Short-term nitisinone discontinuation of hereditary tyrosinemia type 1 mice causes metabolic alterations in glutathione metabolism/biosynthesis and multiple amino acid degradation pathways  

作　　者：Colemonts-Vroninks Haaike Norman P.Brendan Van Laere Sven Davison S.Andrew Marcélis Lionel Casimir Georges Goyens Philippe Claes Paul De Bundel Dimitri Martens Geert Ranganath Lakshminarayan Rao Vanhaecke Tamara Gallagher James A De Kock Joery 

机构地区：[1]Vrije Universiteit Brussel,Liver Therapy&Evolution Team,In Vitro Toxicology and Dermato-Cosmetology(IVTD)Research Group,Faculty of Medicine and Pharmacy,Laarbeeklaan 103,Brussels B-1090,Belgium [2]Vrije Universiteit Brussel,Experimental Pharmacology(EFAR)Research Group,Faculty of Medicine and Pharmacy,Laarbeeklaan 103,Brussels B-1090,Belgium [3]University of Liverpool,Dept.of Musculoskeletal&Ageing Science,Institute of Life Course&Medical Sciences,Liverpool L78TX,United Kingdom [4]Vrije Universiteit Brussel,Interfaculty Center Data Processing and Statistics,Faculty of Medicine and Pharmacy,Laarbeeklaan 103,Brussels B-1090,Belgium [5]Liverpool University Hospitals NHS Foundation Trust,Clinical Biochemistry and Metabolic Medicine,Liverpool L35PS,United Kingdom [6]UniversitéLibre de Bruxelles,Laboratoire de Pédiatrie,Brussels B-1050,Belgium [7]Vrije Universiteit Brussel,In Vitro Liver Disease Modelling Team,In Vitro Toxicology and Dermato-Cosmetology(IVTD)Research Group,Faculty of Medicine and Pharmacy,Laarbeeklaan 103,Brussels B-1090,Belgium [8]AZ Delta General Hospital,Department of Laboratory Medicine,Roeselare 8800,Belgium [9]Ghent University,Department of Biomolecular Medicine,Ghent 9052,Belgium

出　　处：《Genes & Diseases》2023年第5期1759-1762,共4页基因与疾病（英文）

基　　金：funded by the Research Foundation-Flanders(FWO)(No.1518619N and G041521N);the Research Council(OZR)of the Vrije Universiteit Brussel(VUB),the Hercules Foundation,Wetenschappelijk Fonds Willy Gepts(WFWG)from the UZ Brussel and a Medical Grant from Swedish Orphan Biovitrum(SOBI)(No.AIIFUND37).

摘　　要：Hereditary tyrosinemia type 1(HT1)is a life-threatening disease caused by the patient's inability to break down tyrosine due to loss-of-function mutations in the fumarylacetoacetate hydrolase(FAH)enzyme(Fig.S1).Currently,the only available life-saving treatment is nitisinone(NTBC).However,nitisinone therapy comes with debilitating side effects and requires a strict drug regime combined with a tyrosine-and phenylalanine-restricted diet.Consequently,therapy adherence is often experienced as an additional burden.In this study,transcriptional profiling was conducted parallel to high-resolution metabolomics on,respectively,liver tissue and serum samples of Fah-deficient mice.The experimental workflow of our study is shown in Figure 1A.Canonical pathway analyses showed manifest activation of the NRF2-stress response,associated with hepatocellular damage and mainly driven by a markedly increased oxidative burden.Other altered canonical pathways were primarily a downstream consequence of the latter.Furthermore,we observed an overall aminoacidemia and changes related to aminoacyl-tRNA biosynthesis,which postulates that short-term nitisinone discontinuation can already put the patient at risk for hepatocellular carcinoma development.Finally,we did not only identify changes in numerous pathways,directly and indirectly,related to the metabolism of tyrosine and glutathione but also the presence of“side-chain”metabolites,such as y-glutamyl-and N-acetyl-coupled amino acids,indicating that non-directly related pathways like phase II biotransformation reactions are also affected.

关 键 词：CONTINUATION Figure HEREDITARY 

分 类 号：O62[理学—有机化学]