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SAH is a major metabolic sensor mediating worsening metabolic crosstalk in metabolic syndrome
Cueto, Ramon Shen, Wen Liu, Lu Wang, Xianwei Wu, Sheng Mohsin, Sadia Yang, Ling Khan, Mohsin Hu, Wenhui Snyder, Nathaniel W.
Cueto, Ramon
Shen, Wen
Liu, Lu
Wang, Xianwei
Wu, Sheng
Mohsin, Sadia
Yang, Ling
Khan, Mohsin
Hu, Wenhui
Snyder, Nathaniel W.
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Journal article
Date
2024-04-27
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Medical Genetics and Molecular Biochemistry
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https://doi.org/10.1016/j.redox.2024.103139
Abstract
In this study, we observed worsening metabolic crosstalk in mouse models with concomitant metabolic disorders
such as hyperhomocysteinemia (HHcy), hyperlipidemia, and hyperglycemia and in human coronary artery
disease by analyzing metabolic profiles. We found that HHcy worsening is most sensitive to other metabolic
disorders. To identify metabolic genes and metabolites responsible for the worsening metabolic crosstalk, we
examined mRNA levels of 324 metabolic genes in Hcy, glucose-related and lipid metabolic systems. We examined
Hcy-metabolites (Hcy, SAH and SAM) by LS-ESI-MS/MS in 6 organs (heart, liver, brain, lung, spleen, and kidney)
from C57BL/6J mice. Through linear regression analysis of Hcy-metabolites and metabolic gene mRNA levels,
we discovered that SAH-responsive genes were responsible for most metabolic changes and all metabolic
crosstalk mediated by Serine, Taurine, and G3P. SAH-responsive genes worsen glucose metabolism and cause
upper glycolysis activation and lower glycolysis suppression, indicative of the accumulation of glucose/glycogen
and G3P, Serine synthesis inhibition, and ATP depletion. Insufficient Serine due to negative correlation of
PHGDH with SAH concentration may inhibit the folate cycle and transsulfurarion pathway and consequential
reduced antioxidant power, including glutathione, taurine, NADPH, and NAD+. Additionally, we identified SAHactivated pathological TG loop as the consequence of increased fatty acid (FA) uptake, FA β-oxidation and AcCoA production along with lysosomal damage. We concluded that HHcy is most responsive to other metabolic
changes in concomitant metabolic disorders and mediates worsening metabolic crosstalk mainly via SAHresponsive genes, that organ-specific Hcy metabolism determines organ-specific worsening metabolic reprogramming, and that SAH, acetyl-CoA, Serine and Taurine are critical metabolites mediating worsening metabolic
crosstalk, redox disturbance, hypomethylation and hyperacetylation linking worsening metabolic reprogramming in metabolic syndrome.
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Citation
Ramon Cueto, Wen Shen, Lu Liu, Xianwei Wang, Sheng Wu, Sadia Mohsin, Ling Yang, Mohsin Khan, Wenhui Hu, Nathaniel Snyder, Qinghua Wu, Yong Ji, Xiao-Feng Yang, Hong Wang, SAH is a major metabolic sensor mediating worsening metabolic crosstalk in metabolic syndrome,
Redox Biology, Volume 73, 2024, 103139, ISSN 2213-2317, https://doi.org/10.1016/j.redox.2024.103139. (https://www.sciencedirect.com/science/article/pii/S2213231724001150)
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Elsevier
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Redox Biology, Vol. 73
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