Pharmacological correction of neonatal lethal hepatic dysfunction in a murine model of hereditary tyrosinaemia type I

Abstract

Hereditary tyrosinaemia type I, a severe autosomal recessive metabolic disease, affects the liver and kidneys and is caused by deficiency of fumarylacetoacetate hydrolase (FAH). Mice homozygous for a FAH gene disruption have a neonatal lethal phenotype caused by liver dysfunction and do not represent an adequate model of the human disease. Here we demonstrate that treatment of affected animals with 2-(2-nitro-4-trifluoro-methylbenzyol)-1,3-cyclohexanedione abolished neonatal lethality, corrected liver function and partially normalized the altered expression pattern of hepatic mRNAs. The prolonged lifespan of affected animals resulted in a phenotype analogous to human tyrosinaemia type I including hepatocellular carcinoma. The adult FAH-/- mouse will serve as useful model for studies of the pathophysiology and treatment of hereditary tyrosinaemia type I as well as hepatic cancer.

Chronic liver disease in murine hereditary tyrosinemia type 1 induces resistance to cell death

“…into 10 Fah-deficient mice kept healthy by NTBC, which blocks HPD pharmacologically. 8 As expected, all mice became ill and died within approximately 70 hours ( Fig. 2A).…”

“…NTBC blocks the activity of 4-hydroxyphenylpyruvate dioxygenase (HPD), an enzyme acting upstream of FAH in the tyrosine catabolic pathway, and therefore reduces the accumulation of FAA. 8 However, recent preclinical animal data indicate that NTBC provides only incomplete protection from liver disease, in particular HCC. 9 Despite the known mutagenicity of FAA, 4,5 the details of cancer evolution in HT1 have remained unclear.…”

Robust expansion of human hepatocytes in Fah−/−/Rag2−/−/Il2rg−/− mice

“…First, the extent of liver disease and selective pressure can be controlled by administering and withdrawing NTBC 12 . This simplifies animal husbandry and surgery.…”

“…Therefore the Fah mutation was crossed into this background, resulting in Fah/Rag2/Il2rg (FRG) triple mutants. FRG mice grew well and were fully fertile if they were continuously given NTBC in their drinking water 12 . As in conventional Fah −/− mice, NTBC withdrawal in FRG mice resulted in gradual hepatocellular injury and eventual death after 4-8 weeks 11 .…”

“…Fah mutant mice develop liver disease only when the protective drug 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) is withdrawn; they have proven to be a reliable model of liver repopulation with transplanted cells [10][11][12] . Here we report that mice triply mutant for Fah, Rag2 and the common γ-chain of the interleukin receptor can be efficiently repopulated with human hepatocytes.…”