Browsing by Subject "Fetal liver"

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    Primate fetal hepatic responses to maternal obesity: epigenetic signalling pathways and lipid accumulation
    (Wiley, 2018-12-01) Puppala, Sobha; Li, Cun; Glenn, Jeremy P.; Saxena, Romil; Gawrieh, Samer; Quinn, Amy; Palarczyk, Jennifer; Dick, Edward J.; Nathanielsz, Peter W.; Cox, Laura A.; Medicine, School of Medicine
    Key points Maternal obesity (MO) and exposure to a high‐fat, high‐simple‐carbohydrate diet during pregnancy predisposes offspring to obesity, metabolic and cardiovascular disorders in later life. Underlying molecular pathways and potential epigenetic factors that are dysregulated in MO were identified using unbiased transcriptomic methods. There was increased lipid accumulation and severe steatosis in the MO baboon fetal liver suggesting that these offspring are on an early trajectory of non‐alcoholic fatty liver disease and non‐alcoholic steatohepatitis. Abstract Maternal obesity (MO) increases offspring cardiometabolic disease risk. Altered fetal liver development in response to the challenge of MO has metabolic consequences underlying adverse offspring life‐course health outcomes. Little is known about the molecular pathways and potential epigenetic changes regulating primate fetal liver responses to MO. We hypothesized that MO would induce fetal baboon liver epigenetic changes resulting in dysregulation of key metabolic pathways that impact lipid metabolism. MO was induced prior to pregnancy by a high‐fat, high‐fructose diet. Unbiased gene and microRNA (small RNA Seq) abundance analyses were performed on fetal baboon livers at 0.9 gestation and subjected to pathway analyses to identify fetal liver molecular responses to MO. Fetal baboon liver lipid and glycogen content were quantified by the Computer Assisted Stereology Toolbox. In response to MO, fetal livers revealed dysregulation of TCA cycle, proteasome, oxidative phosphorylation, glycolysis and Wnt/β‐catenin signalling pathways together with marked lipid accumulation supporting our hypothesis that multiple pathway dysregulation detrimentally impacts lipid management. This is the first study of MO programming of the non‐human primate fetal liver using unbiased transcriptome analysis to detect changes in hepatic gene expression levels and identify potential microRNA epigenetic regulators of metabolic disruption.
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    β-Glucosylceramide From Allergic Mothers Enhances Offspring Responsiveness to Allergen
    (Frontiers Media, 2021-02) Walker, Matthew T.; Ferrie, Ryan P.; Hoji, Aki; Schroeder-Carter, Lindsay M.; Cohen, Jacob D.; Schnaar, Ronald L.; Cook-Mills, Joan M.; Pediatrics, School of Medicine
    In animals and humans, offspring of allergic mothers have increased responsiveness to allergen and the allergen-specificity of the offspring can be different than that of the mother. In our preclinical models, the mother's allergic responses influence development of the fetus and offspring by elevating numbers of cells in dendritic cell subsets. A major question is the identity of maternal factors of allergic mothers that alter offspring development of responsiveness to allergen. Lipids are altered during allergic responses and lipids are transported to the fetus for growth and formation of fetal membranes. We hypothesized that pro-inflammatory lipids, that are elevated in allergic mothers, are transported to the fetus and regulate fetal immune development. We demonstrate in this report that there was a significant 2-fold increase in β-glucosylceramides (βGlcCer) in allergic mothers, the fetal liver and her offspring. The βGlcCer were transported from mother's plasma, across the placenta, to the fetus and in breastmilk to the offspring. Administration of βGlcCer to non-allergic mothers was sufficient for offspring responses to allergen. Importantly, maternal administration of a clinically relevant pharmacological inhibitor of βGlcCer synthase returned βGlcCer to normal levels in the allergic mothers and her offspring and blocked the offspring increase in dendritic cell subsets and offspring allergen responsiveness. In summary, allergic mothers had increased βGlcCer that was transported to offspring and mediated increases in offspring DCs and responsiveness to allergen. These data have a significant impact on our understanding of mechanisms for development of allergies in offspring of allergic mothers and have the potential to lead to novel interventions that significantly impact risk for allergic disease early in life.