Fumarylacetoacetate Hydrolase Knock-out Rabbit Model for Hereditary Tyrosinemia Type 1

Research output: Contribution to journalArticle

Authors

  • Li Li
  • Quanjun Zhang
  • Huaqiang Yang
  • Qingjian Zou
  • Chengdan Lai
  • Fei Jiang
  • Ping Zhao
  • Zhiwei Luo
  • Jiayin Yang
  • Qian Chen
  • Yan Wang
  • Patrick H Maxwell
  • Wenjuan Li
  • Shuhan Chen
  • Dongye Wang
  • Tak-Shing Siu
  • Sidney Tam
  • Hung-Fat Tse
  • Baoming Qin
  • Xichen Bao
  • Miguel A Esteban
  • Liangxue Lai

External organisations

  • From the CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China, and Guangzhou Medical University, Guangzhou 511436, China.
  • Cardiology Division, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong SAR, China.
  • Department of Ophthalmology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China.
  • State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangdong Provincial Research Center for Liver Fibrosis, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital and.
  • Cambridge Institute for Medical Research, Wellcome Trust/Medical Research Council (MRC) Building, Cambridge CB2 0XY, United Kingdom.
  • Department of Clinical Biochemistry Unit, Queen Mary Hospital, Hong Kong SAR, China.
  • From the CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China, and Guangzhou Medical University, Guangzhou 511436, China, miguel@gibh.ac.cn.
  • From the CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China, and Guangzhou Medical University, Guangzhou 511436, China, lai_liangxue@gibh.ac.cn.

Abstract

Hereditary tyrosinemia type 1 (HT1) is a severe human autosomal recessive disorder caused by the deficiency of fumarylacetoacetate hydroxylase (FAH), an enzyme catalyzing the last step in the tyrosine degradation pathway. Lack of FAH causes accumulation of toxic metabolites (fumarylacetoacetate and succinylacetone) in blood and tissues, ultimately resulting in severe liver and kidney damage with onset that ranges from infancy to adolescence. This tissue damage is lethal but can be controlled by administration of 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC), which inhibits tyrosine catabolism upstream of the generation of fumarylacetoacetate and succinylacetone. Notably, in animals lacking FAH, transient withdrawal of NTBC can be used to induce liver damage and a concomitant regenerative response that stimulates the growth of healthy hepatocytes. Among other things, this model has raised tremendous interest for the in vivo expansion of human primary hepatocytes inside these animals and for exploring experimental gene therapy and cell-based therapies. Here, we report the generation of FAH knock-out rabbits via pronuclear stage embryo microinjection of transcription activator-like effector nucleases. FAH(-/-) rabbits exhibit phenotypic features of HT1 including liver and kidney abnormalities but additionally develop frequent ocular manifestations likely caused by local accumulation of tyrosine upon NTBC administration. We also show that allogeneic transplantation of wild-type rabbit primary hepatocytes into FAH(-/-) rabbits enables highly efficient liver repopulation and prevents liver insufficiency and death. Because of significant advantages over rodents and their ease of breeding, maintenance, and manipulation compared with larger animals including pigs, FAH(-/-) rabbits are an attractive alternative for modeling the consequences of HT1.

Details

Original languageEnglish
Pages (from-to)4755-4763
Number of pages9
JournalJournal of Biological Chemistry
Volume292
Issue number11
Early online date4 Jan 2017
Publication statusPublished - 17 Mar 2017

Keywords

  • Journal Article