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Potential Modulatory Role of Osteoprotegerin in Bone Metabolism of Patients with 21-Hydroxylase Deficiency - GSD 5611

ABSTRACT: Potential Modulatory Role of Osteoprotegerin in Bone Metabolism of Patients with 21-Hydroxylase Deficiency - GSD 5611

PROVIDER: PRJNA377383 | ENA |

REPOSITORIES: ENA

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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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Potential Modulatory Role of Osteoprotegerin in Bone Metabolism of Patients with 21-Hydroxylase Deficiency - GSD 5611

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