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Article

Hereditary Tyrosinemia Type 1 Mice under Continuous Nitisinone Treatment Display Remnants of an Uncorrected Liver Disease Phenotype

by
Jessie Neuckermans
1,
Sien Lequeue
1,
Paul Claes
2,
Anja Heymans
2,
Juliette H. Hughes
3,4,
Haaike Colemonts-Vroninks
1,
Lionel Marcélis
5,
Georges Casimir
5,
Philippe Goyens
5,
Geert A. Martens
6,7,
James A. Gallagher
4,
Tamara Vanhaecke
2,
George Bou-Gharios
4 and
Joery De Kock
1,*
1
Liver Therapy & Evolution Team, In Vitro Toxicology and Dermato-Cosmetology (IVTD) Research Group, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, 1090 Brussels, Belgium
2
In Vitro Liver Disease Modelling Team, In Vitro Toxicology and Dermato-Cosmetology (IVTD) Research Group, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, 1090 Brussels, Belgium
3
Faculty Health, Social Care and Medicine, Edge Hill University, St. Helens Road, Omskirk L39 4QP, UK
4
Department of Musculoskeletal & Ageing Science, Institute of Life Course & Medical Sciences, University of Liverpool, Liverpool L7 8TX, UK
5
Laboratoire de Pédiatrie, Hôpital Universitaire des Enfants Reine Fabiola (HUDERF), Université Libre de Bruxelles, Avenue Jean Joseph Crocq 1-3, 1020 Brussels, Belgium
6
Department of Laboratory Medicine, AZ Delta General Hospital, 8800 Roeselare, Belgium
7
Department of Biomolecular Medicine, Ghent University, 9000 Gent, Belgium
*
Author to whom correspondence should be addressed.
Genes 2023, 14(3), 693; https://doi.org/10.3390/genes14030693
Submission received: 15 February 2023 / Revised: 2 March 2023 / Accepted: 8 March 2023 / Published: 11 March 2023
(This article belongs to the Special Issue Identifying the Molecular Basis of Rare Genetic Diseases)
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Abstract

Hereditary tyrosinemia type 1 (HT1) is a genetic disorder of the tyrosine degradation pathway (TIMD) with unmet therapeutic needs. HT1 patients are unable to fully break down the amino acid tyrosine due to a deficient fumarylacetoacetate hydrolase (FAH) enzyme and, therefore, accumulate toxic tyrosine intermediates. If left untreated, they experience hepatic failure with comorbidities involving the renal and neurological system and the development of hepatocellular carcinoma (HCC). Nitisinone (NTBC), a potent inhibitor of the 4-hydroxyphenylpyruvate dioxygenase (HPD) enzyme, rescues HT1 patients from severe illness and death. However, despite its demonstrated benefits, HT1 patients under continuous NTBC therapy are at risk to develop HCC and adverse reactions in the eye, blood and lymphatic system, the mechanism of which is poorly understood. Moreover, NTBC does not restore the enzymatic defects inflicted by the disease nor does it cure HT1. Here, the changes in molecular pathways associated to the development and progression of HT1-driven liver disease that remains uncorrected under NTBC therapy were investigated using whole transcriptome analyses on the livers of Fah- and Hgd-deficient mice under continuous NTBC therapy and after seven days of NTBC therapy discontinuation. Alkaptonuria (AKU) was used as a tyrosine-inherited metabolic disorder reference disease with non-hepatic manifestations. The differentially expressed genes were enriched in toxicological gene classes related to liver disease, liver damage, liver regeneration and liver cancer, in particular HCC. Most importantly, a set of 25 genes related to liver disease and HCC development was identified that was differentially regulated in HT1 vs. AKU mouse livers under NTBC therapy. Some of those were further modulated upon NTBC therapy discontinuation in HT1 but not in AKU livers. Altogether, our data indicate that NTBC therapy does not completely resolves HT1-driven liver disease and supports the sustained risk to develop HCC over time as different HCC markers, including Moxd1, Saa, Mt, Dbp and Cxcl1, were significantly increased under NTBC.
Keywords: liver disease; hereditary tyrosinemia type 1; nitisinone; transcriptomics; alkaptonuria; hepatocellular carcinoma; gene signature liver disease; hereditary tyrosinemia type 1; nitisinone; transcriptomics; alkaptonuria; hepatocellular carcinoma; gene signature

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MDPI and ACS Style

Neuckermans, J.; Lequeue, S.; Claes, P.; Heymans, A.; Hughes, J.H.; Colemonts-Vroninks, H.; Marcélis, L.; Casimir, G.; Goyens, P.; Martens, G.A.; et al. Hereditary Tyrosinemia Type 1 Mice under Continuous Nitisinone Treatment Display Remnants of an Uncorrected Liver Disease Phenotype. Genes 2023, 14, 693. https://doi.org/10.3390/genes14030693

AMA Style

Neuckermans J, Lequeue S, Claes P, Heymans A, Hughes JH, Colemonts-Vroninks H, Marcélis L, Casimir G, Goyens P, Martens GA, et al. Hereditary Tyrosinemia Type 1 Mice under Continuous Nitisinone Treatment Display Remnants of an Uncorrected Liver Disease Phenotype. Genes. 2023; 14(3):693. https://doi.org/10.3390/genes14030693

Chicago/Turabian Style

Neuckermans, Jessie, Sien Lequeue, Paul Claes, Anja Heymans, Juliette H. Hughes, Haaike Colemonts-Vroninks, Lionel Marcélis, Georges Casimir, Philippe Goyens, Geert A. Martens, and et al. 2023. "Hereditary Tyrosinemia Type 1 Mice under Continuous Nitisinone Treatment Display Remnants of an Uncorrected Liver Disease Phenotype" Genes 14, no. 3: 693. https://doi.org/10.3390/genes14030693

APA Style

Neuckermans, J., Lequeue, S., Claes, P., Heymans, A., Hughes, J. H., Colemonts-Vroninks, H., Marcélis, L., Casimir, G., Goyens, P., Martens, G. A., Gallagher, J. A., Vanhaecke, T., Bou-Gharios, G., & De Kock, J. (2023). Hereditary Tyrosinemia Type 1 Mice under Continuous Nitisinone Treatment Display Remnants of an Uncorrected Liver Disease Phenotype. Genes, 14(3), 693. https://doi.org/10.3390/genes14030693

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