Metabolomics Analysis Reveals Molecular Signatures of Metabolic Complexity in Children with Hypercholesterolemia

Despite the importance of hypercholesterolemia in children, it is overlooked, and there are currently few metabolomics-based approaches available to understand its molecular mechanisms. Children from a birth cohort had their cholesterol levels measured with the aim of identifying the metabolites for the molecular biological pathways of childhood hypercholesterolemia. One hundred and twenty-five children were enrolled and stratified into three groups according to cholesterol levels (acceptable, <170 mg/dL, n = 42; borderline, 170-200 mg/dL, n = 52; and high, >200 mg/dL, n = 31). Plasma metabolomic profiles were obtained by using ¹H-nuclear magnetic resonance (NMR) spectroscopy, and partial least squares-discriminant analysis (PLS-DA) was applied using the MetaboAnalyst 5.0 platform. Metabolites significantly associated with different cholesterol statuses were identified, and random forest classifier models were used to rank the importance of these metabolites. Their associations with serum lipid profile and functional metabolic pathways related to hypercholesterolemia were also assessed. Cholesterol level was significantly positively correlated with LDL-C and Apo-B level, as well as HDL-C and Apo-A1 level separately, whereas HDL-C was negatively correlated with triglyceride level (p < 0.01). Eight metabolites including tyrosine, glutamic acid, ornithine, lysine, alanine, creatinine, oxoglutaric acid, and creatine were significantly associated with the different statuses of cholesterol level. Among them, glutamic acid and tyrosine had the highest importance for different cholesterol statuses using random forest regression models. Carbohydrate and amino acid metabolisms were significantly associated with different cholesterol statuses, with glutamic acid being involved in all amino acid metabolic pathways (FDR-adjusted p < 0.01). Hypercholesterolemia is a significant health concern among children, with up to 25% having high cholesterol levels. Glutamic acid and tyrosine are crucial amino acids in lipid metabolism, with glutamic-acid-related amino acid metabolism playing a significant role in regulating cholesterol levels.