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Untargeted proteomics profiling of liver and plasma in fed and fasted Glycogen Storage Disease type Ia (GSD Ia) mice: towards pathophysiological mechanisms and potential protein biomarkers for hepatic GSD Ia

ABSTRACT: Glycogen storage disease type Ia (GSD Ia) is a rare autosomal recessive disorder caused by a deficiency in glucose 6-phosphatase-α (G6PC). Patients primarily suffer from failure to thrive, hepatomegaly and severe fasting intolerance, biochemically characterized by hypoketotic and hyperlipidemia. Since they display clinical heterogeneity in biochemical symptoms and long-term hepatic complications, preclinical exploration of pathophysiological mechanisms and biomarkers is imperative for better prognosis and monitoring. To achieve this, an untargeted proteomics workflow was employed for identifying protein changes in liver and plasma from liver-specific G6pc knockout GSD Ia mice under fed and fasted conditions. Providing a link between the disease effects of GSD Ia in the liver and how these liver-specific effects present in the circulation under controlled (fed) and metabolic dysregulation (fasted) conditions. In liver proteomics results, protein levels related to the metabolism of glucose and lipids were up-regulated in GSD Ia mice versus controls. Differences were also observed in the proteasome, ribosome, NAD+ metabolism, hepatocellular detoxification, and synthesis of genotoxicity substances.. In plasma proteomics, proteins associated with complement and coagulation cascades decreased in GSD Ia.. The differences in both the liver and plasma were in general more pronounced in fasted GSD Ia mice. The overlapping differentially regulated plasma and liver proteins were subsequently identified for their potential as plasma biomarkers of hepatic complications, namely early-stage liver failure (SERPINA1E, C8b, and MBL2) non-alcoholic fatty liver disease (GPI1, UGP2, ALDOB, ACLY and FASN) and early hepatocellular carcinoma (PSMA4, PSMA7, PSMB5, and SDHA).

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Blood Plasma, Liver

DISEASE(S): Glycogen Storage Disease

SUBMITTER: Justina Clarinda Wolters

LAB HEAD: Dr. J.C.Wolters

PROVIDER: PXD054398 | Pride | 2026-03-16

REPOSITORIES: Pride

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			Action	DRS
	Fasted_Ia_Chow_m36_liver.raw	Raw
	Fasted_Ia_Chow_m37_liver.raw	Raw
	Fasted_Ia_Chow_m37_plasma.raw	Raw
	Fasted_Ia_Chow_m38_liver.raw	Raw
	Fasted_Ia_Chow_m38_plasma.raw	Raw

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Project description:abstract1: Glycogen storage disease type Ia (GSD Ia) is an inborn error of metabolism caused by defective glucose-6-phosphatase (G6PC) activity. GSD Ia patients exhibit severe hepatomegaly due to glycogen and triglyceride (TG) accumulation in the liver. We have previously shown that the activity of Carbohydrate Response Element Binding Protein (ChREBP), a key regulator of glycolysis and de novo lipogenesis, is increased in GSD Ia. In the current study we assessed the contribution of ChREBP to non-alcoholic fatty liver disease (NAFLD) development in a mouse model for hepatic GSD Ia. PMID : 32083759 Abstract2:Glycogen storage disease type 1a (GSD Ia) is an inborn error of metabolism caused by a defect in glucose-6-phosphatase (G6PC) activity, which induces severe hepatomegaly and increases the risk for liver cancer in patients. Hepatic GSD Ia is characterized by constitutive activation of Carbohydrate Response Element Binding Protein (ChREBP), a glucose-sensitive transcription factor that has been proposed as a pro-oncogenic molecular switch that supports tumour progression. Here we studied the contribution of ChREBP signalling on liver disease progression and tumour susceptibility in a mouse model for GSD Ia. Hepatocyte-specific G6pc knockout (L-G6pc-/-) mice were treated with AAV-shChREBP to normalize hepatic ChREBP activity. Hepatic ChREBP normalization induced dysplastic liver growth, massively increased hepatocyte size and sensitized to hepatic inflammation and liver fibrosis in GSD Ia mice. Furthermore, the nuclear levels of the oncoprotein YAP were increased and its transcriptional targets were induced in ChREBP normalized GSD Ia mice. Hepatic ChREBP normalization furthermore induced DNA damage and mitotic activity in GSD Ia mice, while chromosomal instability, cGAS-STING pathway, senescence, and hepatocyte dedifferentiation gene signatures emerged. Upon ChREBP silencing in immortalized human hepatocytes, on the other hand, the induction of YAP target gene expression was paralleled by cell cycle arrest, cell death, and reduced proliferation. In conclusion, our findings indicate that ChREBP activity limits hepatomegaly while protecting against liver disease progression and hepatocellular tumour induction in GSD Ia. These results underline the importance to establish the context-specific roles of ChREBP to define its therapeutic potential. PMID:37085901

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Untargeted proteomics profiling of liver and plasma in fed and fasted Glycogen Storage Disease type Ia (GSD Ia) mice: towards pathophysiological mechanisms and potential protein biomarkers for hepatic GSD Ia

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