Functional iron deficiency in toxic milk mutant mice (tx-J) despite high hepatic ferroportin: a critical role of decreased GPI–ceruloplasmin expression in liver macrophages

Jończy, Aneta; Lipiński, Paweł; Ogórek, Mateusz; Starzyński, Rafał R.; Krzysztofik, Daria; Bednarz, Aleksandra; Krzeptowski, Wojciech; Szudzik, Mateusz; Haberkiewicz, Olga; Miłoń, Agnieszka; Grzmil, Paweł; Lenartowicz, Małgorzata

doi:10.1039/c9mt00035f

Cited by 16 publications

(11 citation statements)

References 76 publications

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“…observed in the organ and accordingly liver was injured. In particular, the appearance of the organ revealed with intravital microscopy was striking as sinusoids were hardly visible, and hepatocytes were enlarged and their nuclei were barely evident, a phenotype coinciding with hematoxylin-stained liver sections (33). Moreover, numerous autofluorescent bodies could be detected.…”

Section: Discussionmentioning

confidence: 87%

“…We revealed that at least some neutrophils express the copper transporter -CTR1, and moreover some of them express both ATP7A and ATP7B (up to 5% of neutrophils). While expression of ATP7A is anticipated in most cell types (21), ATP7B expression was so far only reported in hepatocytes and KCs (33). To the best of our knowledge, expression of ATP7 isoforms was not studied in neutrophils so far.…”

Section: Discussionmentioning

confidence: 93%

“…KCs are macrophages of the liver that are central to both the hepatic and systemic response to infection (60). As they normally express ATP7B to regulate their copper levels, they are as overloaded with the element as hepatocytes (33), which most probably results in their death. In fact, KCs cooperate with platelets during the early stages of systemic inflammation as platelets facilitate a crosstalk between KCs and pathogens/their derivatives (43).…”

Section: Discussionmentioning

confidence: 99%

“…Experiments were performed on 7/8-month-old male mice. The age was adjusted in such a way that a 6-month point of very high copper concentration was reached (33).…”

Section: Atp7b Toxic Milk Mice (The Wilson Disease Model)mentioning

confidence: 99%

“…Thus, if ATP7B is malfunctioning, this process is impaired as well as subsequent copper excretion into the bile, which results in copper accumulation in the liver, brain, and, to a lower extent, in other tissues (29,30). By 6 months of age, copper concentration can be over 50-fold more than that of a normal adult animal (33).…”

Section: Introductionmentioning

confidence: 99%

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Reduced Neutrophil Extracellular Trap (NET) Formation During Systemic Inflammation in Mice With Menkes Disease and Wilson Disease: Copper Requirement for NET Release

et al. 2020

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Neutrophil extracellular traps (NETs) contribute to pathological disorders, and their release was directly linked to numerous diseases. With intravital microscopy (IVM), we showed previously that NETs also contribute to the pathology of systemic inflammation and are strongly deposited in liver sinusoids. Over a decade since NET discovery, still not much is known about the metabolic or microenvironmental aspects of their formation. Copper is a vital trace element essential for many biological processes, albeit its excess is potentially cytotoxic; thus, copper levels are tightly controlled by factors such as copper transporting ATPases, ATP7A, and ATP7B. By employing IVM, we studied the impact of copper on NET formation during endotoxemia in liver vasculature on two mice models of copper excess or deficiency, Wilson (ATP7B mutants) and Menkes (ATP7A mutants) diseases, respectively. Here, we show that respective ATP7 mutations lead to diminished NET release during systemic inflammation despite unaltered intrinsic capacity of neutrophils to cast NETs as tested ex vivo. In Menkes disease mice, the in vivo effect is mostly due to diminished neutrophil infiltration of the liver as unmutated mice with a subchronic copper deficiency release even more NETs than their controls during endotoxemia, whereas in Wilson disease mice, excess copper directly diminishes the capacity to release NETs, and this was further confirmed by ex vivo studies on isolated neutrophils co-cultured with exogenous copper and a copper-chelating agent. Taken together, the study extends our understanding on how microenvironmental factors affect NET release by showing that copper is not a prerequisite for NET release but its excess affects the trap casting by neutrophils.

