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Molecular Pathogenesis of Liver Injury in Hereditary Tyrosinemia 1

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Hereditary Tyrosinemia

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 959))

Abstract

Untreated HT1 rapidly degenerates into very severe liver complications often resulting in liver cancer. The molecular basis of the pathogenic process in HT1 is still unclear. The murine model of FAH-deficiency is a suitable animal model, which represents all phenotypic and biochemical manifestations of the human disease on an accelerated time scale. After removal of the drug 2-(2-N-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC), numerous signaling pathways involved in cell proliferation, differentiation and cancer are rapidly deregulated in FAH deficient mice. Among these, the Endoplasmic reticulum (ER) pathway, the heat stress response (HSR), the Nrf2, MEK and ERK pathways, are highly represented. The p21 and mTOR pathways critical regulators of proliferation and tumorigenesis have also been found to be dysregulated. The changes in these pathways are described and related to the development of liver cancer.

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Abbreviations

AFP:

Alpha feto protein

AKT:

Protein kinase B

CHOP:

C/EBP homologous protein

ER stress:

Endoplasmic reticulum stress

ERAD:

ER-stress associated degradation

ERK:

Extracellular signal-regulated kinase

FAA:

Fumarylacetoacetate

FAH:

Fumarylacetoacetate hydrolase

GSH:

Glutathione

HT1:

Hereditary tyrosinemia type 1

MAA:

Maleylacetoacetate

MCL-1:

Myeloid cell leukemia 1

SAC:

Succinylacetone

URP:

Unfolded protein response

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Acknowledgements

Work in RMT’s lab was supported by the Canadian Institute of Health Research (CIHR) and La Fondation Pierre Lavoie (GO). FA received post-doctoral fellowships from PROTEO.

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Authors and Affiliations

  1. Laboratoire de génétique cellulaire et développementale, Département de biologie moléculaire, biochimie médicale et pathologie, Faculté de médecine, Institut de biologie intégrative et des systèmes (IBIS) and PROTEO, Université Laval, 1030 avenue de la médecine, Québec, QC, G1V 0A6, Canada

    Robert M. Tanguay & Francesca Angileri

  2. Department of Gastroenterology, Medizinische Hochschule Hannover, Carl-Neuberg Str.1, 30625, Hannover, Germany

    Arndt Vogel

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  1. Robert M. Tanguay
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  2. Francesca Angileri
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  3. Arndt Vogel
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Correspondence to Robert M. Tanguay .

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Editors and Affiliations

  1. Department of Molecular Biology, Medical Biochemistry and Pathology, Medical School, Université Laval, Québec, Québec, Canada

    Robert M. Tanguay

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Tanguay, R.M., Angileri, F., Vogel, A. (2017). Molecular Pathogenesis of Liver Injury in Hereditary Tyrosinemia 1. In: Tanguay, R. (eds) Hereditary Tyrosinemia. Advances in Experimental Medicine and Biology, vol 959. Springer, Cham. https://doi.org/10.1007/978-3-319-55780-9_4

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