Oxidative Stress, Glutathione Metabolism, and Liver Regeneration Pathways Are Activated in Hereditary Tyrosinemia Type 1 Mice upon Short-Term Nitisinone Discontinuation
Hereditary tyrosinemia type 1 (HT1) is an inherited condition in which the body is unable to break down the amino acid tyrosine due to mutations in the fumarylacetoacetate hydrolase (FAH) gene, coding for the final enzyme of the tyrosine degradation pathway. As a consequence, HT1 patients accumulate...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2020-12-01
|
| Series: | Genes |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2073-4425/12/1/3 |
| _version_ | 1797543851488968704 |
|---|---|
| author | Haaike Colemonts-Vroninks Jessie Neuckermans Lionel Marcelis Paul Claes Steven Branson Georges Casimir Philippe Goyens Geert A. Martens Tamara Vanhaecke Joery De Kock |
| author_facet | Haaike Colemonts-Vroninks Jessie Neuckermans Lionel Marcelis Paul Claes Steven Branson Georges Casimir Philippe Goyens Geert A. Martens Tamara Vanhaecke Joery De Kock |
| author_sort | Haaike Colemonts-Vroninks |
| collection | DOAJ |
| description | Hereditary tyrosinemia type 1 (HT1) is an inherited condition in which the body is unable to break down the amino acid tyrosine due to mutations in the fumarylacetoacetate hydrolase (FAH) gene, coding for the final enzyme of the tyrosine degradation pathway. As a consequence, HT1 patients accumulate toxic tyrosine derivatives causing severe liver damage. Since its introduction, the drug nitisinone (NTBC) has offered a life-saving treatment that inhibits the upstream enzyme 4-hydroxyphenylpyruvate dioxygenase (HPD), thereby preventing production of downstream toxic metabolites. However, HT1 patients under NTBC therapy remain unable to degrade tyrosine. To control the disease and side-effects of the drug, HT1 patients need to take NTBC as an adjunct to a lifelong tyrosine and phenylalanine restricted diet. As a consequence of this strict therapeutic regime, drug compliance issues can arise with significant influence on patient health. In this study, we investigated the molecular impact of short-term NTBC therapy discontinuation on liver tissue of Fah-deficient mice. We found that after seven days of NTBC withdrawal, molecular pathways related to oxidative stress, glutathione metabolism, and liver regeneration were mostly affected. More specifically, NRF2-mediated oxidative stress response and several toxicological gene classes related to reactive oxygen species metabolism were significantly modulated. We observed that the expression of several key glutathione metabolism related genes including <i>Slc7a11</i> and <i>Ggt1</i> was highly increased after short-term NTBC therapy deprivation. This stress response was associated with the transcriptional activation of several markers of liver progenitor cells including <i>Atf3</i>, <i>Cyr61</i>, <i>Ddr1</i>, <i>Epcam</i>, <i>Elovl7</i>, and <i>Glis3</i>, indicating a concreted activation of liver regeneration early after NTBC withdrawal. |
| first_indexed | 2024-03-10T13:51:32Z |
| format | Article |
| id | doaj.art-6e7a0c70a38b48d69a1e8ccd1903fcb0 |
| institution | Directory Open Access Journal |
| issn | 2073-4425 |
| language | English |
| last_indexed | 2024-03-10T13:51:32Z |
| publishDate | 2020-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Genes |
| spelling | doaj.art-6e7a0c70a38b48d69a1e8ccd1903fcb02023-11-21T02:04:46ZengMDPI AGGenes2073-44252020-12-01121310.3390/genes12010003Oxidative Stress, Glutathione Metabolism, and Liver Regeneration Pathways Are Activated in Hereditary Tyrosinemia Type 1 Mice upon Short-Term Nitisinone DiscontinuationHaaike Colemonts-Vroninks0Jessie Neuckermans1Lionel Marcelis2Paul Claes3Steven Branson4Georges Casimir5Philippe Goyens6Geert A. Martens7Tamara Vanhaecke8Joery De Kock9Department of In Vitro Toxicology and Dermato-Cosmetology (IVTD), Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussels, BelgiumDepartment of In Vitro Toxicology and Dermato-Cosmetology (IVTD), Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussels, BelgiumLaboratoire de Pédiatrie, Hôpital Universitaire des Enfants Reine Fabiola (HUDERF), Université Libre de Bruxelles (ULB), Avenue J.J. Crocq 1-3, 1020 Brussels, BelgiumDepartment of In Vitro Toxicology and Dermato-Cosmetology (IVTD), Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussels, BelgiumDepartment of In Vitro Toxicology and Dermato-Cosmetology (IVTD), Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussels, BelgiumLaboratoire de Pédiatrie, Hôpital Universitaire des Enfants Reine Fabiola (HUDERF), Université Libre de Bruxelles (ULB), Avenue J.J. Crocq 1-3, 1020 Brussels, BelgiumLaboratoire de Pédiatrie, Hôpital Universitaire des Enfants Reine Fabiola (HUDERF), Université Libre de Bruxelles (ULB), Avenue J.J. Crocq 1-3, 1020 Brussels, BelgiumDepartment of Laboratory Medicine, AZ Delta General Hospital, Deltalaan 1, 8800 Roeselare, BelgiumDepartment of In Vitro Toxicology and Dermato-Cosmetology (IVTD), Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussels, BelgiumDepartment of In Vitro Toxicology and Dermato-Cosmetology (IVTD), Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussels, BelgiumHereditary tyrosinemia type 1 (HT1) is an inherited condition in which the body is unable to break down the amino acid tyrosine due to