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Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

“…Experiments were performed on 7/8-month-old male mice. The age was adjusted in such a way that a 6-month point of very high copper concentration was reached (33).…”

Section: Atp7b Toxic Milk Mice (The Wilson Disease Model)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Reduced Neutrophil Extracellular Trap (NET) Formation During Systemic Inflammation in Mice With Menkes Disease and Wilson Disease: Copper Requirement for NET Release

et al. 2020

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Toxic milk mice models of Wilson’s disease

Hadrian

Przybyłkowski

2021

Mol Biol Rep

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Wilson’s disease (WD) is a rare genetic disorder inherited as an autosomal recessive trait. The signs and symptoms of this disease are related to dysfunctional ATP7B protein which leads to copper accumulation and cellular damage. The organs that are most commonly affected by WD are the liver and brain. The dysfunctional ATP7B homolog has previously been identified in many different species, including two naturally occurring murine models called toxic milk mice. The aim of this paper was to compare the toxic milk mouse described by Rauch (tx) to that from Jackson Laboratory (txJ) through a review of studies on these two groups of mice. The two mice strains differ in the type of carried mutation and the phenotype of the disease. The data of the studies showed that the tx mice developed mild chronic hepatitis but suffered severe organ destruction with faster progression to full-liver cirrhosis. No changes were noted in the neurological and behavioral status of this strain despite the described toxic accumulation of copper and neuronal destruction in their brain. On the other hand, though the Jackson toxic milk mice (txJ) also presented chronic hepatitis, the condition was a bit milder with slower progression to end-stage disease. Moreover, hepatocyte suitable to perform neurobehavioral research as their phenotype characterized by tremors and locomotor disabilities better corresponds with the cliniconeurological picture of the humans.

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Identification of lncRNA-miRNA-mRNA Networks in the Lenticular Nucleus Region of the Brain Contributes to Hepatolenticular Degeneration Pathogenesis and Therapy

Hao,

Yang,

Yang

et al. 2023

Mol Neurobiol

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Long non-coding RNAs (lncRNAs) are a recently discovered group of non-coding RNAs that play a crucial role in the regulation of various human diseases, especially in the study of nervous system diseases which has garnered significant attention. However, there is limited knowledge on the identification and function of lncRNAs in hepatolenticular degeneration (HLD). The objective of this study was to identify novel lncRNAs and determine their involvement in the networks associated with HLD. We conducted a comprehensive analysis of RNA sequencing (RNA-seq) data, reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and computational biology to identify novel lncRNAs and explore their potential mechanisms in HLD. We identified 212 differently expressed lncRNAs, with 98 upregulated and 114 downregulated. Additionally, 32 differently expressed mRNAs were found, with 15 upregulated and 17 downregulated. We obtained a total of 1131 pairs of co-expressed lncRNAs and mRNAs by Pearson correlation test and prediction and annotation of the lncRNA-targeted miRNA-mRNA network. The differential lncRNAs identified in this study were found to be involved in various biological functions and signaling pathways. These include translational initiation, motor learning, locomotors behavior, dioxygenase activity, integral component of postsynaptic membrane, neuroactive ligand-receptor interaction, nuclear factor-kappa B (NF-κB) signaling pathway, cholinergic synapse, sphingolipid signaling pathway, and Parkinson’s disease signaling pathway, as revealed by the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Six lncRNAs, including XR_001782921.1 (P < 0.01), XR_ 001780581.1 (P < 0.01), ENSMUST_00000207119 (P < 0.01), XR_865512.2 (P < 0.01), TCONS_00005916 (P < 0.01), and TCONS_00020683 (P < 0.01), showed significant differences in expression levels between the model group and normal group by RT-qPCR. Among these, four lncRNAs (TCONS_00020683, XR_865512.2, XR_001780581.1, and ENSMUST00000207119) displayed a high degree of conservation. This study provides a unique perspective for the pathogenesis and therapy of HLD by constructing the lncRNA-miRNA-mRNA network. This insight provides a foundation for future exploration in this field.

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Functional iron deficiency in toxic milk mutant mice (tx-J) despite high hepatic ferroportin: a critical role of decreased GPI–ceruloplasmin expression in liver macrophages

Abstract: Jackson toxic milk mutant mice (tx-J) carrying a missense mutation in the Atp7b gene are animal models of the Wilson disease.

Cited by 16 publications

References 76 publications

Reduced Neutrophil Extracellular Trap (NET) Formation During Systemic Inflammation in Mice With Menkes Disease and Wilson Disease: Copper Requirement for NET Release

Reduced Neutrophil Extracellular Trap (NET) Formation During Systemic Inflammation in Mice With Menkes Disease and Wilson Disease: Copper Requirement for NET Release

Toxic milk mice models of Wilson’s disease

Identification of lncRNA-miRNA-mRNA Networks in the Lenticular Nucleus Region of the Brain Contributes to Hepatolenticular Degeneration Pathogenesis and Therapy

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