Chronic Liver Disease in Murine Hereditary Tyrosinemia Type 1 Induces Resistance to Cell Death

Arndt Vogel, Inge E.T. Van Den Berg, Muhsen Al-Dhalimy, John Groopman, Ching Nan Ou, Olga Ryabinina, Mihail S. Iordanov, Milton Finegold, Markus Grompe

Research output: Contribution to journalArticle

46 Scopus citations

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 ifthey 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.

Original languageEnglish (US)
Pages (from-to)433-443
Number of pages11
JournalHepatology
Volume39
Issue number2
DOIs
StatePublished - Feb 1 2004

ASJC Scopus subject areas

  • Hepatology

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    Vogel, A., Van Den Berg, I. E. T., Al-Dhalimy, M., Groopman, J., Ou, C. N., Ryabinina, O., Iordanov, M. S., Finegold, M., & Grompe, M. (2004). Chronic Liver Disease in Murine Hereditary Tyrosinemia Type 1 Induces Resistance to Cell Death. Hepatology, 39(2), 433-443. https://doi.org/10.1002/hep.20077