Metabolomics-driven identification of perturbations in amino acid and sphingolipid metabolism as therapeutic targets in a rat model of anorexia nervosa disease using chemometric analysis and a multivariate analysis platform.

ABSTRACT

It is important to explore novel therapeutic targets and develop an effective strategy for the treatment of anorexia nervosa. In this work, serum samples were analyzed using ultra-performance liquid chromatography coupled with quadrupole time-of flight mass spectrometry (UPLC/Q-TOF MS) coupled with chemometric analysis and multivariate analysis to obtain the metabolites and their corresponding pathways. In addition, knock-in and knock-down of the key enzyme in vivo was performed to verify the reliability of the obtained metabolic pathway, which is closely associated with the anorexia nervosa pathomechanism and the potential targets. There were significant differences in the biochemical parameters between the model group and the control group. A total of 26 potential biomarkers were identified to resolve the difference between the control and model rats, which were closely related to amino acid metabolism, sphingolipid metabolism, arachidonic acid metabolism, the citrate cycle, and so forth. According to the ingenuity pathway analysis, we further elucidated the relationship between the gene, protein, and metabolite alteration in anorexia nervosa, which are involved in cellular compromise, lipid metabolism, small molecule biochemistry, cell signaling, molecular transport, nucleic acid metabolism, cell morphology, cellular function and maintenance. Arginosuccinate synthetase (ASS) deficiency was accompanied by a significant downregulation of the ß-endorphin and ghrelin in the animal models. The metabolites and pathways obtained using the metabolomics strategy may provide valuable information for the early treatment for anorexia nervosa.