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Gilles Mithieux-Fabienne Rajas

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1 Gilles Mithieux-Fabienne Rajas
MRAR Evolution of GSD1a with time in a liver-specific model of the pathology Gilles Mithieux-Fabienne Rajas Inserm u.855/Université Lyon 1 October 2nd, 2010, Milan

2 Dysregulation of glucose homeostasis
Mirror metabolic diseases Type 2 diabetes Prevalence: 5-8% Epidemic Endogenous glucose production ++++ HIGH glucose blood GSD1a Prevalence: 1: Rare disease No endogenous glucose production LOW glucose blood

3 Endogenous glucose production and Glucose-6 Phosphatase
Glycogenolysis Gluconeogenesis G6PT Glucose -6 P Glucose-6 P Glucose + Pi Cytosol Endoplasmic reticulum G6PC GSD1a GSD1b G6Pase complex Liver Kidney Intestine G6PC: catalytic subunit (liver, kidney and intestine) EGP -G6PT : transport subunit (ubiquitous)

4 Phenotype of GSD1a Hypoglycemia Liver disease:
Hepatomegaly with accumulation of glycogen Liver steatosis Liver adenomas (or carcinomas) Kidney disease: Nephromegaly with accumulation of glycogen - Renal failure Intestinal disease (under-estimated): -digestion dysfunction Diarrheas GSD 1a liver normal liver

5 Mouse models of GSD1a Total invalidation of g6pc :
glucose Total invalidation of g6pc : Lethal without injection of glucose every 8 hours (Chou et al, 1999) Tissue-specific invalidation of g6pc : (Mutel et al., J Hepatol, 2010) in the Liver and/or Intestine and/or Kidney + invalidation inducible by tamoxifen -To know if expression of G6Pase at one site is sufficient to compensate the lack of expression at the others -To study the mechanisms of the deficiency organ by organ Liver gene therapy

6 x = Targeted invalidation of G6Pase in liver of mice B6.SACre ERT2/+
G6pclox/lox B6.G6pclox/lox B6.SACreERT2/+ Liver-specific Cre * ** 20 40 60 80 -/- +/- +/+ G6Pase activity (U/g prot) Injection of tamoxifen (1mg/day for 5 days) at 6-8 weeks L.G6pc-/- J.Hepatol. in press

7 Metabolic effects of hepatic G6pc deletion with time
LG6pc-/- mice Control mice A B 50 100 150 200 Glucose (mg/dL) 10 d 1 mth 6 mth 18 mth 10 20 30 40 3 6 9 12 15 18 Body weight (g) Time after gene deletion (month) C 1 2 3 4 TG (g/L) 10 d 1 mth 6 mth 18 mth ** * D E F 1 2 3 Cholesterol (g/L) 10 d 1 mth 6 mth 18 mth ** 10 20 30 40 Uric acid (mg/L) 10 d 1 mth 6 mth 18 mth * 2 4 6 Lactic acid (mM) 10 d 1 mth 6 mth 18 mth ** Improvement of plasmatic parameters with time, except for cholesterol

8 L.G6pc-/- mice develop hepatomegaly and steatosis
1 2 3 4 10 d 1 mth 18 mth Liver weight (g) ** 20 40 60 80 10 d 1 mth 18 mth Glycogen content (mg/g of liver) ** 20 40 60 80 10 d 1 mth 18 mth (mg/g of liver) TG content ** LG6pc-/- mice Control mice Control L-G6pc-/- Liver disease: Accumulation of glycogen in the liver of LG6pc-/- mice: HEPATOMEGALY Triglyceride storage in the liver of LG6pc-/- mice: STEATOSIS Development of hepatic adenomas with time

9 Late appearance of hepatocellular adenoma in L.G6pc-/- mice
Follow up of mouse liver by MRI from 3 months to 18 months In collaboration with O. Beuf & F. Pilleul, Creatis, Lyon MRI 7.0 Tesla Liver of a LG6pc-/- mouse 12 months 18 months Muttel et al, J.Hepatol. in press

10 Late appearance of hepacellular adenoma in L.G6pc-/- mice
Control liver Livers of LG6pc-/- mice Time after G6pc deletion % mice with lesions Size of lesions <6 months 9 months 15 1 mm 12 months 30 1-2 mm 15 months 40-50 1-3 mm 18 months 100 1-10 mm

11 Adenoma without steatosis - small hepatocytes
Development of adenoma in the liver of Lg6pc-/- mice Histology study Liver adenomas (80%) Liver pre-carcinomas (20%) Ad Adenoma with steatosis and large hepatocytes Adenoma without steatosis - small hepatocytes Loss of tissue organization Absence of portal space Necrosis and inflammation Glycogenic nuclei

12 LG6pc-/- mice exhibit all the hepatic symptoms of the human pathology
In conclusion LG6pc-/- mice exhibit all the hepatic symptoms of the human pathology Viable, permitting to study the liver pathology along the mouse life Liver disease characteristic of GSD1a: Hepatomegaly Liver steatosis Liver adenomas…and pre-carcinomas No apparent kidney disease No apparent intestinal disease Excellent model to gene therapy

13 Thanks to Fabienne Rajas Armelle Penhoat Valérie Large Amandine Stein
Elodie Mutel Aya Abdul-Wahed Sylvie Casteras Anne Stefanutti Isabelle Houberdon Gilles Mithieux UMR Inserm u.855/UCBL, Lyon MRI Olivier Beuf Frank Pilleul Niri Ramamonjisoa Sophie Cavassila Hélène Ratiney Créatis, Lyon

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