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Glycogen storage disease type Ia (GSD‐Ia) is an inherited metabolic disease caused by a deficiency in glucose‐6‐phosphatase‐α (G6Pase‐α or G6PC) which plays a critical role in blood glucose homeostasis by catalyzing the hydrolysis of glucose‐6‐phosphate (G6P) to glucose and phosphate in the terminal step of glycogenolysis and gluconeogenesis. Patients with GSD‐Ia manifest life‐threatening fasting hypoglycemia along with the excessive accumulation of hepatic glycogen and triglycerides which results in hepatomegaly and a risk of long‐term complications such as hepatocellular adenoma and carcinoma (HCA/HCC). The etiology of HCA/HCC development in GSD‐Ia, however, is unknown. Recent studies have shown that the livers in model animals of GSD‐Ia display impairment of autophagy, a cellular recycling process which is critical for energy metabolism and cellular homeostasis. However, molecular mechanisms of autophagy impairment and its involvement in pathogenesis in GSD‐Ia are still under investigation. Here, we summarize the latest advances for signaling pathways implicated in hepatic autophagy impairment and the roles of autophagy in hepatic tumorigenesis in GSD‐Ia. In addition, recent evidence has illustrated that autophagy plays an important role in hepatic metabolism and liver‐directed gene therapy mediated by recombinant adeno‐associated virus (rAAV). Therefore, we highlight the possible role of hepatic autophagy in metabolic control and rAAV‐mediated gene therapy for GSD‐Ia. In this review, we also provide potential therapeutic strategies for GSD‐Ia on the basis of molecular mechanisms underlying hepatic autophagy impairment in GSD‐Ia. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • High-calorie diet accelerates tumor incidence and transformation in GSDI livers. • A Warburg-like metabolic reprogramming predisposes GSDI livers to HCC development. • Metabolic perturbations lead to the loss of cellular defenses in GSDI livers. • GSDI livers and tumors exhibit loss of tumor suppressor expression. • HCC present a concomitant expression of epithelial and mesenchymal markers. 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.G6pc −/− 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 β-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-β1 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. Lay summary Glycogen storage disease type Ia (GSD1a) is a rare metabolic disease characterized by hypoglycemia, steatosis, excessive glycogen accumulation and tumor development in the liver. In this study, we have observed that GSDIa livers reprogram their metabolism in a similar way to cancer cells, which facilitates tumor formation and progression, in the absence of hepatic fibrosis. Moreover, hepatic burden due to overload of glycogen and lipids in the cells leads to a decrease in cellular defenses, such as autophagy, which could further promote tumorigenesis in the case of GSDI. [ABSTRACT FROM AUTHOR]