title: Chronic liver disease in murine hereditary tyrosinemia type 1 induces resistance to cell death.
abstract: The murine model of hereditary tyrosinemia type 1 (HT1) was used to analyze the relationship between chronic liver disease and programmed cell death in vivo. In healthy fumarylacetoacetate hydrolase deficient mice (Fah(-/-)), protected from liver injury by the drug 2-(2- nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC), the tyrosine metabolite homogentisic acid (HGA) caused rapid hepatocyte death. In contrast, all mice survived the same otherwise lethal dose of HGA if they had preexisting liver damage induced by NTBC withdrawal. Similarly, Fah(-/-) animals with liver injury were also resistant to apoptosis induced by the Fas ligand Jo-2 and to necrosis-like cell death induced by acetaminophen (APAP). Molecular studies revealed a marked up-regulation of the antiapoptotic heat shock proteins (Hsp) 27, 32, and 70 and of c-Jun in hepatocytes of stressed mice. In addition, the p38 and Jun N-terminal kinase (JNK) stress-activated kinase pathways were markedly impaired in the cell-death resistant liver. In conclusion, these results provide evidence that chronic liver disease can paradoxically result in cell death resistance in vivo. Stress-induced failure of cell death programs may lead to an accumulation of damaged cells and therefore enhance the risk for cancer as observed in HT1 and other chronic liver diseases.
authors.affiliation: Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR 97239, USA. vogela@ohsu.edu
authors.forename: Arndt
authors.initials: A
authors.lastname: Vogel
authors.forename: Inge E T
authors.initials: IE
authors.lastname: van Den Berg
authors.forename: Muhsen
authors.initials: M
authors.lastname: Al-Dhalimy
authors.forename: John
authors.initials: J
authors.lastname: Groopman
authors.forename: Ching-Nan
authors.initials: CN
authors.lastname: Ou
authors.forename: Olga
authors.initials: O
authors.lastname: Ryabinina
authors.forename: Mihail S
authors.initials: MS
authors.lastname: Iordanov
authors.forename: Milton
authors.initials: M
authors.lastname: Finegold
authors.forename: Markus
authors.initials: M
authors.lastname: Grompe
mesh_terms: D000082:Acetaminophen; D018712:Analgesics, Non-Narcotic; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D002492:Central Nervous System Depressants / Q000494:pharmacology; D002908:Chronic Disease; D003512:Cyclohexanones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000431:Ethanol / Q000494:pharmacology; D053222:Fas Ligand Protein; D005978:Glutathione / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006713:Homogentisic Acid / Q000378:metabolism; D006867:Hydrolases / Q000235:genetics*; D017114:Liver Failure, Acute / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000494:pharmacology; D051379:Mice; D008817:Mice, Mutant Strains; D016328:NF-kappa B / Q000378:metabolism; D009336:Necrosis; D009579:Nitrobenzoates / Q000494:pharmacology; D018384:Oxidative Stress / Q000502:physiology; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D020176:Tyrosinemias / Q000378:metabolism* / Q000473:pathology*; D015854:Up-Regulation; D019014:fas Receptor / Q000378:metabolism
chemical_list: D018712:Analgesics, Non-Narcotic; D002492:Central Nervous System Depressants; D003512:Cyclohexanones; D004791:Enzyme Inhibitors; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D018840:HSP70 Heat-Shock Proteins; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D009579:Nitrobenzoates; D016755:Proto-Oncogene Proteins c-jun; D019014:fas Receptor; D000082:Acetaminophen; D000431:Ethanol; D006867:Hydrolases; C020156:fumarylacetoacetase; D005978:Glutathione; C077073:nitisinone; D006713:Homogentisic Acid