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Shashikadze, B.* ; Valla, L.* ; Lombardo, S.D.* ; Prehn, C. ; Haid, M. ; Riols, F. ; Stöckl, J.B.* ; Elkhateib, R.* ; Renner, S.* ; Rathkolb, B. ; Menche, J.* ; Hrabě de Angelis, M. ; Wolf, E.* ; Kemter, E.* ; Fröhlich, T.*

Maternal hyperglycemia induces alterations in hepatic amino acid, glucose and lipid metabolism of neonatal offspring: Multi-omics insights from a diabetic pig model.

Mol. Metab. 75:101768 (2023)
DOI PMC
Creative Commons Lizenzvertrag
Open Access Gold möglich sobald Verlagsversion bei der ZB eingereicht worden ist.
Objective: To gain mechanistic insights into adverse effects of maternal hyperglycemia on the liver of neonates, we performed a multi-omics analysis of liver tissue from piglets developed in genetically diabetic (mutant INS gene induced diabetes of youth; MIDY) or wild-type (WT) pigs. Methods: Proteome, metabolome and lipidome profiles of liver and clinical parameters of serum samples from 3-day-old WT piglets (n = 9) born to MIDY mothers (PHG) were compared with those of WT piglets (n = 10) born to normoglycemic mothers (PNG). Furthermore, protein–protein interaction network analysis was used to reveal highly interacting proteins that participate in the same molecular mechanisms and to relate these mechanisms with human pathology. Results: Hepatocytes of PHG displayed pronounced lipid droplet accumulation, although the abundances of central lipogenic enzymes such as fatty acid-synthase (FASN) were decreased. Additionally, circulating triglyceride (TG) levels were reduced as a trend. Serum levels of non-esterified free fatty acids (NEFA) were elevated in PHG, potentially stimulating hepatic gluconeogenesis. This is supported by elevated hepatic phosphoenolpyruvate carboxykinase (PCK1) and circulating alanine transaminase (ALT) levels. Even though targeted metabolomics showed strongly elevated phosphatidylcholine (PC) levels, the abundances of multiple key enzymes involved in major PC synthesis pathways – most prominently those from the Kennedy pathway – were paradoxically reduced in PHG liver. Conversely, enzymes involved in PC excretion and breakdown such as PC-specific translocase ATP-binding cassette 4 (ABCB4) and phospholipase A2 were increased in abundance. Conclusions: Our study indicates that maternal hyperglycemia without confounding obesity induces profound molecular changes in the liver of neonatal offspring. In particular, we found evidence for stimulated gluconeogenesis and hepatic lipid accumulation independent of de novo lipogenesis. Reduced levels of PC biosynthesis enzymes and increased levels of proteins involved in PC translocation or breakdown may represent counter-regulatory mechanisms to maternally elevated PC levels. Our comprehensive multi-omics dataset provides a valuable resource for future meta-analysis studies focusing on liver metabolism in newborns from diabetic mothers.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Clinical Parameters ; Liver ; Maternal Diabetes ; Metabolomics ; Neonates ; Pig Model ; Protein–protein Interaction ; Proteomics; Fatty Liver-disease; Beta-cell Function; Insulin-resistance; Women; Obesity; Steatosis; Fetal; Phosphatidylcholine; Gluconeogenesis; Homeostasis
ISSN (print) / ISBN 2212-8778
e-ISSN 2212-8778
Zeitschrift Molecular Metabolism
Quellenangaben Band: 75, Heft: , Seiten: , Artikelnummer: 101768 Supplement: ,
Verlag Elsevier
Verlagsort Amsterdam
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed