Abstract 15325: SAH-Responsive Genes Mediate Worsening Metabolic Crosstalk Between Homocysteine-Methionine, Glucose-Related &Lt Lipid Metabolic Systems

Abstract

Introduction: Hyperhomocysteinemia (HHcy) is an independent risk factor for cardiovascular disease, and other chronic disease. We recently proposed that the homocysteine-methionine (H-M) cycle is a metabolic sensor system responsible for pathological signaling in chronic disease. We identified metabolic worsening crosstalk between HHcy, hyperglycemia and hyperlipidemia in concomitant mouse disease models and in human coronary artery disease. Research Question: What is the molecular mechanism mediating worsening metabolic crosstalk in concomitant metabolic disorders? Methods: mRNA levels of 324 metabolic genes in three metabolic systems were examined, including 119 for H-M, 95 for glucose-related and 110 genes for lipid in 21 human and 20 mouse organs. Organs were classified based on specific metabolic gene expression. Hcy-metabolites were measured in 6 mouse organs (heart, liver, brain, lung, spleen, and kidney) by LS-ESI-MS/MS. Hcy-metabolites responsive genes were identified by linear regression analyses between metabolites and gene expression levels and used to establish Hcy-metabolites responsive metabolic networks. Results: We identified 7 Hcy-, 64 SAH- and 18 SAM:SAH-responsive genes and 3 pathological SAH-responsive cross-talking metabolites (serine, taurine and glycine 3 phosphate). SAH-responsive genes associated with activated upper glycolysis and suppressed lower glycolysis leading to glycolysis-related redox imbalance. A negative correlation between SAH and serine synthesis enzyme PHGDH suggests that increased SAH may suppress serine synthesis which leads to the impairment of transsulfuration, and taurine reduction. SAH-related taurine reduction can further negatively impact cholesterol (CH) degradation. SAH-related upper glycolysis activation leads to the increase of G3P synthesis, which is a substrate for triglyceride (TG) synthesis. In addition, SAH levels may activate fatty acid uptake and β-oxidation leading to elevated acetyl-CoA, CH and TG synthesis. Conclusion: H-M cycle is a metabolic sensor system. Production change of serine, taurine and G3P via SAH-responsive metabolic genes can be the key cross-talking metabolites responsible for worsening metabolic crosstalk in metabolic syndrome.