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Stem Cell Res. 2014 Jul;13(1):144-53. doi: 10.1016/j.scr.2014.05.003. Epub 2014 May 14.

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

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Division of Transplant Surgery, Department of Surgery, Mayo Clinic, Rochester, MN, USA; Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA.
Division of Transplant Surgery, Department of Surgery, Mayo Clinic, Rochester, MN, USA.
Children's Hospital of Philadelphia, Department of Pediatric General Thoracic and Fetal Surgery, Philadelphia, PA, USA.
Division of Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR, USA.
Department of Comparative Medicine, Mayo Clinic, Scottsdale, AZ, USA.
Department of Pathology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.
Oregon Stem Cell Center, Oregon Health and Science University, Portland, OR, USA.
Division of Transplant Surgery, Department of Surgery, Mayo Clinic, Rochester, MN, USA. Electronic address:


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.

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