Hepatic estrogen receptor α contributes to stage-specific coupling of liver metabolism and proliferation during pregnancy

Background and aims Pregnancy requires dynamic, stage-specific adaptations of maternal liver metabolism and growth to sustain fetal development while preserving systemic homeostasis. Estrogen signaling increases markedly during pregnancy and is primarily mediated in hepatocytes by estrogen receptor α (ERα). Although hepatic ERα regulates female liver metabolism under non-pregnant conditions, its contribution to pregnancy-induced hepatic remodeling remains unclear. Methods We studied non-pregnant and pregnant control and liver-specific ERα knockout (LERKO) mice across gestational stages using longitudinal physiological measurements, liver transcriptomics, targeted metabolomics, histological assessment of cell proliferation, and metabolic phenotyping. Results In control mice, pregnancy elicited sequential hepatic remodeling, with early induction of cell-cycle programs, a mid-gestational peak of hepatocyte proliferation accompanied by transient suppression of metabolic pathways, and late metabolic reactivation. Chronic hepatic ERα deficiency altered this temporal pattern. LERKO livers showed premature activation of proliferative and anabolic transcriptional programs, an early increase in mTORC1-related S6 phosphorylation relative to the non-pregnant state, and changes in amino acid- and fatty acid-related metabolic pathways. At mid-gestation, LERKO mice displayed reduced hepatocyte proliferation, altered expression of metabolic and insulin-related genes, blunted gestational improvement in glucose tolerance with no detectable genotype difference in insulin tolerance, and altered light/dark-phase metabolic organization. Conclusions These findings indicate that hepatic ERα contributes to the appropriate stage-specific coupling of liver growth, metabolic remodeling, and insulin-responsive signaling during pregnancy. Its loss is associated with gestational hepatic maladaptation and altered systemic metabolic responses, providing a framework for investigating estrogen-dependent mechanisms in pregnancy-associated metabolic and liver disorders.