Targeted deletion of liver glucose-6 phosphatase mimics glycogen storage disease type 1a including development of multiple adenomas

J Hepatol. 2011 Mar;54(3):529-37. doi: 10.1016/j.jhep.2010.08.014. Epub 2010 Oct 1.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoma, Liver Cell / enzymology
  • Adenoma, Liver Cell / etiology*
  • Adenoma, Liver Cell / pathology
  • Animals
  • Base Sequence
  • DNA Primers
  • Disease Models, Animal
  • Fatty Liver / enzymology
  • Fatty Liver / etiology
  • Fatty Liver / pathology
  • Female
  • Gene Knockout Techniques
  • Gene Targeting
  • Glucose-6-Phosphatase / antagonists & inhibitors*
  • Glucose-6-Phosphatase / genetics*
  • Glycogen Storage Disease Type I / enzymology
  • Glycogen Storage Disease Type I / etiology
  • Glycogen Storage Disease Type I / genetics
  • Hepatomegaly / enzymology
  • Hepatomegaly / etiology
  • Hepatomegaly / pathology
  • Humans
  • Liver / enzymology*
  • Liver Neoplasms, Experimental / enzymology
  • Liver Neoplasms, Experimental / etiology*
  • Liver Neoplasms, Experimental / pathology
  • Male
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Non-alcoholic Fatty Liver Disease


  • DNA Primers
  • Glucose-6-Phosphatase

Supplementary concepts

  • Hepatorenal form of glycogen storage disease