Impaired Biliary Excretion of Copper and Lysosomal Enzymes in Long-Evans Cinnamon Rat.

Abe, Shigeto; Yamazaki, Kiyoshi; Takikawa, Shugo; Suzuki, Kazuyuki

doi:10.1620/tjem.172.355

Cited by 5 publications

(3 citation statements)

References 25 publications

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“…Although the cytosolic copper has been discussed to be the reactive species [39], our finding that in LEC rats virtually all cytosolic copper is bound to MT supports the findings by others [40] that cytosolic copper is not directly toxic. There is increasing evidence [25,41] that the toxic form of copper is located in the lysosomes. According to earlier results, this copper is considered to be loosely associated to insoluble polymers of oxidized MT and MT-degradation products and therefore is redox reactive [24,25].…”

Section: Discussionmentioning

confidence: 99%

Tetrathiomolybdate in the treatment of acute hepatitis in an animal model for Wilson disease

Klein

Arora

Lichtmannegger

et al. 2004

Journal of Hepatology

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Section: Discussionmentioning

confidence: 99%

Tetrathiomolybdate in the treatment of acute hepatitis in an animal model for Wilson disease

Klein

Arora

Lichtmannegger

et al. 2004

Journal of Hepatology

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“…Interestingly, in hepatocytes exposed to elevated copper levels, one of the copper transporters, Atp7b, moves from the Golgi to lysosomes and imports metal into their lumen [ 52 ]. Moreover, in vivo models of copper overload demonstrated that increased copper loading in the liver leads to increased activity of lysosomal enzymes and reduces their structural integrity [ 53 ]. These data allow us to speculate that in macrophages, copper treatment and the disruption of lysosomal function may exert somewhat similar effects, affecting the stability of Fpn in an iron-independent manner.…”

Section: Discussionmentioning

confidence: 99%

The Role of Copper in the Regulation of Ferroportin Expression in Macrophages

Jończy

Mazgaj

Smuda

et al. 2021

Cells

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The critical function of ferroportin (Fpn) in maintaining iron homeostasis requires complex and multilevel control of its expression. Besides iron-dependent cellular and systemic control of Fpn expression, other metals also seem to be involved in regulating the Fpn gene. Here, we found that copper loading significantly enhanced Fpn transcription in an Nrf2-dependent manner in primary bone-marrow-derived macrophages (BMDMs). However, prolonged copper loading resulted in decreased Fpn protein abundance. Moreover, CuCl2 treatment induced Fpn expression in RAW 264.7 macrophages at both the mRNA and protein level. These data suggest that cell-type-specific regulations have an impact on Fpn protein stability after copper loading. Transcriptional suppression of Fpn after lipopolysaccharide (LPS) treatment contributes to increased iron storage inside macrophages and may result in anemia of inflammation. Here, we observed that in both primary BMDMs and RAW 264.7 macrophages, LPS treatment significantly decreased Fpn mRNA levels, but concomitant CuCl2 stimulation counteracted the transcriptional suppression of Fpn and restored its expression to the control level. Overall, we show that copper loading significantly enhances Fpn transcription in macrophages, while Fpn protein abundance in response to CuCl2 treatment, depending on macrophage type and factors specific to the macrophage population, can influence Fpn regulation in response to copper loading.

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“…ATP7B (WND) expression is highest in liver tissue, with lower expression patterns in the brain and kidney (Bull et al 1993;Tanzi et al 1993;Yamaguchi et al 1994). ATP7A (MNK) expression is observed in most extra-hepatic adult tissues, with high expression in the intestinal mucosa, kidney and neuronal cells (Abe et al 1994;Monty et al 2005). Recent evidence has changed our understanding of expression patterns and the interplay of MNK and WND expressed in the same cells (Linz and Lutsenko 2007).…”

Section: A) Lessons From Co-expressing Cu-atpasesmentioning

confidence: 99%

The multi-layered regulation of copper translocating P-type ATPases

et al. 2009

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The copper-translocating Menkes (ATP7A, MNK protein) and Wilson (ATP7B, WND protein) P-type ATPases are pivotal for copper (Cu) homeostasis, functioning in the biosynthetic incorporation of Cu into copper-dependent enzymes of the secretory pathway, Cu detoxification via Cu efflux, and specialized roles such as systemic Cu absorption (MNK) and Cu excretion (WND). Essential to these functions is their Cu and hormone-responsive distribution between the trans-Golgi network (TGN) and exocytic vesicles located at or proximal to the apical (WND) or basolateral (MNK) cell surface. Intriguingly, MNK and WND Cu-ATPases expressed in the same tissues perform distinct yet complementary roles. While intramolecular differences may specify their distinct roles, cellular signaling components are predicted to be critical for both differences and synergy between these enzymes. This review focuses on these mechanisms, including the cell signaling pathways that influence trafficking and bi-functionality of Cu-ATPases. Phosphorylation events are hypothesized to play a central role in Cu homeostasis, promoting multi-layered regulation and cross-talk between cuproenzymes and Cu-independent mechanisms.

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Impaired Biliary Excretion of Copper and Lysosomal Enzymes in Long-Evans Cinnamon Rat.

Cited by 5 publications

References 25 publications

Tetrathiomolybdate in the treatment of acute hepatitis in an animal model for Wilson disease

Tetrathiomolybdate in the treatment of acute hepatitis in an animal model for Wilson disease

The Role of Copper in the Regulation of Ferroportin Expression in Macrophages

The multi-layered regulation of copper translocating P-type ATPases

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