Dietary exacerbation of metabolic stress leads to accelerated hepatic carcinogenesis in glycogen storage disease type Ia

Background & Aims: Glycogen storage disease type Ia (GSDIa) is a rare genetic disease associated with glycogen accumulation in hepatocytes and steatosis. With age, most adult patients with GSDIa develop hepatocellular adenomas (HCA), which can progress to hepatocellular carcinomas (HCC). In this study, we characterized metabolic reprogramming and cellular defense alterations during tumorigenesis in the liver of hepatocyte-specific G6pc deficient (L.G6pc(-/-)) mice, which develop all the hepatic hallmarks of GSDIa. Methods: Liver metabolism and cellular defenses were assessed at pretumoral (four months) and tumoral (nine months) stages in L.G6pc(-/-) mice fed a high fat/high sucrose (HF/HS) diet. Results: In response to HF/HS diet, hepatocarcinogenesis was highly accelerated since 85% of L.G6p(-/-) mice developed multiple hepatic tumors after nine months, with 70% classified as HCA and 30% as HCC. Tumor development was associated with high expression of malignancy markers of HCC, i.e. alpha-fetoprotein, glypican 3 and beta-catenin. In addition, L.G6pc(-/-) livers exhibited loss of tumor suppressors. Interestingly, L.G6pc(-/-) steatosis exhibited a low-inflammatory state and was less pronounced than in wild-type livers. This was associated with an absence of epithelial-mesenchymal transition and fibrosis, while HCA/HCC showed a partial epithelial-mesenchymal transition in the absence of TGF-beta 1 increase. In HCA/HCC, glycolysis was characterized by a marked expression of PK-M2, decreased mitochondrial OXPHOS and a decrease of pyruvate entry in the mitochondria, confirming a "Warburg-like" phenotype. These metabolic alterations led to a decrease in antioxidant defenses and autophagy and chronic endoplasmic reticulum stress in L.G6pc(-/-) livers and tumors. Interestingly, autophagy was reactivated in HCA/HCC. Conclusion: The metabolic remodeling in L.G6pc(-/-) liver generates a preneoplastic status and leads to a loss of cellular defenses and tumor suppressors that facilitates tumor development in GSDI. (C) 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.