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. FRG mice (C57Bl/6J background) are characterized by a triple knockout of Fah−/−, Rag2−/− and Il2rg−/− and served as experimental model for HT1. FRG mice (in triplicate) were either continuously treated with 16 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.