Emerging roles of autophagy in hepatic tumorigenesis and therapeutic strategies in glycogen storage disease type Ia: A review

• Published in: Journal of inherited metabolic disease Vol. 44; no. 1; pp. 118 - 128
• Main Authors: Cho, Jun‐Ho, Weinstein, David A., Lee, Young Mok
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01-01-2021; Blackwell Publishing Ltd
• Subjects: Adenoma; Animals; Autophagy; Carcinogenesis - pathology; Carcinoma, Hepatocellular - enzymology; Carcinoma, Hepatocellular - prevention & control; Dependovirus - genetics; Disease Models, Animal; Energy metabolism; Etiology; Gene therapy; Genetic Therapy - methods; Genetic Vectors - administration & dosage; Gluconeogenesis; Glucose; Glucose - metabolism; Glucose-6-Phosphatase - genetics; Glucose-6-Phosphatase - metabolism; glucose‐6‐phosphatase‐α; Glycogen; Glycogen Storage Disease Type I - complications; Glycogen Storage Disease Type I - enzymology; Glycogen Storage Disease Type I - therapy; hepatocellular adenoma and carcinoma; Homeostasis; Humans; Hypoglycemia; Liver - enzymology; Liver cancer; liver metabolism; Liver Neoplasms - enzymology; Liver Neoplasms - prevention & control; Metabolic disorders; Metabolism; Mice; Mice, Knockout; Molecular modelling; Phagocytosis; Signal Transduction; Storage diseases; Triglycerides; Tumorigenesis; gene therapy; liver metabolism; autophagy; hepatocellular adenoma and carcinoma; glucose-6-phosphatase-α
• ISSN: 0141-8955; 1573-2665
• DOI: 10.1002/jimd.12267

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.