Targeted deletion of liver glucose-6 phosphatase mimics glycogen storage disease type 1a including development of multiple adenomas.
OBJECTIVE
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.
Institut National de la Santé et de la Recherche Médicale, U855, Lyon F-69008, France.
Elodie
E
Mutel
Aya
A
Abdul-Wahed
Nirilanto
N
Ramamonjisoa
Anne
A
Stefanutti
Isabelle
I
Houberdon
Sophie
S
Cavassila
Frank
F
Pilleul
Olivier
O
Beuf
Amandine
A
Gautier-Stein
Armelle
A
Penhoat
Gilles
G
Mithieux
Fabienne
F
Rajas
D018248:Adenoma, Liver Cell / Q000201:enzymology / Q000209:etiology* / Q000473:pathology; D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000201:enzymology / Q000209:etiology / Q000473:pathology; D005260:Female; D055786:Gene Knockout Techniques; D018390:Gene Targeting; D005952:Glucose-6-Phosphatase / Q000037:antagonists & inhibitors* / Q000235:genetics*; D005953:Glycogen Storage Disease Type I / Q000201:enzymology / Q000209:etiology / Q000235:genetics; D006529:Hepatomegaly / Q000201:enzymology / Q000209:etiology / Q000473:pathology; D006801:Humans; D008099:Liver / Q000201:enzymology*; D008114:Liver Neoplasms, Experimental / Q000201:enzymology / Q000209:etiology* / Q000473:pathology; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D065626:Non-alcoholic Fatty Liver Disease
D017931:DNA Primers; D005952:Glucose-6-Phosphatase