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

Autor:	Shashikadze B; Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, LMU Munich, 81377 Munich, Germany., Valla L; Molecular Animal Breeding and Biotechnology, Gene Center and Department of Veterinary Sciences, LMU Munich, 81377 Munich, Germany; MWM Biomodels GmbH, 84184 Tiefenbach, Germany., Lombardo SD; Max Perutz Labs, Vienna Biocenter Campus (VBC), 1030 Vienna, Austria; University of Vienna, Center for Molecular Biology, Department of Structural and Computational Biology, 1030 Vienna, Austria; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria., Prehn C; Metabolomics and Proteomics Core (MPC), Helmholtz Zentrum München, 85764 Neuherberg, Germany., Haid M; Metabolomics and Proteomics Core (MPC), Helmholtz Zentrum München, 85764 Neuherberg, Germany., Riols F; Metabolomics and Proteomics Core (MPC), Helmholtz Zentrum München, 85764 Neuherberg, Germany., Stöckl JB; Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, LMU Munich, 81377 Munich, Germany., Elkhateib R; Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, LMU Munich, 81377 Munich, Germany., Renner S; Molecular Animal Breeding and Biotechnology, Gene Center and Department of Veterinary Sciences, LMU Munich, 81377 Munich, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany; Center for Innovative Medical Models (CiMM), LMU Munich, 85764 Oberschleißheim, Germany., Rathkolb B; Molecular Animal Breeding and Biotechnology, Gene Center and Department of Veterinary Sciences, LMU Munich, 81377 Munich, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany; Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Munich, 85764 Neuherberg, Germany., Menche J; Max Perutz Labs, Vienna Biocenter Campus (VBC), 1030 Vienna, Austria; University of Vienna, Center for Molecular Biology, Department of Structural and Computational Biology, 1030 Vienna, Austria; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria; University of Vienna, Faculty of Mathematics, 1090 Vienna, Austria., Hrabĕ de Angelis M; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany; Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Munich, 85764 Neuherberg, Germany; Experimental Genetics, School of Life Science Weihenstephan, Technische Universität München, 85354 Freising, Germany., Wolf E; Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, LMU Munich, 81377 Munich, Germany; Molecular Animal Breeding and Biotechnology, Gene Center and Department of Veterinary Sciences, LMU Munich, 81377 Munich, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany; Center for Innovative Medical Models (CiMM), LMU Munich, 85764 Oberschleißheim, Germany., Kemter E; Molecular Animal Breeding and Biotechnology, Gene Center and Department of Veterinary Sciences, LMU Munich, 81377 Munich, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany; Center for Innovative Medical Models (CiMM), LMU Munich, 85764 Oberschleißheim, Germany. Electronic address: kemter@genzentrum.lmu.de., Fröhlich T; Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, LMU Munich, 81377 Munich, Germany. Electronic address: frohlich@genzentrum.lmu.de.
Jazyk:	angličtina
Zdroj:	Molecular metabolism [Mol Metab] 2023 Sep; Vol. 75, pp. 101768. Date of Electronic Publication: 2023 Jul 04.
DOI:	10.1016/j.molmet.2023.101768
Abstrakt:	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. Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (Copyright © 2023 The Authors. Published by Elsevier GmbH.. All rights reserved.)
Databáze:	MEDLINE
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