Project description:Fumarylacetoacetate hydrolase (Fah), the last enzyme of the tyrosine degradation pathway, is specifically expressed in hepatocytes in the liver. Loss of Fah leads to liver failure in mice within 6-8 weeks. This can be prevented by blocking tyrosine degradation upstream of Fah with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC). Here, we investigate the impact of p21 on global gene expression in Fah deficiency. Experiment Overall Design: Livers from adult wildtype, Fah or Fah, p21 knockout mice were analyzed either after continuous treatment (ON) with NTBC or after NTBC withdrawal for 14 days (OFF).
Project description:Fumarylacetoacetate hydrolase (Fah), the last enzyme of the tyrosine degradation pathway, is specifically expressed in hepatocytes in the liver. Loss of Fah leads to liver failure in mice within 6-8 weeks. This can be prevented by blocking tyrosine degradation upstream of Fah with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC). Here, we investigate the impact of p21 on global gene expression in Fah deficiency. Keywords: treatment, genotype
Project description:Reprogramming metabolism plays an important role in tumor cells for maintaining their abnormal biologic behaviors. Therefore, special factors could regulate metabolic processes and influence the overall status of tumor cells. This phenomenon was obviously found in melanoma. Fumarylacetoacetate hydrolase (fumarylacetoacetase, FAH) is an enzyme encoded by the FAH gene located on the chromosome 15q25.1 region and contains 14 exons. FAH enzyme catalyzes the hydrolysis of 4- fumarylacetoacetase into fumarate and acetoacetate. It is the last enzyme in the subpathway from L-phenylalanine and tyrosine degradation. Mutations in the FAH gene cause type I tyrosinemia, which is a hereditary error of metabolism that is characterized by increased tyrosine levels in the blood and urine of patients. In the present study, we will explore whether FAH is an essential enzyme to promote multiple metabolic processes and elucidate the functions of FAH in melanoma. Gene microarrays and bioinformatics analysis of the differentially expressed genes (DEGs) were performed using A375 cells, and we concentrated on the biologic functions of FAH. In general, our work revealed several functional mechanisms of FAH in melanoma, which indicated FAH might be a potentially therapeutic target and an independent prognostic indicator for this disease.
Project description: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 to identify changes in molecular pathways associated to the development and progression of the liver pathogenesis of HT1 that remain uncorrected under NTBC therapy by using gene expression profiling of Fah-deficient mouse livers subjected to continuous NTBC therapy and after seven days of NTBC therapy discontinuation. As a control of a TIMD without hepatic manifestation, we used the Hgd-deficient mouse model of AKU, also under continuous NTBC treatment and after seven days of NTBC therapy discontinuation. Consequently, we identified a set of 25 genes that discriminates HT1 livers from AKU livers, even under continuous NTBC therapy, as such representing remnants of an HT1-driven residual uncorrected liver disease phenotype.
Project description: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.
Project description: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.
