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Title: Robust effect of metabolic syndrome on major metabolic pathways in the myocardium

Abstract

Although the high-fat-diet-induced metabolic syndrome (MetS) is a precursor of human cardiac pathology, the myocardial metabolic state in MetS is far from clear. The discrepancies in metabolite handling between human and small animal models and the difficulties inherent in obtaining human tissue complicate the identification of the myocardium-specific metabolic response in patients. Here we use the large animal model of swine that develops the hallmark criteria of human MetS. Our comparative metabolomics together with transcriptomics and computational nonnegative matrix factorization (NMF) interpretation of the data exposes significant decline in metabolites related to the fatty acid oxidation, glycolysis, and pentose phosphate pathway. Behind the reversal lies decreased expression of enzymes that operate in the pathways. We showed that diminished glycogen deposition is a metabolic signature of MetS in the pig myocardium. The depletion of glycogen arises from disbalance in expression of genes that break down and synthesize glycogen. We show robust acetoacetate accumulation and activated expression of key enzymes in ketone body formation, catabolism and transporters, suggesting a shift in fuel utilization in MetS. A contrasting enrichment in O-GlcNAcylated proteins uncovers hexosamine pathway and O-GlcNAcase (OGA) expression involvement in the myocardial response to MetS. Although the hexosamine biosynthetic pathway (HBP) activitymore » and the availability of the UDP-GlcNAc substrate in the MetS myocardium is low, the level of O-GlcNacylated proteins is high as the O-GlcNacase is significantly diminished. Our data support the perception of transcriptionally driven myocardial alterations in expression of standard fatty acids, glucose metabolism, glycogen, and ketone body related enzymes and subsequent paucity of their metabolite products in MetS. This aberrant energy metabolism in the MetS myocardium provide insight into the pathogenesis of CVD in MetS.« less

Authors:
; ; ; ; ; ; ; ; ; ; ; ; ORCiD logo;
Publication Date:
Research Org.:
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division; USDOE Laboratory Directed Research and Development (LDRD) Program
OSTI Identifier:
1576685
Alternate Identifier(s):
OSTI ID: 1629306; OSTI ID: 1807822
Report Number(s):
LA-UR-17-30146
Journal ID: ISSN 1932-6203; 10.1371/journal.pone.0225857
Grant/Contract Number:  
LDRD 20180060DR; AC52-06NA25396; 89233218CNA000001
Resource Type:
Published Article
Journal Name:
PLoS ONE
Additional Journal Information:
Journal Name: PLoS ONE Journal Volume: 14 Journal Issue: 12; Journal ID: ISSN 1932-6203
Publisher:
Public Library of Science (PLoS)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES

Citation Formats

Karimi, Maryam, Pavlov, Vasile I., Ziegler, Olivia, Sriram, Nivedita, Yoon, Se-Young, Agbortoko, Vahid, Alexandrova, Stoiana, Asara, John, Sellke, Frank W., Sturek, Michael, Feng, Jun, Alexandrov, Boian S., Usheva, Anny, and Bianchi, ed., Cesario. Robust effect of metabolic syndrome on major metabolic pathways in the myocardium. United States: N. p., 2019. Web. doi:10.1371/journal.pone.0225857.
Karimi, Maryam, Pavlov, Vasile I., Ziegler, Olivia, Sriram, Nivedita, Yoon, Se-Young, Agbortoko, Vahid, Alexandrova, Stoiana, Asara, John, Sellke, Frank W., Sturek, Michael, Feng, Jun, Alexandrov, Boian S., Usheva, Anny, & Bianchi, ed., Cesario. Robust effect of metabolic syndrome on major metabolic pathways in the myocardium. United States. https://doi.org/10.1371/journal.pone.0225857
Karimi, Maryam, Pavlov, Vasile I., Ziegler, Olivia, Sriram, Nivedita, Yoon, Se-Young, Agbortoko, Vahid, Alexandrova, Stoiana, Asara, John, Sellke, Frank W., Sturek, Michael, Feng, Jun, Alexandrov, Boian S., Usheva, Anny, and Bianchi, ed., Cesario. Mon . "Robust effect of metabolic syndrome on major metabolic pathways in the myocardium". United States. https://doi.org/10.1371/journal.pone.0225857.
@article{osti_1576685,
title = {Robust effect of metabolic syndrome on major metabolic pathways in the myocardium},
author = {Karimi, Maryam and Pavlov, Vasile I. and Ziegler, Olivia and Sriram, Nivedita and Yoon, Se-Young and Agbortoko, Vahid and Alexandrova, Stoiana and Asara, John and Sellke, Frank W. and Sturek, Michael and Feng, Jun and Alexandrov, Boian S. and Usheva, Anny and Bianchi, ed., Cesario},
abstractNote = {Although the high-fat-diet-induced metabolic syndrome (MetS) is a precursor of human cardiac pathology, the myocardial metabolic state in MetS is far from clear. The discrepancies in metabolite handling between human and small animal models and the difficulties inherent in obtaining human tissue complicate the identification of the myocardium-specific metabolic response in patients. Here we use the large animal model of swine that develops the hallmark criteria of human MetS. Our comparative metabolomics together with transcriptomics and computational nonnegative matrix factorization (NMF) interpretation of the data exposes significant decline in metabolites related to the fatty acid oxidation, glycolysis, and pentose phosphate pathway. Behind the reversal lies decreased expression of enzymes that operate in the pathways. We showed that diminished glycogen deposition is a metabolic signature of MetS in the pig myocardium. The depletion of glycogen arises from disbalance in expression of genes that break down and synthesize glycogen. We show robust acetoacetate accumulation and activated expression of key enzymes in ketone body formation, catabolism and transporters, suggesting a shift in fuel utilization in MetS. A contrasting enrichment in O-GlcNAcylated proteins uncovers hexosamine pathway and O-GlcNAcase (OGA) expression involvement in the myocardial response to MetS. Although the hexosamine biosynthetic pathway (HBP) activity and the availability of the UDP-GlcNAc substrate in the MetS myocardium is low, the level of O-GlcNacylated proteins is high as the O-GlcNacase is significantly diminished. Our data support the perception of transcriptionally driven myocardial alterations in expression of standard fatty acids, glucose metabolism, glycogen, and ketone body related enzymes and subsequent paucity of their metabolite products in MetS. This aberrant energy metabolism in the MetS myocardium provide insight into the pathogenesis of CVD in MetS.},
doi = {10.1371/journal.pone.0225857},
journal = {PLoS ONE},
number = 12,
volume = 14,
place = {United States},
year = {2019},
month = {12}
}

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