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

Abstract

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.

Graphical Abstract

Keywords:

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

Acknowledgements

We appreciate the support of Nipro Corporation, Osaka, Japan (donation of Artificial Placenta circuit consumables) and Siemens Australia (generous RP500 consumables).

Presentation

This work has previously been presented, in part, at the 2023 SRI annual meeting in Brisbane, Australia and features in the conference abstract book.

Disclosure statement

Author Shinichi KAWAMURA is employed by Nipro Corporation. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Data availability statement

The data that support the findings of this study are openly available in Figshare.

Appendix 1: http://doi.org/10.6084/m9.figshare.24550780.

Appendix 2: http://doi.org/10.6084/m9.figshare.24180687.

Additional information

Funding

This work was supported by grants from the Channel 7 Telethon Trust, the Department of Health, Government of Western Australia, and an in-kind donation from Nipro Corporation, Osaka, Japan. Dr. Kemp was supported by the Women and Infants Research Foundation and the National Health and Medical Research Council (grants GNT1049148 and GNT1162572).