Sexually Dimorphic Response to Hepatic Injury in Newborn Suffering from Intrauterine Growth Restriction

Area of Science:

• Developmental biology
• Hepatology
• Immunology

Background:

• Intrauterine growth restriction (IUGR) impairs fetal development, leading to reduced liver function and increased chronic liver disease risk.
• Early life plasticity offers a potential window to reverse adverse fetal programming outcomes.
• Sex-specific responses to IUGR-induced liver injury are not well understood.

Purpose of the Study:

• To investigate the sex-specific cellular and molecular mechanisms of liver injury and regeneration in a piglet model of IUGR.
• To identify potential therapeutic targets for mitigating IUGR-related hepatic damage.

Main Methods:

• scRNA-seq analysis of liver tissue from IUGR and control piglets.
• Biochemical profiling and assessment of hypoxic stress response.
• Investigation of Apolipoprotein A4 (APOA4) and PPARα activation.

Main Results:

• IUGR piglets exhibited sex-dependent hepatic injury patterns.
• IUGR females displayed fibroblast-driven T cell reprogramming, promoting inflammation resolution and liver regeneration.
• IUGR males showed exacerbated liver injury, impaired regeneration due to inflammation and disrupted lipid metabolism, with elevated APOA4.

Conclusions:

• Hepatic injury and regeneration in IUGR are sexually dimorphic, with distinct immune and metabolic responses.
• APOA4 may serve as a biomarker, and PPARα activation shows therapeutic potential for IUGR males.
• Understanding these sex differences is crucial for developing targeted interventions for IUGR-associated liver disease.