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

• Autori principali: Roberta Resaz (Autore), Cristina Vanni (Autore), Daniela Segalerba (Autore), Angela R. Sementa (Autore), Luca Mastracci (Autore), Federica Grillo (Autore), Daniele Murgia (Autore), Maria Carla Bosco (Autore), Janice Y. Chou (Autore), Ottavia Barbieri (Autore), Luigi Varesio (Autore), Alessandra Eva (Autore)
• Natura: Libro
• Pubblicazione: The Company of Biologists, 2014-09-01T00:00:00Z.
• Soggetti: article
• Accesso online: Connect to this object online.
• Notes: 1754-8403; 1754-8411; 10.1242/dmm.014878
• Keywords: Glycogen storage disease type 1a; Glucose-6-phosphatase-α; Animal model; Hepatomegaly; Hepatic steatosis; Hepatocellular adenoma; Hepatocellular carcinoma; Medicine; R; Pathology; RB1-214
• Source: Disease Models & Mechanisms, Vol 7, Iss 9, Pp 1083-1091 (2014)

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.