Hypoxic pregnancy promotes fibrosis and increases stress metabolites in the ovine fetal liver

Fetal chronic hypoxia is a common pregnancy complication associated with fetal growth restriction. Growth-restricted offspring have a higher risk for liver metabolic disease. Our objective was to better understand how chronic hypoxia impacts the developing fetal liver. We hypothesized that hypoxia promotes hepatocellular injury, shifts nutrient metabolism, and activates energetic and oxidative stress in the fetal liver. We used an ovine model of chronic hypoxia where pregnant ewes were housed under normoxic (CON) or hypoxic (HOX) conditions for 30 days in late gestation. Fetal liver was obtained, histologically analysed and profiled using bulk-RNA sequencing and metabolomics. Nutrient and oxidative stress signalling pathways were also measured. HOX fetuses had greater hepatic periportal collagen deposition. Metabolomics and transcriptomics predicted disruptions in central carbon metabolism, mitochondrial dysfunction and decreased oxidative phosphorylation. In support, we found potentiation of the gluconeogenic pathway and increased lactate production, pyruvate oxidation and AMPK activation. By contrast to the predicted effects, hypoxic livers maintained mitochondrial oxidation and antioxidant capacity. Interestingly, acylcarnitines were increased, yet hepatic triglyceride content was similar. Although there was little activation of oxidative stress markers, such as lipid peroxidation or oxidized glutathione, we uncovered a unique profile of liver stress-related metabolites in association with periportal collagen. Thus, hypoxic pregnancy increased fetal hepatic collagen deposition, indicating liver injury, in association with a unique profile of liver stress metabolites and adaptations in central carbon metabolism. These results provide new insight into how chronic fetal hypoxia may initiate fibrotic and metabolic liver disease risk in offspring of adverse pregnancy. KEY POINTS: Chronic exposure to hypoxic pregnancy increased fetal hepatic collagen deposition, indicating hepatocellular injury. Hypoxic fetal livers had a unique profile of stress metabolites and adaptations in central carbon metabolism. This provides new insight into how hypoxia, a common pregnancy complication associated with fetal growth restriction, may initiate fibrotic and metabolic liver disease risk.