{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T22:17:33Z","timestamp":1785536253117,"version":"3.56.0"},"reference-count":28,"publisher":"The Company of Biologists","issue":"9","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,9,1]]},"abstract":"<jats:p>Glycogen storage disease type 1a (GSD-1a) is caused by a deficiency in glucose-6-phosphatase-\u03b1 (G6Pase-\u03b1), and is characterized by impaired glucose homeostasis and a high risk of developing hepatocellular adenomas (HCAs). A globally G6Pase-\u03b1-deficient (G6pc\u2212\/\u2212) 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-\u03b1-deficient (LS\u2011G6pc\u2212\/\u2212) 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\u2011G6pc\u2212\/\u2212 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\u2011G6pc\u2212\/\u2212 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\u201320 months showed the presence of multiple HCAs and in one case late development of hepatocellular carcinoma (HCC). In conclusion, LS\u2011G6pc\u2212\/\u2212 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.<\/jats:p>","DOI":"10.1242\/dmm.014878","type":"journal-article","created":{"date-parts":[[2014,8,21]],"date-time":"2014-08-21T13:21:42Z","timestamp":1408627302000},"page":"1083-1091","source":"Crossref","is-referenced-by-count":22,"title":["Development of hepatocellular adenomas and carcinomas in mice with liver-specific G6Pase-\u03b1 deficiency"],"prefix":"10.1242","volume":"7","author":[{"given":"Roberta","family":"Resaz","sequence":"first","affiliation":[{"name":"Laboratory of Molecular Biology, Istituto Gannina Gaslini, 16147 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Vanni","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology, Istituto Gannina Gaslini, 16147 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Segalerba","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology, Istituto Gannina Gaslini, 16147 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela R.","family":"Sementa","sequence":"additional","affiliation":[{"name":"Department of Pediatric Pathology, Istituto Gannina Gaslini, 16147 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Mastracci","sequence":"additional","affiliation":[{"name":"Department of Surgical and Diagnostic Sciences (DISC), Anatomic Pathology Unit, University of Genova, 16132 Genova, Italy"},{"name":"IRCCS AOU San Martino-IST, National Cancer Research Institute, 16132 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Grillo","sequence":"additional","affiliation":[{"name":"Department of Surgical and Diagnostic Sciences (DISC), Anatomic Pathology Unit, University of Genova, 16132 Genova, Italy"},{"name":"IRCCS AOU San Martino-IST, National Cancer Research Institute, 16132 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniele","family":"Murgia","sequence":"additional","affiliation":[{"name":"Department of Pediatric Pathology, Istituto Gannina Gaslini, 16147 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Carla","family":"Bosco","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology, Istituto Gannina Gaslini, 16147 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janice Y.","family":"Chou","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ottavia","family":"Barbieri","sequence":"additional","affiliation":[{"name":"IRCCS AOU San Martino-IST, National Cancer Research Institute, 16132 Genova, Italy"},{"name":"Department of Experimental Medicine (DIMES), University of Genova, 16132 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luigi","family":"Varesio","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology, Istituto Gannina Gaslini, 16147 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Eva","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology, Istituto Gannina Gaslini, 16147 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","reference":[{"key":"2021042501184207100_b1-0071083","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1056\/NEJM198401193100306","article-title":"Cornstarch therapy in type I glycogen-storage disease","volume":"310","author":"Chen","year":"1984","journal-title":"N. Engl. J. Med."},{"key":"2021042501184207100_b2-0071083","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/nrendo.2010.189","article-title":"Glycogen storage disease type I and G6Pase-\u03b2 deficiency: etiology and therapy","volume":"6","author":"Chou","year":"2010","journal-title":"Nat. Rev. Endocrinol."