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Genova, Italy

Resaz R.,Laboratory of Molecular Biology | Vanni C.,Laboratory of Molecular Biology | Segalerba D.,Laboratory of Molecular Biology | Sementa A.R.,Istituto Gannina Gaslini | And 11 more authors.
DMM Disease Models and Mechanisms | Year: 2014

Glycogen storage disease type 1a (GSD-1a) is caused by a deficiency in glucose-6-phosphatase-aα (G6Pase-aα), and is characterized by impaired glucose homeostasis and a high risk of developing hepatocellular adenomas (HCAs). A globally G6Pase-aα- 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 liverspecific G6Pase-aα-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. LSG6pc-/-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. © 2014. Published by The Company of Biologists Ltd. Source

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