title: Development of hepatocellular adenomas and carcinomas in mice with liver-specific G6Pase-α deficiency.
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.
authors.affiliation: Laboratory of Molecular Biology, Istituto Gannina Gaslini, 16147 Genova, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Resaz
authors.affiliation: Laboratory of Molecular Biology, Istituto Gannina Gaslini, 16147 Genova, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Vanni
authors.affiliation: Laboratory of Molecular Biology, Istituto Gannina Gaslini, 16147 Genova, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Segalerba
authors.affiliation: Department of Pediatric Pathology, Istituto Gannina Gaslini, 16147 Genova, Italy.
authors.forename: Angela R
authors.initials: AR
authors.lastname: Sementa
authors.affiliation: Department of Surgical and Diagnostic Sciences (DISC), Anatomic Pathology Unit, University of Genova, 16132 Genova, Italy IRCCS AOU San Martino-IST, National Cancer Research Institute, 16132 Genova, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Mastracci
authors.affiliation: Department of Surgical and Diagnostic Sciences (DISC), Anatomic Pathology Unit, University of Genova, 16132 Genova, Italy IRCCS AOU San Martino-IST, National Cancer Research Institute, 16132 Genova, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Grillo
authors.affiliation: Department of Pediatric Pathology, Istituto Gannina Gaslini, 16147 Genova, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Murgia
authors.affiliation: Laboratory of Molecular Biology, Istituto Gannina Gaslini, 16147 Genova, Italy.
authors.forename: Maria Carla
authors.initials: MC
authors.lastname: Bosco
authors.affiliation: Section on Cellular Differentiation, Program on Developmental Endocrinology and Genetics, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892-1830, USA.
authors.forename: Janice Y
authors.initials: JY
authors.lastname: Chou
authors.affiliation: IRCCS AOU San Martino-IST, National Cancer Research Institute, 16132 Genova, Italy Department of Experimental Medicine (DIMES), University of Genova, 16132 Genova, Italy.
authors.forename: Ottavia
authors.initials: O
authors.lastname: Barbieri
authors.affiliation: Laboratory of Molecular Biology, Istituto Gannina Gaslini, 16147 Genova, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Varesio
authors.affiliation: Laboratory of Molecular Biology, Istituto Gannina Gaslini, 16147 Genova, Italy alessandraeva@ospedale-gaslini.ge.it.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Eva
mesh_terms: D000236:Adenoma / Q000201:enzymology / Q000473:pathology*; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000473:pathology*; D005954:Glucosephosphate Dehydrogenase / Q000235:genetics*; D008113:Liver Neoplasms / Q000201:enzymology / Q000473:pathology*; D051379:Mice
chemical_list: D005954:Glucosephosphate Dehydrogenase
keywords: Animal model; Glucose-6-phosphatase-α; Glycogen storage disease type 1a; Hepatic steatosis; Hepatocellular adenoma; Hepatocellular carcinoma; Hepatomegaly