},{"key":"2021042501184207100_b3-0071083","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1007\/s10545-005-7500-2","article-title":"Hepatocellular carcinoma in glycogen storage disease type Ia: a case series","volume":"28","author":"Franco","year":"2005","journal-title":"J. Inherit. Metab. Dis."},{"key":"2021042501184207100_b4-0071083","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1038\/sj.gt.3302650","article-title":"Long-term correction of murine glycogen storage disease type Ia by recombinant adeno-associated virus-1-mediated gene transfer","volume":"13","author":"Ghosh","year":"2006","journal-title":"Gene Ther."},{"key":"2021042501184207100_b5-0071083","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1056\/NEJM197602192940805","article-title":"Continuous nocturnal intragastric feeding for management of type 1 glycogen-storage disease","volume":"294","author":"Greene","year":"1976","journal-title":"N. Engl. J. Med."},{"key":"2021042501184207100_b6-0071083","doi-asserted-by":"crossref","first-page":"5532","DOI":"10.1074\/jbc.274.9.5532","article-title":"Inactivation of the glucose 6-phosphate transporter causes glycogen storage disease type 1b","volume":"274","author":"Hiraiwa","year":"1999","journal-title":"J. Biol. Chem."},{"key":"2021042501184207100_b7-0071083","doi-asserted-by":"crossref","first-page":"3833","DOI":"10.1016\/j.febslet.2007.07.013","article-title":"Neutrophilia and elevated serum cytokines are implicated in glycogen storage disease type Ia","volume":"581","author":"Kim","year":"2007","journal-title":"FEBS Lett."},{"key":"2021042501184207100_b8-0071083","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1016\/j.jhep.2007.11.014","article-title":"Necrotic foci, elevated chemokines and infiltrating neutrophils in the liver of glycogen storage disease type Ia","volume":"48","author":"Kim","year":"2008","journal-title":"J. Hepatol."},{"key":"2021042501184207100_b9-0071083","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1016\/0016-5085(91)90483-2","article-title":"Growth in adulthood after liver transplantation for glycogen storage disease type I","volume":"101","author":"Kirschner","year":"1991","journal-title":"Gastroenterology"},{"key":"2021042501184207100_b10-0071083","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1354\/vp.38-1-83","article-title":"Canine model and genomic structural organization of glycogen storage disease type Ia (GSD Ia)","volume":"38","author":"Kishnani","year":"2001","journal-title":"Vet. Pathol."},{"key":"2021042501184207100_b11-0071083","doi-asserted-by":"crossref","first-page":"1281","DOI":"10.1038\/sj.gt.3302774","article-title":"Early, sustained efficacy of adeno-associated virus vector-mediated gene therapy in glycogen storage disease type Ia","volume":"13","author":"Koeberl","year":"2006","journal-title":"Gene Ther."},{"issue":"Suppl. 1","key":"2021042501184207100_b12-0071083","doi-asserted-by":"crossref","first-page":"S53","DOI":"10.1007\/s00431-002-1004-y","article-title":"Glycogen storage disease type I: indications for liver and\/or kidney transplantation","volume":"161","author":"Labrune","year":"2002","journal-title":"Eur. J. Pediatr."},{"issue":"Suppl. 1","key":"2021042501184207100_b13-0071083","doi-asserted-by":"crossref","first-page":"S46","DOI":"10.1007\/s00431-002-1002-0","article-title":"Glycogen storage disease type I: pathophysiology of liver adenomas","volume":"161","author":"Lee","year":"2002","journal-title":"Eur. J. Pediatr."},{"key":"2021042501184207100_b14-0071083","doi-asserted-by":"crossref","first-page":"1719","DOI":"10.1002\/hep.25717","article-title":"Prevention of hepatocellular adenoma and correction of metabolic abnormalities in murine glycogen storage disease type Ia by gene therapy","volume":"56","author":"Lee","year":"2012","journal-title":"Hepatology"},{"key":"2021042501184207100_b15-0071083","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1038\/ng0696-203","article-title":"Glucose-6-phosphatase dependent substrate transport in the glycogen storage disease type-1a mouse","volume":"13","author":"Lei","year":"1996","journal-title":"Nat. Genet."},{"issue":"Suppl. 2","key":"2021042501184207100_b16-0071083","doi-asserted-by":"crossref","first-page":"S43","DOI":"10.1007\/PL00014320","article-title":"Liver transplantation for glycogen storage disease types I, III, and IV","volume":"158","author":"Matern","year":"1999","journal-title":"Eur. J. Pediatr."},{"key":"2021042501184207100_b17-0071083","first-page":"47","article-title":"Glycogen storage disease type I\u2014between chronic ambulatory follow-up and pediatric emergency","volume":"16","author":"Moraru","year":"2007","journal-title":"J. Gastrointestin. Liver Dis."