Dataset Information

Hepatocyte-specific Cas9-mediated editing of G6pc and Slc37a4 elicits comparable biochemical and regulatory responses between glycogen storage disease (GSD) type Ia and Ib mice

ABSTRACT: Glycogen storage disease type I (GSD I) is an autosomal recessive inborn error of carbohydrate metabolism. Patients with GSD type Ia and Ib exhibit overlapping and distinct symptoms and complications. Notably, GSD Ia patients show more severe hypertriglyceridemia and higher risk of hepatic tumors than GSD Ib patients. Given the liver's pivotal role in these processes, this study utilized hepatocyte-specific CRISPR/Cas9-mediated gene editing to explore the pathophysiological and biochemical differences between hepatic GSD Ia and Ib. Additionally, hepatic histology, transcriptomics, and proteomics analysis was performed. Compared to controls, GSD Ia and Ib mice showed hepatomegaly, fasting hypoglycemia, hyperlactatemia, and increased uric acid in plasma, which was more pronounced in GSD Ia than Ib. Both GSD I subtypes showed similar reductions in hepatic acetyl-CoA precursor pool enrichment and inceases in de novo biosynthesis of hepatic stearate and oleate. Interestingly, only GSD Ia mice showed significantly elevated plasma triglyceride, uric acid, and hepatic phosphate sugars. These metabolic changes were reflected at the level of transcriptomics and proteomics results. Moreover, altered mRNAs and protein levels related to nucleotide-binding oligomerization domain (NOD) signaling pathways, infection and inflammation, liver disease, and chemical carcinogenesis were more pronounced in GSD Ia mice. Overall, the metabolic disturbance was more severe in hepatocyte-specific GSD Ia than Ib mice, consistent with the clinical phenotype on patients. The metabolic disorders and specific metabolites, genes, and proteins identified in this study provided new insights into the potential therapeutic targets for GSD I patients, highlighting the need for subtype-specific treatment strategies.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Liver

SUBMITTER: Justina Clarinda Wolters

LAB HEAD: Dr. JC Wolters

PROVIDER: PXD066807 | Pride | 2026-07-02

REPOSITORIES: Pride

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Hepatocyte-specific Cas9-mediated editing of G6pc and Slc37a4 elicits comparable biochemical and regulatory responses between glycogen storage disease (GSD) type Ia and Ib mice.

Krishnamurthy Kishore A KA Xiao Ruiqi R Rutten Martijn G S MGS Bos Trijnie T Bleeker Aycha A Zhang Mingjia M de Vries Hilda I HI Koster Mirjam M Huijkman Nicolette N Smit Marieke M Kloosterhuis Niels N Boer Theo T Schomakers Bauke B van Weeghel Michel M van de Sluis Bart B Wolters Justina C JC Bakker Barbara M BM Oosterveer Maaike H MH

Molecular metabolism 20260610

<h4>Background/objective</h4>Glycogen storage disease type I (GSD I) is an autosomal recessive inborn error of carbohydrate metabolism. Patients with GSD type Ia and Ib exhibit overlapping and distinct symptoms and complications. Notably, GSD Ia patients show more severe hypertriglyceridemia and higher risk of hepatic tumors than GSD Ib patients.<h4>Methods</h4>Given the liver's pivotal role in these processes, this study utilized hepatocyte-specific CRISPR/Cas9-mediated somatic gene editing to ...[more]

PMID: 42270039

Similar Datasets

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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