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

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• 作者：Elodie Mutel¹ ; ² ; ³ ; Aya Abdul-Wahed¹ ; ² ; ³ ; Nirilanto Ramamonjisoa² ; ³ ; ⁴ ; Anne Stefanutti¹ ; ² ; ³ ; Isabelle Houberdon¹ ; ² ; ³ ; Sophie Cavassila² ; ³ ; ⁴ ; Frank Pilleul² ; ³ ; ⁴ ; Olivier Beuf² ; ³ ; ⁴ ; Amandine Gautier-Stein¹ ; ² ; ³ ; Armelle Penhoat¹ ; ² ; ³ ; Gilles Mithieux¹ ; ² ; ³ ; Fabienne Rajas¹ ; ² ; ³ ; ^{fabienne.rajas@univ-lyon1.fr}
• 关键词：Glycogen storage disease ; Glucose-6 phosphatase ; Endogenous glucose production ; Hepatic steatosis ; Hepatic adenomas
• 刊名：Journal of Hepatology
• 出版年：2011
• 出版时间：March 2011
• 年：2011
• 卷：54
• 期：3
• 页码：529-537
• 全文大小：2787 K

文摘

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.