This PhD thesis of Alagere Kishore investigates the regulation of glucose 6-phosphatase (G6PC)-independent glucose production in hepatic Glycogen Storage Disease (GSD) types Ia and Ib, aiming to optimize glucose homeostasis and reduce hepatic glycogen accumulation. Building on prior research, this work explores the role of carbohydrate-responsive element-binding protein (ChREBP) in glucose and glycogen metabolism, particularly under conditions where G6PC function is impaired.
In an acute GSD Ib model induced by the G6P transporter inhibitor S4048, ChREBP was shown to regulate glucose metabolism, with its downregulation exacerbating the GSD Ib phenotype. Notably, ChREBP downregulation increased hepatic glycogen accumulation and altered glucokinase (GCK) activity, independent of GCKR regulation. Additionally, ChREBP appeared to influence lysosomal glycogen breakdown, affecting the expression of STBD1 and the activity of acid alpha-glucosidase (GAA).
The thesis also compares the metabolic profiles of hepatic GSD Ia and Ib mice, revealing distinct differences in lipid metabolism and glycolytic pathways. A novel ex vivo model using precision-cut liver slices (PCLS) was developed to further explore hepatic glucose production and AMPK signaling. Key findings include the varying effects of gluconeogenic precursors and the validation of PCLS for studying GSD-related glucose production.
This research offers new insights into ChREBP’s role and AMPK signaling in hepatic glucose and glycogen metabolism. Its future implications set the stage for further studies that will utilize both in vivo and ex vivo models to focus on the detailed mechanisms of ChREBP-mediated and AMPK-mediated regulation and its clinical applications.