mutations in the fumarylacetoacetate hydrolase (FAH) gene, coding for the final enzyme of the tyrosine degradation pathway. As a consequence, HT1 patients accumulate toxic tyrosine derivatives causing severe liver damage. Since its introduction, the drug nitisinone (NTBC) has offered a life-saving treatment that inhibits the upstream enzyme 4-hydroxyphenylpyruvate dioxygenase (HPD), thereby preventing production of downstream toxic metabolites. However, HT1 patients under NTBC therapy remain unable to degrade tyrosine. To control the disease and side-effects of the drug, HT1 patients need to take NTBC as an adjunct to a lifelong tyrosine and phenylalanine restricted diet. As a consequence of this strict therapeutic regime, drug compliance issues can arise with significant influence on patient health. In this study, we investigated the molecular impact of short-term NTBC therapy discontinuation on liver tissue of Fah-deficient mice. We found that after seven days of NTBC withdrawal, molecular pathways related to oxidative stress, glutathione metabolism, and liver regeneration were mostly affected. More specifically, NRF2-mediated oxidative stress response and several toxicological gene classes related to reactive oxygen species metabolism were significantly modulated. We observed that the expression of several key glutathione metabolism related genes including <i>Slc7a11</i> and <i>Ggt1</i> was highly increased after short-term NTBC therapy deprivation. This stress response was associated with the transcriptional activation of several markers of liver progenitor cells including <i>Atf3</i>, <i>Cyr61</i>, <i>Ddr1</i>, <i>Epcam</i>, <i>Elovl7</i>, and <i>Glis3</i>, indicating a concreted activation of liver regeneration early after NTBC withdrawal.https://www.mdpi.com/2073-4425/12/1/3hereditary liver diseasetyrosinemia type 1nitisinonetranscriptomicsoxidative stressglutathione metabolism |
| spellingShingle | Haaike Colemonts-Vroninks Jessie Neuckermans Lionel Marcelis Paul Claes Steven Branson Georges Casimir Philippe Goyens Geert A. Martens Tamara Vanhaecke Joery De Kock Oxidative Stress, Glutathione Metabolism, and Liver Regeneration Pathways Are Activated in Hereditary Tyrosinemia Type 1 Mice upon Short-Term Nitisinone Discontinuation Genes hereditary liver disease tyrosinemia type 1 nitisinone transcriptomics oxidative stress glutathione metabolism |
| title | Oxidative Stress, Glutathione Metabolism, and Liver Regeneration Pathways Are Activated in Hereditary Tyrosinemia Type 1 Mice upon Short-Term Nitisinone Discontinuation |
| title_full | Oxidative Stress, Glutathione Metabolism, and Liver Regeneration Pathways Are Activated in Hereditary Tyrosinemia Type 1 Mice upon Short-Term Nitisinone Discontinuation |
| title_fullStr | Oxidative Stress, Glutathione Metabolism, and Liver Regeneration Pathways Are Activated in Hereditary Tyrosinemia Type 1 Mice upon Short-Term Nitisinone Discontinuation |
| title_full_unstemmed | Oxidative Stress, Glutathione Metabolism, and Liver Regeneration Pathways Are Activated in Hereditary Tyrosinemia Type 1 Mice upon Short-Term Nitisinone Discontinuation |
| title_short | Oxidative Stress, Glutathione Metabolism, and Liver Regeneration Pathways Are Activated in Hereditary Tyrosinemia Type 1 Mice upon Short-Term Nitisinone Discontinuation |
| title_sort | oxidative stress glutathione metabolism and liver regeneration pathways are activated in hereditary tyrosinemia type 1 mice upon short term nitisinone discontinuation |
| topic | hereditary liver disease tyrosinemia type 1 nitisinone transcriptomics oxidative stress glutathione metabolism |
| url | https://www.mdpi.com/2073-4425/12/1/3 |
| work_keys_str_mv | AT haaikecolemontsvroninks oxidativestressglutathionemetabolismandliverregenerationpathwaysareactivatedinhereditarytyrosinemiatype1miceuponshorttermnitisinonediscontinuation AT jessieneuckermans oxidativestressglutathionemetabolismandliverregenerationpathwaysareactivatedinhereditarytyrosinemiatype1miceuponshorttermnitisinonediscontinuation AT lionelmarcelis oxidativestressglutathionemetabolismandliverregenerationpathwaysareactivatedinhereditarytyrosinemiatype1miceuponshorttermnitisinonediscontinuation AT paulclaes oxidativestressglutathionemetabolismandliverregenerationpathwaysareactivatedinhereditarytyrosinemiatype1miceuponshorttermnitisinonediscontinuation AT stevenbranson oxidativestressglutathionemetabolismandliverregenerationpathwaysareactivatedinhereditarytyrosinemiatype1miceuponshorttermnitisinonediscontinuation AT georgescasimir oxidativestressglutathionemetabolismandliverregenerationpathwaysareactivatedinhereditarytyrosinemiatype1miceuponshorttermnitisinonediscontinuation AT philippegoyens oxidativestressglutathionemetabolismandliverregenerationpathwaysareactivatedinhereditarytyrosinemiatype1miceuponshorttermnitisinonediscontinuation AT geertamartens oxidativestressglutathionemetabolismandliverregenerationpathwaysareactivatedinhereditarytyrosinemiatype1miceuponshorttermnitisinonediscontinuation AT tamaravanhaecke oxidativestressglutathionemetabolismandliverregenerationpathwaysareactivatedinhereditarytyrosinemiatype1miceuponshorttermnitisinonediscontinuation AT joerydekock oxidativestressglutathionemetabolismandliverregenerationpathwaysareactivatedinhereditarytyrosinemiatype1miceuponshorttermnitisinonediscontinuation |