},{"key":"2021042501184207100_b18-0071083","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1016\/j.jhep.2010.08.014","article-title":"Targeted deletion of liver glucose-6 phosphatase mimics glycogen storage disease type 1a including development of multiple adenomas","volume":"54","author":"Mutel","year":"2011","journal-title":"J. Hepatol."},{"key":"2021042501184207100_b19-0071083","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1002\/dvg.20538","article-title":"Generation of mice with a conditional allele for G6pc","volume":"47","author":"Peng","year":"2009","journal-title":"Genesis"},{"key":"2021042501184207100_b20-0071083","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1097\/00000478-198806000-00008","article-title":"Adenomas in glycogen storage disease type 1. Two cases with unusual histologic features","volume":"12","author":"Poe","year":"1988","journal-title":"Am. J. Surg. Pathol."},{"key":"2021042501184207100_b21-0071083","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1074\/jbc.274.1.305","article-title":"Dual roles for glucokinase in glucose homeostasis as determined by liver and pancreatic beta cell-specific gene knock-outs using Cre recombinase","volume":"274","author":"Postic","year":"1999","journal-title":"J. Biol. Chem."},{"issue":"Suppl. 1","key":"2021042501184207100_b22-0071083","doi-asserted-by":"crossref","first-page":"S20","DOI":"10.1007\/s00431-002-0999-4","article-title":"Glycogen storage disease type I: diagnosis, management, clinical course and outcome. Results of the European Study on Glycogen Storage Disease Type I (ESGSD I)","volume":"161","author":"Rake","year":"2002","journal-title":"Eur. J. Pediatr."},{"key":"2021042501184207100_b23-0071083","doi-asserted-by":"crossref","first-page":"1263","DOI":"10.1016\/j.jhep.2011.02.033","article-title":"Treatment of newborn G6pc(\u2212\/\u2212) mice with bone marrow-derived myelomonocytes induces liver repair","volume":"55","author":"Resaz","year":"2011","journal-title":"J. Hepatol."},{"key":"2021042501184207100_b24-0071083","doi-asserted-by":"crossref","first-page":"2155","DOI":"10.1093\/hmg\/11.18.2155","article-title":"Sustained hepatic and renal glucose-6-phosphatase expression corrects glycogen storage disease type Ia in mice","volume":"11","author":"Sun","year":"2002","journal-title":"Hum. Mol. Genet."},{"key":"2021042501184207100_b25-0071083","doi-asserted-by":"crossref","first-page":"2008","DOI":"10.1093\/clinchem\/33.11.2008","article-title":"Glycogen storage disease type I: laboratory data and diagnosis","volume":"33","author":"Wakid","year":"1987","journal-title":"Clin. Chem."},{"key":"2021042501184207100_b26-0071083","first-page":"323","article-title":"Change in lipid components in the adipose and liver tissues of regucalcin transgenic rats with increasing age: suppression of leptin and adiponectin gene expression","volume":"20","author":"Yamaguchi","year":"2007","journal-title":"Int. J. Mol. Med."},{"key":"2021042501184207100_b27-0071083","doi-asserted-by":"crossref","first-page":"1076","DOI":"10.1038\/mt.2010.64","article-title":"Complete normalization of hepatic G6PC deficiency in murine glycogen storage disease type Ia using gene therapy","volume":"18","author":"Yiu","year":"2010","journal-title":"Mol. Ther."},{"key":"2021042501184207100_b28-0071083","doi-asserted-by":"crossref","first-page":"828","DOI":"10.1074\/jbc.275.2.828","article-title":"Correction of glycogen storage disease type 1a in a mouse model by gene therapy","volume":"275","author":"Zingone","year":"2000","journal-title":"J. Biol. Chem."}],"container-title":["Disease Models &amp; Mechanisms"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/journals.biologists.com\/dmm\/article-pdf\/7\/9\/1083\/1867856\/1083.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dmm\/article-pdf\/7\/9\/1083\/1867856\/1083.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,4,25]],"date-time":"2021-04-25T01:21:09Z","timestamp":1619313669000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.biologists.com\/dmm\/article\/7\/9\/1083\/3655\/Development-of-hepatocellular-adenomas-and"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,9,1]]},"references-count":28,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2014,9,1]]}},"URL":"https:\/\/doi.org\/10.1242\/dmm.014878","relation":{},"ISSN":["1754-8411","1754-8403"],"issn-type":[{"value":"1754-8411","type":"electronic"},{"value":"1754-8403","type":"print"}],"subject":[],"published":{"date-parts":[[2014,9,1]]}}}