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Hypoxic Pregnancy Promotes Fibrosis and Increases Stress Metabolites in the Ovine Fetal Liver

ABSTRACT: Fetal hypoxemia is a common pregnancy complication associated with fetal growth restriction (FGR). Offspring born with FGR have a higher risk for postnatal liver metabolic disease and injury. Our objective was to better understand how hypoxemia impacts the developing fetal liver. We hypothesized hypoxemia promotes hepatocellular injury, shifts nutrient metabolism, and activates energetic and oxidative stress signaling pathways in the fetal liver. To test this, we used an established ovine model of hypoxia during late gestation. Pregnant ewes were housed in isobaric chambers under normoxia (CON) or hypoxic (HOX) conditions for 30 days, and fetal liver biopsies were analyzed. Compared to CON, HOX fetuses had asymmetrical growth restriction, higher hemoglobin concentration, and greater liver collagen deposition localized in periportal regions. HOX liver had unique metabolic profiles, including shifts to amino acid and central carbon metabolism and increased stress metabolites. The hepatic transcriptome of HOX fetuses included downregulation of genes involved in glutathione synthesis and redox balance and upregulation of mitochondrial dysfunction and downregulation of oxidative phosphorylation genes. Despite predicted oxidative stress, there was no difference in lipid peroxidation, oxidative phosphorylation complex abundance, or antioxidant response proteins NRF2, NQO1 or SOD2. In summary, hypoxic pregnancy increased fetal hepatic collagen deposition, an indicator of hepatic injury, with a unique profile of liver stress metabolites and metabolic adaptations in central carbon metabolism. These results provide new insight into how fetal hypoxia may initiate fibrotic and metabolic liver disease risk in exposed offspring.

ORGANISM(S): Ovis aries

PROVIDER: GSE282736 | GEO | 2025/06/01

REPOSITORIES: GEO

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Project description:The liver is a major site for synthesis, storage and redistribution of carbohydrates, proteins and lipids. In addition, it is well-known that maternal obesity (MO) increases risk of offspring cardiovascular disease (CVD), diabetes and obesity. However, the mechanisms by which the MO intrauterine environment predisposes offspring to CVD and metabolic dysregulation are unknown. The goal of this study was to assess the impact of MO on primate fetal liver and identify underlying molecular mechanisms by which MO increases disease risk. The goal of this study was to identify candidate molecular mechanisms underlying MO in the near-term non-human primate (NHP) fetal liver. This is the first study of NHP fetal MO livers using unbiased transcriptome analysis to quantify hepatic gene expression, identify dysregulated signaling pathways and potential miRNAs regulating the disrupted metabolic processes. Unbiased gene (arrays) and microRNA (miRNA; small RNA-Seq) abundances were quantified in near-term (0.9 Gestation (0.9G)) baboon fetal livers (control (CON) = 6; MO = 5) and subjected to pathway and network analyses (GeneSifter, Ingenuity® Pathway Analysis (IPA)) to identify a coordinated molecular response to MO. Lipid and glycogen content (CON = 16; MO = 16) were quantified by Computer Assisted Stereology Toolbox (CAST) in 0.9G livers. Pairwise comparisons showed 933 differentially expressed genes between CON and MO livers: 350 genes were upregulated and 583 were downregulated. Pathway analysis revealed upregulation of Wnt/β-catenin signaling and downregulation of tricarboxylic acid (TCA) cycle, proteasome, oxidative phosphorylation and glycolysis pathways in MO fetal livers compared with CON. Inversely expressed miRNAs that target genes in these pathways provide additional support for the importance of these pathways in fetal liver metabolic regulation. Consistent with the observed pathway changes in MO, we found hepatic lipid content was threefold greater in MO than CON fetal livers (p=0.02). Molecular genetic analyses of CON and MO fetal baboon livers revealed dysregulation of Wnt/β-catenin signaling, TCA cycle, proteasome, oxidative phosphorylation and glycolysis pathways in MO livers, all of which are central to fatty acid metabolism and lipid storage. The marked lipid accumulation in MO fetal livers supports our hypothesis that dysregulation of these pathways detrimentally impacts lipid management. Furthermore, our findings demonstrate the detrimental impact of MO on fetal liver development and suggest impaired hepatic function prior to birth.

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Hypoxic Pregnancy Promotes Fibrosis and Increases Stress Metabolites in the Ovine Fetal Liver

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