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

Disease models & mechanisms

PubMedID: 25147298

Resaz R, Vanni C, Segalerba D, Sementa AR, Mastracci L, Grillo F, Murgia D, Bosco MC, Chou JY, Barbieri O, Varesio L, Eva A. Development of hepatocellular adenomas and carcinomas in mice with liver-specific G6Pase-a deficiency. Dis Model Mech. 2014;7(9):1083-91.
Glycogen storage disease type 1a (GSD-1a) is caused by a deficiency in glucose-6-phosphatase-a (G6Pase-a), and is characterized by impaired glucose homeostasis and a high risk of developing hepatocellular adenomas (HCAs). A globally G6Pase-a-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-a-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.