Gene expression profiling of Fah-deficient mouse livers upon short-term nitisinone discontinuation

Hereditary tyrosinemia type 1 (HT1) is a severe genetic disorder that affects the liver due to a defective fumarylacetoacetate hydrolase (Fah) enzyme in hepatocytes. The drug nitisinone (NTBC) has offered a life-saving treatment for HT1 patients by inhibiting the upstream enzyme 4-hydroxyphenylpyruvate dioxygenase (HPD). We used microarray analyses to define the impact of short-term (ie. seven days) NTBC therapy discontinuation on the gene expression profile of liver tissue of Fah-deficient mice. Consequently, we investigated the modulation of canonical pathways related to oxidative stress, glutathione metabolism and liver regeneration. FAH5981SB mice (C57Bl/6J background) bears a single point mutation (G>A loss) in the final nucleotide of exon 8 within the Fah gene, ultimately leading to formation of truncated, unstable and degraded Fah protein and served thereby as experimental model for HT1. Fah deficient mice were either continuously treated with 8 mg/l NTBC through their drinking water or deprived from NTBC therapy for seven consecutive days. Withdrawal samples were collected seven days after NTBC discontinuation.