Maternal Nutrient Restriction Disrupts Gene Expression and Metabolites Associated with Urea Cycle, Steroid Synthesis, Glucose Homeostasis, and Glucuronidation in Fetal Calf Liver

This study aimed to understand the mechanisms underlying the effects of maternal undernutrition (MUN) on liver growth and metabolism in Japanese Black fetal calves (8.5 months in utero) using an approach that integrates metabolomics and transcriptomics. Dams were fed 60% (low-nutrition; LN) or 120% (high-nutrition; HN) of their overall nutritional requirements during gestation. We found that MUN markedly decreased the body and liver weights of the fetuses; metabolomic analysis revealed that aspartate, glycerol, alanine, gluconate 6-phosphate, and ophthalmate levels were decreased, whereas UDP-glucose, UDP-glucuronate, octanoate, and 2-hydroxybutyrate levels were decreased in the LN fetal liver (<i>p</i> ≤ 0.05). According to metabolite set enrichment analysis, the highly different metabolites were associated with metabolisms including the arginine and proline metabolism, nucleotide and sugar metabolism, propanoate metabolism, glutamate metabolism, porphyrin metabolism, and urea cycle. Transcriptomic and qPCR analyses revealed that MUN upregulated <i>QRFPR</i> and downregulated genes associated with the glucose homeostasis (<i>G6PC</i>, <i>PCK1</i>, <i>DPP4</i>), ketogenesis (<i>HMGCS2</i>), glucuronidation (<i>UGT1A1</i>, <i>UGT1A6</i>, <i>UGT2A1</i>), lipid metabolism (<i>ANGPTL4</i>, <i>APOA5</i>, <i>FADS2</i>), cholesterol and steroid homeostasis (<i>FDPS</i>, <i>HSD11B1</i>, <i>HSD17B6</i>), and urea cycle (<i>CPS1</i>, <i>ASS1</i>, <i>ASL</i>, <i>ARG2</i>). These metabolic pathways were extracted as relevant terms in subsequent gene ontology/pathway analyses. Collectively, these results indicate that the citrate cycle was maintained at the expense of activities of the energy metabolism, glucuronidation, steroid hormone homeostasis, and urea cycle in the liver of MUN fetuses.