Untargeted Proteomics Profiling of Liver and Plasma in Fed and Fasted Liver-Specific Glycogen Storage Disease Type Ia (GSD Ia) Mice: Toward Potential Protein Biomarkers.

Glycogen storage disease type Ia (GSD Ia) is a rare autosomal recessive inherited disorder of carbohydrate metabolism, caused by a deficiency in glucose 6-phosphatase-α (G6PC1). Patients primarily suffer from failure to thrive, hepatomegaly, and severe fasting intolerance, biochemically characterized by hypoketotic, hypoglycemia, and hyperlipidemia. Because of clinical and biochemical heterogeneity, identifying biomarkers is imperative for prognosis and monitoring. An untargeted proteomics workflow was employed for identifying protein changes in liver and plasma from hepatocyte-specific G6pc knockout mice under fed and fasted conditions. This links the effect of hepatic G6Pase/G6pc deficiency to circulating protein biomarkers and allows assessment of the relationship with different clinical circumstances and long-term complications. In the liver, the main differences between hepatic GSD Ia mice versus controls were observed in proteins related to carbohydrate and lipid metabolism, proteasome, ribosome, NAD+ metabolism, and mitochondria. In GSD Ia mouse plasma, proteins were mainly down-regulated in the complement and coagulation cascades. Effects in hepatic GSD Ia mice were in general more pronounced under fasting conditions. Several potential biomarkers that showed significant alterations in both liver and plasma were identified. These include proteins involved in carbohydrate and lipid metabolism (e.g., UGP2, ALDOB, and FASN), complement and coagulation cascades (SERPINA1E, C8b, and MBL2), 20S proteasome subunits (PSMA4, PSMA7, and PSMB5), and the electron transport chain (SDHA). Their consistent changes observed in both the liver and circulation indicate their potential as circulating biomarkers reflecting liver condition. Together with their reported associations with liver diseases, we hypothesize that they could monitor hepatic complications.