SAH is a major metabolic sensor mediating worsening metabolic crosstalk in metabolic syndrome
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
Affiliations
Ramon Cueto
Center for Metabolic Disease Research, Lewis Kats School of Medicine, Temple University, Philadelphia, PA, USA
Wen Shen
Center for Metabolic Disease Research, Lewis Kats School of Medicine, Temple University, Philadelphia, PA, USA; Department of Cardiovascular Medicine, The Second Affiliated Hospital of Nanchang University, China
Lu Liu
Center for Metabolic Disease Research, Lewis Kats School of Medicine, Temple University, Philadelphia, PA, USA
Xianwei Wang
Center for Metabolic Disease Research, Lewis Kats School of Medicine, Temple University, Philadelphia, PA, USA
Sheng Wu
Center for Metabolic Disease Research, Lewis Kats School of Medicine, Temple University, Philadelphia, PA, USA
Sadia Mohsin
Cardiovascular Research Center, Lewis Kats School of Medicine, Temple University, Philadelphia, PA, USA
Ling Yang
Medical Genetics & Molecular Biochemistry, Lewis Kats School of Medicine, Temple University, Philadelphia, PA, USA
Mohsin Khan
Center for Metabolic Disease Research, Lewis Kats School of Medicine, Temple University, Philadelphia, PA, USA
Wenhui Hu
Center for Metabolic Disease Research, Lewis Kats School of Medicine, Temple University, Philadelphia, PA, USA
Nathaniel Snyder
Center for Metabolic Disease Research, Lewis Kats School of Medicine, Temple University, Philadelphia, PA, USA
Qinghua Wu
Department of Cardiovascular Medicine, The Second Affiliated Hospital of Nanchang University, China
Yong Ji
Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, China
Xiao-Feng Yang
Center for Metabolic Disease Research, Lewis Kats School of Medicine, Temple University, Philadelphia, PA, USA; Cardiovascular Research Center, Lewis Kats School of Medicine, Temple University, Philadelphia, PA, USA
Hong Wang
Center for Metabolic Disease Research, Lewis Kats School of Medicine, Temple University, Philadelphia, PA, USA; Corresponding author. Center for Metabolic Disease Research, Temple University School of Medicine, 3500 North Broad Street, Philadelphia, PA, 19140, USA.
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 SAH-activated pathological TG loop as the consequence of increased fatty acid (FA) uptake, FA β-oxidation and Ac-CoA 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 SAH-responsive 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.