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Background and aims

Glycogen storage disease type 1a (GSD1a) is an inherited disease caused by a deficiency in the catalytic subunit of the glucose-6 phosphatase enzyme (G6Pase). GSD1a is characterized by hypoglycaemia, hyperlipidemia, and lactic acidosis with associated hepatic (including hepatocellular adenomas), renal, and intestinal disorders. A total G6pc (catalytic subunit of G6Pase) knock-out mouse model has been generated that mimics the human pathology. However, these mice rarely live longer than 3 months and long-term liver pathogenesis cannot be evaluated. Herein, we report the long-term characterization of a liver-specific G6pc knock-out mouse model (L-G6pc(-/-)).

Methods

We generated L-G6pc(-/-) mice using an inducible CRE-lox strategy and followed up the development of hepatic tumours using magnetic resonance imaging.

Results

L-G6pc(-/-) mice are viable and exhibit normoglycemia in the fed state. They develop hyperlipidemia, lactic acidosis, and uricemia during the first month after gene deletion. However, these plasmatic parameters improved after 6 months. L-G6pc(-/-) mice develop hepatomegaly with glycogen accumulation and hepatic steatosis. Using an MRI approach, we could detect hepatic nodules with diameters of less than 1 mm, 9 months after induction of deficiency. Hepatic nodules (1 mm) were detected in 30-40% of L-G6pc(-/-) mice at 12 months. After 18 months, all L-G6pc(-/-) mice developed multiple hepatocellular adenomas of 1-10 mm diameter.

Conclusions

This is the first report of a viable animal model of the hepatic pathology of GSD1a, including the late development of hepatocellular adenomas."xsd:string
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http://purl.uniprot.org/citations/21109326http://purl.uniprot.org/core/author"Rajas F."xsd:string
http://purl.uniprot.org/citations/21109326http://purl.uniprot.org/core/author"Mithieux G."xsd:string
http://purl.uniprot.org/citations/21109326http://purl.uniprot.org/core/author"Penhoat A."xsd:string
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http://purl.uniprot.org/citations/21109326http://purl.uniprot.org/core/author"Beuf O."xsd:string
http://purl.uniprot.org/citations/21109326http://purl.uniprot.org/core/author"Pilleul F."xsd:string
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http://purl.uniprot.org/citations/21109326http://purl.uniprot.org/core/author"Cavassila S."xsd:string
http://purl.uniprot.org/citations/21109326http://purl.uniprot.org/core/author"Houberdon I."xsd:string
http://purl.uniprot.org/citations/21109326http://purl.uniprot.org/core/author"Mutel E."xsd:string
http://purl.uniprot.org/citations/21109326http://purl.uniprot.org/core/author"Ramamonjisoa N."xsd:string
http://purl.uniprot.org/citations/21109326http://purl.uniprot.org/core/date"2011"xsd:gYear
http://purl.uniprot.org/citations/21109326http://purl.uniprot.org/core/name"J Hepatol"xsd:string
http://purl.uniprot.org/citations/21109326http://purl.uniprot.org/core/pages"529-537"xsd:string
http://purl.uniprot.org/citations/21109326http://purl.uniprot.org/core/title"Targeted deletion of liver glucose-6 phosphatase mimics glycogen storage disease type 1a including development of multiple adenomas."xsd:string
http://purl.uniprot.org/citations/21109326http://purl.uniprot.org/core/volume"54"xsd:string
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