Oxidative Stress, Glutathione Metabolism, and Liver Regeneration Pathways Are Activated in Hereditary Tyrosinemia Type 1 Mice upon Short-Term Nitisinone Discontinuation

Colemonts-Vroninks, Haaike; Neuckermans, Jessie; Marcélis, Lionel; Claes, Paul; Branson, Steven; Casimir, Georges; Goyens, Philippe; Martens, Guy; Vanhaecke, Tamara; Kock, Joery De

doi:10.3390/genes12010003

Cited by 9 publications

(7 citation statements)

References 59 publications

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“…2f, g). Among these, glutathione metabolism plays an important role in defensing against oxidant 33,34 , and was recently reported to be activated in liver regeneration 35 . In addition, polyamine metabolites (e.g., spermine and spermidine) are well-known pro-regenerative metabolites [36][37][38] .…”

Section: Identification Of Key Metabolites Associated With Higher Regenerative Potentialmentioning

confidence: 99%

Cross-species metabolomic analysis identifies uridine as a potent regeneration promoting factor

Liu

Geng

et al. 2022

Cell Discov

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Regenerative capacity declines throughout evolution and with age. In this study, we asked whether metabolic programs underlying regenerative capability might be conserved across species, and if so, whether such metabolic drivers might be harnessed to promote tissue repair. To this end, we conducted metabolomic analyses in two vertebrate organ regeneration models: the axolotl limb blastema and antler stem cells. To further reveal why young individuals have higher regenerative capacity than the elderly, we also constructed metabolic profiles for primate juvenile and aged tissues, as well as young and aged human stem cells. In joint analyses, we uncovered that active pyrimidine metabolism and fatty acid metabolism correlated with higher regenerative capacity. Furthermore, we identified a set of regeneration-related metabolite effectors conserved across species. One such metabolite is uridine, a pyrimidine nucleoside, which can rejuvenate aged human stem cells and promote regeneration of various tissues in vivo. These observations will open new avenues for metabolic intervention in tissue repair and regeneration.

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Section: Identification Of Key Metabolites Associated With Higher Regenerative Potentialmentioning

confidence: 99%

Cross-species metabolomic analysis identifies uridine as a potent regeneration promoting factor

Liu

Geng

et al. 2022

Cell Discov

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“…Sample collection was carried out according to the previously mentioned protocol [ 34 ]. Briefly, at 12 weeks of age, the mice of both experimental groups were anesthetized via intraperitoneal injection of a mixture of ketamine (87.5 mg/kg Ketamidor ® (Ecuphar, Catalonia, Spain)) and xylazine (12.5 mg/kg Rompun ® (Bayer, Leverkusen, Germany)).…”

Section: Methodsmentioning

confidence: 99%

“…The DBS cards were analyzed as previously reported [ 34 ]. DBS cards were air-dried at room temperature for at least 24 h prior to analysis.…”

Section: Methodsmentioning

confidence: 99%

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

Neuckermans

Lequeue

Claes

et al. 2023

Genes

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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.

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“…The transcriptional profile of TLR, cytokine and regulatory mediators by MSCs was determined by quantitative polymerase chain reaction (qPCR) as previously performed [ 79 , 80 , 81 ]. Total mRNA was extracted using the TriPure Isolation Reagent TM (Roche Applied Science) and quantified at 260 nm using a Nanodrop TM spectrophotometer (Thermo Scientific, Waltham, MA, USA).…”

Section: Methodsmentioning

confidence: 99%

Transcriptional Profile of Cytokines, Regulatory Mediators and TLR in Mesenchymal Stromal Cells after Inflammatory Signaling and Cell-Passaging

Merimi

Buyl

Daassi

et al. 2021

IJMS

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Adult human subcutaneous adipose tissue (AT) harbors a rich population of mesenchymal stromal cells (MSCs) that are of interest for tissue repair. For this purpose, it is of utmost importance to determine the response of AT-MSCs to proliferative and inflammatory signals within the damaged tissue. We have characterized the transcriptional profile of cytokines, regulatory mediators and Toll-like receptors (TLR) relevant to the response of MSCs. AT-MSCs constitutively present a distinct profile for each gene and differentially responded to inflammation and cell-passaging. Inflammation leads to an upregulation of IL-6, IL-8, IL-1β, TNFα and CCL5 cytokine expression. Inflammation and cell-passaging increased the expression of HGF, IDO1, PTGS1, PTGS2 and TGFβ. The expression of the TLR pattern was differentially modulated with TLR 1, 2, 3, 4, 9 and 10 being increased, whereas TLR 5 and 6 downregulated. Functional enrichment analysis demonstrated a complex interplay between cytokines, TLR and regulatory mediators central for tissue repair. This profiling highlights that following a combination of inflammatory and proliferative signals, the sensitivity and responsive capacity of AT-MSCs may be significantly modified. Understanding these transcriptional changes may help the development of novel therapeutic approaches.

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Oxidative Stress, Glutathione Metabolism, and Liver Regeneration Pathways Are Activated in Hereditary Tyrosinemia Type 1 Mice upon Short-Term Nitisinone Discontinuation

Cited by 9 publications

References 59 publications

Cross-species metabolomic analysis identifies uridine as a potent regeneration promoting factor

Cross-species metabolomic analysis identifies uridine as a potent regeneration promoting factor

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

Transcriptional Profile of Cytokines, Regulatory Mediators and TLR in Mesenchymal Stromal Cells after Inflammatory Signaling and Cell-Passaging

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