title: Hepatic stress in hereditary tyrosinemia type 1 (HT1) activates the AKT survival pathway in the fah-/- knockout mice model.
abstract: OBJECTIVE
  The AKT survival pathway is involved in a wide variety of human cancers. We investigated the implication of this pathway in hereditary tyrosinemia type 1 (HT1), a metabolic disease exhibiting hepatocellular carcinoma (HCC), despite treatment with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexadione (NTBC) which prevents liver damage. HT1 is an autosomal recessive disorder caused by accumulation of toxic metabolites due to a deficiency in fumarylacetoacetate hydrolase (FAH), the last enzyme in the catabolism of tyrosine.
  
  
  METHODS
  NTBC withdrawal in the murine fah(-/-) knockout model was used to analyze in vivo the correlation between pathophysiological, biochemical and histological features consistent with hepatocarcinogenesis and activation of the AKT survival pathway.
  
  
  RESULTS
  The HT1 stress initiated by NTBC discontinuation causes a progressive increase of liver and kidney pathophysiology. A stable activation of the AKT survival pathway is observed in the liver but not in kidneys of fah(-/-) mice. Hepatic survival is reinforced by inhibition of mitochondrial-mediated apoptosis through inactivation of Bad and induction of BCl-X(L) and BCl-2.
  
  
  CONCLUSIONS
  The chronic stress induced by liver disease in HT1 activates the AKT survival signal and inhibits intrinsic apoptosis to confer cell death resistance in vivo and favor hepatocarcinogenesis.
authors: Laboratory of Cell and Developmental Genetics, Department of Medicine and CREFSIP, Pav. Marchand, Université Laval, Québec, Canada G1K 7P4.
authors: Diana
authors: D
authors: Orejuela
authors: Rossana
authors: R
authors: Jorquera
authors: Anne
authors: A
authors: Bergeron
authors: Milton J
authors: MJ
authors: Finegold
authors: Robert M
authors: RM
authors: Tanguay
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000209:etiology*; D003512:Cyclohexanones / Q000494:pharmacology; D004195:Disease Models, Animal; D006867:Hydrolases / Q000172:deficiency*; D008113:Liver Neoplasms / Q000209:etiology*; D051379:Mice; D018345:Mice, Knockout; D009579:Nitrobenzoates / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology; D015398:Signal Transduction; D020176:Tyrosinemias / Q000150:complications / Q000378:metabolism*; D051020:bcl-X Protein / Q000502:physiology
chemical_list: C494812:Bcl2l1 protein, mouse; D003512:Cyclohexanones; D009579:Nitrobenzoates; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D051057:Proto-Oncogene Proteins c-akt; D006867:Hydrolases; C020156:fumarylacetoacetase; C077073:nitisinone