Fumarylacetoacetate hydrolase deficient pigs are a novel large animal model of metabolic liver disease

Raymond D. Hickey, Shennen A. Mao, Jaime Glorioso, Joseph B. Lillegard, James E. Fisher, Bruce Amiot, Piero Rinaldo, Cary Harding, Ronald Marler, Milton J. Finegold, Markus Grompe, Scott L. Nyberg

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Hereditary tyrosinemia type I (HT1) is caused by deficiency in fumarylacetoacetate hydrolase (FAH), an enzyme that catalyzes the last step of tyrosine metabolism. The most severe form of the disease presents acutely during infancy, and is characterized by severe liver involvement, most commonly resulting in death if untreated. Generation of FAH+/- pigs was previously accomplished by adeno-associated virus-mediated gene knockout in fibroblasts and somatic cell nuclear transfer. Subsequently, these animals were outbred and crossed to produce the first FAH-/- pigs.FAH-deficiency produced a lethal defect in utero that was corrected by administration of 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3 cyclohexanedione (NTBC) throughout pregnancy. Animals on NTBC were phenotypically normal at birth; however, the animals were euthanized approximately four weeks after withdrawal of NTBC due to clinical decline and physical examination findings of severe liver injury and encephalopathy consistent with acute liver failure. Biochemical and histological analyses, characterized by diffuse and severe hepatocellular damage, confirmed the diagnosis of severe liver injury. FAH-/- pigs provide the first genetically engineered large animal model of a metabolic liver disorder. Future applications of FAH-/- pigs include discovery research as a large animal model of HT1 and spontaneous acute liver failure, and preclinical testing of the efficacy of liver cell therapies, including transplantation of hepatocytes, liver stem cells, and pluripotent stem cell-derived hepatocytes.

Original languageEnglish (US)
Pages (from-to)144-153
Number of pages10
JournalStem Cell Research
Volume13
Issue number1
DOIs
StatePublished - 2014

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Metabolic Diseases
Liver Diseases
Swine
Animal Models
Liver
Acute Liver Failure
Hepatocytes
Tyrosinemias
Dependovirus
Pluripotent Stem Cells
Gene Knockout Techniques
Genetically Modified Animals
Wounds and Injuries
Brain Diseases
Cell- and Tissue-Based Therapy
Liver Transplantation
Physical Examination
Tyrosine
fumarylacetoacetase
Stem Cells

ASJC Scopus subject areas

  • Cell Biology
  • Developmental Biology
  • Medicine(all)

Cite this

Hickey, R. D., Mao, S. A., Glorioso, J., Lillegard, J. B., Fisher, J. E., Amiot, B., ... Nyberg, S. L. (2014). Fumarylacetoacetate hydrolase deficient pigs are a novel large animal model of metabolic liver disease. Stem Cell Research, 13(1), 144-153. https://doi.org/10.1016/j.scr.2014.05.003

Fumarylacetoacetate hydrolase deficient pigs are a novel large animal model of metabolic liver disease. / Hickey, Raymond D.; Mao, Shennen A.; Glorioso, Jaime; Lillegard, Joseph B.; Fisher, James E.; Amiot, Bruce; Rinaldo, Piero; Harding, Cary; Marler, Ronald; Finegold, Milton J.; Grompe, Markus; Nyberg, Scott L.

In: Stem Cell Research, Vol. 13, No. 1, 2014, p. 144-153.

Research output: Contribution to journalArticle

Hickey, RD, Mao, SA, Glorioso, J, Lillegard, JB, Fisher, JE, Amiot, B, Rinaldo, P, Harding, C, Marler, R, Finegold, MJ, Grompe, M & Nyberg, SL 2014, 'Fumarylacetoacetate hydrolase deficient pigs are a novel large animal model of metabolic liver disease', Stem Cell Research, vol. 13, no. 1, pp. 144-153. https://doi.org/10.1016/j.scr.2014.05.003
Hickey, Raymond D. ; Mao, Shennen A. ; Glorioso, Jaime ; Lillegard, Joseph B. ; Fisher, James E. ; Amiot, Bruce ; Rinaldo, Piero ; Harding, Cary ; Marler, Ronald ; Finegold, Milton J. ; Grompe, Markus ; Nyberg, Scott L. / Fumarylacetoacetate hydrolase deficient pigs are a novel large animal model of metabolic liver disease. In: Stem Cell Research. 2014 ; Vol. 13, No. 1. pp. 144-153.
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