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Gilles Mithieux-Fabienne Rajas Inserm u.855/Université Lyon 1

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 2 nd , 2010, Milan. Dysregulation of glucose homeostasis. Mirror metabolic diseases. GSD1a Prevalence: 1:100 000 Rare disease

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Gilles Mithieux-Fabienne Rajas Inserm u.855/Université Lyon 1

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  1. 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 • GSD1a • Prevalence: 1:100 000 • Rare disease • No endogenous glucose production • LOW glucose blood • Type 2 diabetes • Prevalence: 5-8% • Epidemic • Endogenous glucose production ++++ • HIGH glucose blood

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

  4. normal liver GSD 1a liver 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

  5. Mouse models of GSD1a 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. Targeted invalidation of G6Pase in liver of mice 80 ** 60 * 40 G6Pase activity (U/g prot) 20 0 -/- +/- +/+ x = B6.SACre ERT2/+ G6pclox/lox B6.SACreERT2/+ B6.G6pclox/lox Liver-specific Cre 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 Body weight (g) 40 30 A B 20 Time after gene deletion (month) 10 50 200 40 0 150 Glucose (mg/dL) 30 100 20 50 18 mth 10 d 10 d 1 mth 1 mth 6 mth 6 mth 18 mth 18 mth 18 mth 18 mth 10 d 10 d 1 mth 1 mth 6 mth 6 mth 10 d 6 mth 1 mth 3 10 ** 0 0 ** 0 3 6 9 12 15 18 4 2 ** ** TG (g/L) ** Cholesterol (g/L) 3 * ** 1 2 0 1 ** * ** 0 6 * 4 Uric acid (mg/L) Lactic acid (mM) 2 0 LG6pc-/- mice Control mice C D E F Improvement of plasmatic parameters with time, except for cholesterol

  8. L.G6pc-/- mice develop hepatomegaly and steatosis ** ** ** L-G6pc-/- Control ** Glycogen content (mg/g of liver) TG content (mg/g of liver) ** ** 4 Liver weight (g) ** ** 3 2 10 d 1 mth 18 mth 80 1 60 0 10 d 1 mth 18 mth 40 20 0 80 60 40 20 0 10 d 1 mth 18 mth LG6pc-/- mice Control mice 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

  11. Ad Ad Development of adenoma in the liver of Lg6pc-/- mice • Histology study Liver adenomas (80%) Liver pre-carcinomas (20%) • 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. 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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