Upregulation of hepatic nuclear receptors in extremely preterm ovine fetuses undergoing artificial placenta therapy

Hideyuki Ikeda, Shimpei Watanabe, Shinichi Sato, Erin L. Fee, Sean W.D. Carter, Yusaku Kumagai, Tsukasa Takahashi, Shinichi Kawamura, Takushi Hanita, Sebastian E. Illanes, Mahesh A. Choolani, Masatoshi Saito, Atsuo Kikuchi, Matthew W. Kemp, Haruo Usuda*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Objective: Extremely preterm infants have low Nuclear Receptor (NR) expression in their developing hepatobiliary systems, as they rely on the placenta and maternal liver for compensation. NRs play a crucial role in detoxification and the elimination of both endogenous and xenobiotic substances by regulating key genes encoding specific proteins. In this study, we utilized an Artificial Placenta Therapy (APT) platform to examine the liver tissue expression of NRs of extremely preterm ovine fetuses. This fetal model, resembling a “knockout placenta,” lacks placental and maternal support, while maintaining a healthy extrauterine survival. Methods: Six ovine fetuses at 95 ± 1 d gestational age (GA; term = ∼150 d)/∼600 g delivery weight were maintained on an APT platform for a period of 120 h (APT Group). Six age-matched, in utero control fetuses were delivered at 99–100 d GA (Control Group). Fetal liver tissue samples and blood samples were collected at delivery from both groups and assessed mRNA expression of NRs and target transporters involved in the hepatobiliary transport system using quantitative PCR. Data were tested for group differences with ANOVA (p <.05 deemed significant). Results: mRNA expression of NRs was identified in both the placenta and the extremely preterm ovine fetal liver. The expression of HNF4α, LRH1, LXR, ESR1, PXR, CAR, and PPARα/γ were significantly elevated in the liver of the APT Group compared to the Control Group. Moreover, target transporters NTCP, OATP1B3, BSEP, and MRP4 were upregulated, whereas MRP2 and MRP3 were unchanged. Although there was no evidence of liver necrosis or apoptotic changes histologically, there was an impact in the fetal liver of the ATP group at the tissue level with a significant increase in TNFα mRNA, a cytokine involved in liver inflammation, and blood elevation of transaminases. Conclusion: A number of NRs in the fetal liver were significantly upregulated after loss of placental-maternal support. However, the expression of target transporter genes appeared to be insufficient to compensate role of the placenta and maternal liver and avoid fetal liver damage, potentially due to insufficient excretion of organic anions.

Original languageEnglish
Article number2301651
Pages (from-to)1-12
Number of pages12
JournalJournal of Maternal-Fetal and Neonatal Medicine
Issue number1
StatePublished - 2024

Bibliographical note

Publisher Copyright:
© 2024 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.


  • Nuclear receptor
  • artificial placenta
  • bile transport
  • preterm infant
  • transcription factor


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