Development of hepatocellular adenomas and carcinomas in mice with liver-specific G6Pase-α deficiency.

Roberta Resaz,Luca Mastracci,Maria Carla Bosco,Cristina Vanni,Federica Grillo,Ottavia Barbieri,Daniele Murgia,Angela R Sementa,Janice Y Chou,Daniela Segalerba,Luigi Varesio,Alessandra Eva

doi:10.1242/dmm.014878

Abstract

Glycogen storage disease type 1a (GSD-1a) is caused by a deficiency in glucose-6-phosphatase-α (G6Pase-α), and is characterized by impaired glucose homeostasis and a high risk of developing hepatocellular adenomas (HCAs). A globally G6Pase-α-deficient (G6pc−/−) mouse model that shows pathological features similar to those of humans with GSD-1a has been developed. These mice show a very severe phenotype of disturbed glucose homeostasis and rarely live beyond weaning. We generated liver-specific G6Pase-α-deficient (LS‑G6pc−/−) mice as an alternative animal model for studying the long-term pathophysiology of the liver and the potential treatment strategies, such as cell therapy. LS‑G6pc−/− mice were viable and exhibited normal glucose profiles in the fed state, but showed significantly lower blood glucose levels than their control littermates after 6 hours of fasting. LS‑G6pc−/− mice developed hepatomegaly with glycogen accumulation and hepatic steatosis, and progressive hepatic degeneration. Ninety percent of the mice analyzed developed amyloidosis by 12 months of age. Finally, 25% of the mice sacrificed at age 10–20 months showed the presence of multiple HCAs and in one case late development of hepatocellular carcinoma (HCC). In conclusion, LS‑G6pc−/− mice manifest hepatic symptoms similar to those of human GSD-1a and, therefore, represent a valid model to evaluate long-term liver pathogenesis of GSD-1a.

Highlights

The authors characterized the progression of liver degeneration in LS-G6pc–/– mice and demonstrated that these mice exhibit hepatic symptoms similar to those of human Glycogen storage disease type 1a (GSD-1a), including hepatomegaly, steatosis and glycogen accumulation
25% of LS-G6pc–/– mice developed liver nodules by 10-20 months of age. These nodules were identified as adenomas and in one case as hepatocellular carcinoma
These mice manifested most of the hepatic symptoms of the human pathology, including hepatomegaly, steatosis and glycogen accumulation

Summary

Introduction

Glycogen storage disease type 1a (GSD-1a) is an autosomal recessive disorder caused by mutations in glucose-6-phosphatase-α (G6Pase-α; encoded by G6PC), an enzyme expressed primarily in. The patients manifest hypoglycemia, growth retardation, hepatomegaly and nephromegaly with consequent compromised liver and kidney functions. The current treatment of GSD-1a is based on the control of symptomatic hypoglycemia by naso-gastric infusion of glucose and frequent oral administration of cornstarch (Greene et al, 1976; Chen et al, 1984).

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Conclusion