Identification of the functional pathways altered by placental cell exposure to high glucose: lessons from the transcript and metabolite interactome

Abstract

The specific consequences of hyperglycaemia on placental metabolism and function are incompletely understood but likely contribute to poor pregnancy outcomes associated with diabetes mellitus (DM). This study aimed to identify the functional biochemical pathways perturbed by placental exposure to high glucose levels through integrative analysis of the trophoblast transcriptome and metabolome. The human trophoblast cell line, BeWo, was cultured in 5 or 25 mM glucose, as a model of the placenta in DM. Transcriptomic analysis using microarrays, demonstrated 5632 differentially expressed gene transcripts (≥± 1.3 fold change (FC)) following exposure to high glucose. These genes were used to generate interactome models of transcript response using BioGRID (non-inferred network: 2500 nodes (genes) and 10541 protein-protein interactions). Ultra performance-liquid chromatography-mass spectrometry (MS) and gas chromatography-MS analysis of intracellular extracts and culture medium were used to assess the response of metabolite profiles to high glucose concentration. The interactions of altered genes and metabolites were assessed using the MetScape interactome database, resulting in an integrated model of systemic transcriptome (2969 genes) and metabolome (41 metabolites) response within placental cells exposed to high glucose. The functional pathways which demonstrated significant change in response to high glucose included fatty acid β-oxidation, phospholipid metabolism and phosphatidylinositol phosphate signalling.

Mendelian Randomization Analysis Support Causal Associations of HbA1c with Circulating Triglyceride, Total and Low-density Lipoprotein Cholesterol in a Chinese Population

“…A previous experimental study demonstrated that hyperglycemia status could suppress fatty acid oxidation and accelerate TG accumulation 43 . This was confirmed by another recent experiment on trophoblast cell line, which identified significant changes on multiple lipid metabolic pathways, including fatty acid β-oxidation, phospholipid metabolism and phosphatidylinositol phosphate signaling, in response to high glucose environment 44 . These findings may suggest an interference effect of hyperglycemia on lipidic metabolism.…”

The effect of high glucose on lipid metabolism in the human placenta

“…Initially, we sought to confirm our prediction from previous work 3 – that lipid metabolism is altered in a choriocarcinoma cell-line (BeWo) exposed to high (25 mM) glucose levels - by assessing the effect of such glucose concentrations on the triglyceride content of placental explants isolated from uncomplicated pregnancies at term (Table 1). The data presented in Fig.…”

“…Maternal hyperglycemia is associated with fetal macrosomia 2 , yet the role of the placenta, the organ responsible for transferring oxygen and nutrients from mother to fetus, in mediating this effect is not well understood. Our previous work using an unbiased systems biology approach to study a placental cell line (BeWo) response to high glucose levels highlighted aberrant trophoblast lipid metabolism and β-fatty acid oxidation 3 .…”

Serum Levels and Placental Expression of NGAL in Gestational Diabetes Mellitus

“…It is well known that the placenta is an endocrine organ, which secretes various molecules to maintain normal physiological function during pregnancy [32,33]. In vitro studies demonstrated that placental cells exert significant metabolic changes in response to high glucose, including fatty acid β-oxidation, phospholipid metabolism, and phosphatidylinositol phosphate signaling [34]. e umbilical cord is the link between the mother and the fetus and plays an important role in fetal waste metabolism and material exchange with the mother.…”