Hepatic estrogen receptor α is required for stage specific coupling of liver metabolism and proliferation during pregnancy
Background and Aims: Pregnancy requires dynamic, stage-specific adaptations in maternal liver metabolism and growth to sustain fetal development while preserving systemic homeostasis. Estrogen signaling, which significantly increases during pregnancy, is primarily mediated in hepatocytes by estrogen receptor (ER). Although hepatic ER regulates female liver metabolism under non-pregnant…
Pregnancy demands precise and synchronized modifications in liver metabolism and growth to support fetal development while maintaining overall stability. Estrogen plays a crucial role in this process, primarily through its effects on hepatocytes. Despite its significance, the exact contribution of hepatic estrogen receptor (ER) to pregnancy-induced liver remodeling is not well understood.
Researchers investigated the role of hepatic ER in pregnant and non-pregnant mice, both with and without liver-specific ER knockout (LERKO), utilizing various methods including physiological measurements, transcriptomics, metabolomics, and histological assessment.
The study found that pregnancy triggers a series of changes in the liver, starting with the early activation of cell-cycle programs, followed by a peak in hepatocyte proliferation around the middle of pregnancy, during which certain metabolic processes are temporarily inhibited, and concluding with the reactivation of specific metabolic pathways.
However, when hepatic ER is deficient, this orderly progression is disrupted. LERKO livers show an early onset of proliferation and anabolic transcription, changes in amino acid and fatty acid metabolism, and a misalignment in the timing of AKT-mTORC1 signaling.
By mid-pregnancy, LERKO mice exhibit reduced hepatocyte proliferation, altered expression of metabolic and insulin-related genes, an inability to adapt to changing glucose levels despite normal insulin resistance, and modifications in their circadian metabolic rhythms. These findings indicate that hepatic ER is essential for the correct timing and coordination of liver growth, metabolic adjustments, and insulin signaling during pregnancy.
The absence of hepatic ER leads to liver maladaptation during gestation and systemic metabolic issues, offering insights into the estrogen-dependent processes involved in pregnancy-related metabolic disorders.
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