bilirubin glucuronidation during the neonatal period. We will review the recent advances made towards understanding biological and molecular events impacting BMJ, especially regarding the role of extrahepatic UGT1A1 expression.

Keywords: Bilirubin; Extra hepatic; Gilbert's Syndrome; Humanized UGT1 Mice; UDP-glucuronosyltransferase 1A1.

Fig. 1. Metabolic pathway of bilirubin in hepatocytes

OATPs and OATs uptake bilirubin into hepatocytes, while bilirubin is passively absorbed into the hepatocytes. Bilirubin is further transported into the luminal side of ER to be conjugated by UGT1A1. There might be a carrier that transport bilirubin and bilirubin-glucuronide across the ER membrane. Bilirubin-glucuronide is transported into the bile ducts by MRP2.

Fig. 2. Survival curves of hUGT1 and Ugt1^−/− mice

Due to the accumulation of lethal levels of TSB, most of Ugt1^−/− mice die within 7 days after birth (thicker lines). Humanization with the UGT1 locus rescues neonatal lethality, although 5–10% of newborn hUGT1 mice are still lethal (thin line). Black thick line indicates the survival curve of Ugt1^−/− mice reported by Nguyen et al., (2008). Gray thick line indicates the survival curve of Ugt1^−/− mice reported by Bortolussi et al., (2012).

Fig. 3. Total serum bilirubin levels in neonatal hUGT1 and wild-type mice

Mean TSB levels in neonatal hUGT1 and wild-type mice were shown. Stars indicate the TSB levels of hUGT1 mice that developed seizures.

Fig. 4. Schematic representation of pathways in intestinal cells

In neonatal hUGT1 mice, UGT1A1 metabolizes bilirubin in the gastrointestinal tract to prevent the accumulation of bilirubin. Intestinal UGT1A1 is under control by IKK/NF-κB (p50/p65) signaling. In the breast-fed neonates, breast milk can inhibit the NF-κB-mediated transcription of UGT1A1. Meanwhile, breast milk can also inhibit the bilirubin glucuronidation. NEMO, NF-κB essential modulator.