Understanding hepatic Glycogen Storage Disease type Ia: role of phenotypic heterogeneity and nutrient sensors

Patients with Glycogen Storage Disease type Ia (GSD Ia), a rare inherited disease affecting glucose metabolism, are at increased risk for liver tumour development but harbour interindividual differences in disease presentation and progression. The studies in this thesis focus on modelling clinical heterogeneity in GSD Ia in mice, and understanding the mechanisms underlying liver tumour development in GSD Ia. As both aspects are currently unresolved, they pose major challenges to optimal healthcare for GSD Ia patients. We show that somatic CRISPR/Cas9-mediated editing of hepatic glucose-6-phosphatase (G6pc, the gene affected in GSD Ia) allows to generate a spectrum of GSD Ia phenotypes and to simultaneously edit multiple hepatic genes. This approach may hence be employed to investigate the contribution of individual differences between patients, such as variations in residual G6PC1 activity and the interaction between G6PC1 other genes, to liver tumour development in GSD Ia. In addition, our work shows that activation of the nutrient sensor Carbohydrate Response Element Binding Protein (ChREBP) protects against advanced liver disease and decelerates liver tumour development in GSD Ia. Insights from this work help to better understand mechanisms underlying tumorigenesis in GSD Ia, and highlight the importance of establishing the content-specific roles of ChREBP to define its therapeutic potential. Finally, our work on the nutrient sensor Sirtuin 1 (SIRT1) reveals previously unknown adaptations in NAD+ and methyl (one-carbon) metabolism in hepatic GSD Ia, which may provide novel directions for (pre)clinical research on and therapy development for GSD Ia.

Dissertation: http://hdl.handle.net/11370/30d1e0cd-bcac-4ac9-9229-888e4faecbaf