Enhanced Lysosomal Glycogen Breakdown is associated with Liver Tumorigenesis in Glycogen Storage Disease Type III

Abstract

International audienceBackground & Aims: Glycogen storage disease type III (GSDIII) is a rare metabolic disorder caused by mutations in the glycogen debranching enzyme (AGL), leading to hepatic glycogen accumulation, fibrosis and increased hepatocellular carcinoma (HCC) risk. This study investigates the metabolic mechanisms driving liver tumorigenesis in an Agl-/- model of GSDIII. Methods: Liver and tumor samples from 14-month-old Agl-/- and Agl+/+ mice, and liver biopsies from GSDIII patients (n=4), were analyzed using histological, biochemical and molecular approaches. Results: Agl-/- mice recapitulated key features of GSDIII, including a 3.5-fold hepatic glycogen overload (p<0.001), and chronic liver disease. More than 30% of the animals developed liver tumors, associated to a 2.5-fold increase in α-fetoprotein levels (p<0.005). Despite marked reductions in glucose (7.5-fold, p<0.0001), glucose-6 phosphate (6.2-fold, p<0.0001), lactate (8-fold, p<0.005), cholesterol (1.9-fold, p<0.001) and triglyceride levels (6.2-fold, p<0.001) in the liver, glycaemia was maintained at around 87.0±9.6 mg/dl after 6h of fasting, through activated extrahepatic, but not hepatic, gluconeogenesis. Intriguingly, most tumors exhibited lower glycogen content than surrounding tissue (3.3-fold decrease, p<0.0001), associated with increased lysosomal α-acid glucosidase activity (19.5±5.5 in tumor vs 9.9±2.0 mmol/h/mg in Agl -/-liver; p<0.0005) and the presence of glycophagosomes. PAS-negative staining in GSDIII patient HCCs supported these observations. Although YAP nuclear staining varied between tumors, overall increased YAP nuclear localization and CTGF expression suggest that Hippo/YAP pathway inhibition could contribute to tumorigenesis in GSDIII hepatocytes.Conclusions: In GSDIII, liver metabolism is characterized by the accumulation of structurally abnormal glycogen and a significant reduction of key energy substrates. In this metabolic context, enhanced lysosomal glycogen degradation may support tumor growth, highlighting a mechanistic link between glycogen metabolism and the development of liver cancer