Restriction of Manganese Intake Prevents the Onset of Brain Manganese Overload in Zip14−/− Mice

Wu, Yuze; Wei, Guojun; Zhao, Ningning

doi:10.3390/ijms22136773

Cited by 5 publications

(13 citation statements)

References 33 publications

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“…The age-associated differences in murine manganese metabolism were previously reported, showing that 3-week-old mice appeared to have higher liver manganese concentrations than 12-week-old mice [ 31 ]. Our results have shown that hepatic ZIP8 is downregulated in mice exposed to high manganese during the neonatal period (in 3-week-old mice), but not in mice receiving a high-manganese diet after reaching maturity.…”

Section: Resultsmentioning

confidence: 96%

“…We developed our neonatal manganese overload model by feeding breeder mice a purified diet containing 20 ppm (control) or 2000 ppm (high) of manganese throughout mating, gestation, and lactation. Our previous study determined that the manganese content in the maternal milk from mice on the high-manganese diet was about 3 times that from mice on the control diet [ 31 ]. Given that this dietary intervention led to an alteration in breast milk manganese content, the pups experienced differences in manganese intake before weaning.…”

Section: Resultsmentioning

confidence: 99%

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The Regulation of ZIP8 by Dietary Manganese in Mice

Zhao

2023

IJMS

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ZIP8 is a newly identified manganese transporter. A lack of functional ZIP8 results in severe manganese deficiency in both humans and mice, indicating that ZIP8 plays a crucial role in maintaining body manganese homeostasis. Despite a well-acknowledged connection between ZIP8 and manganese metabolism, how ZIP8 is regulated under high-manganese conditions remains unclear. The primary goal of this study was to examine the regulation of ZIP8 by high-manganese intake. We used both neonatal and adult mouse models in which mice were supplied with dietary sources containing either a normal or a high level of manganese. We discovered that high-manganese intake caused a reduction in liver ZIP8 protein in young mice. Since a decrease in hepatic ZIP8 leads to reduced manganese reabsorption from the bile, our study identified a novel mechanism for the regulation of manganese homeostasis under high-manganese conditions: high dietary manganese intake results in a decrease in ZIP8 in the liver, which in turn decreases the reabsorption of manganese from the bile to prevent manganese overload in the liver. Interestingly, we found that a high-manganese diet did not cause a decrease in hepatic ZIP8 in adult animals. To determine the potential reason for this age-dependent variation, we compared the expressions of liver ZIP8 in 3-week-old and 12-week-old mice. We found that liver ZIP8 protein content in 12-week-old mice decreases when compared with that of 3-week-old mice under normal conditions. Overall, results from this study provide novel insights to facilitate the understanding of ZIP8’s function in regulating manganese metabolism.

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Section: Resultsmentioning

confidence: 96%

Section: Resultsmentioning

confidence: 99%

The Regulation of ZIP8 by Dietary Manganese in Mice

Zhao

2023

IJMS

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“…However, the extent of manganese accumulation caused by the loss of intestinal ZIP14 was not as severe as that observed in Zip14 −/− mice because it has been reported that the blood manganese levels in Zip14 −/− mice of a similar age were about 15 times as high as the wild-type (WT) littermates [ 28 ]. We hypothesize that since hepatic ZIP14 was intact in Zip14 -In-KO mice, excess manganese resulting from the loss of intestinal ZIP14 could be partially removed through hepatobiliary excretion, leading to less severe manganese loading in Zip14 -In-KO mice.…”

Section: Resultsmentioning

confidence: 99%

“…ZIP14 inactivation primarily impairs the central nervous system and leads to neurodegenerative symptoms due to manganese hyperaccumulation in the brain. For example, the brain manganese in 6-to-12-week-old Zip14 −/− mice was reported to be about 10 times as high as that in WT mice [ 28 ]. In the present study, we examined the effect of tissue-specific Zip14 deletion on brain manganese in 9-week-old mice and found that Zip14 -L-KO mice had normal brain manganese while Zip14 -In-KO mice developed increased brain manganese loading (increased by 40% in male mice and by 20% in female mice) when compared with the Zip14 flox/flox control mice ( Figure 6 A,B).…”

Section: Resultsmentioning

confidence: 99%

“…Recent studies using intestine-specific Zip14 -knockout ( Zip14 -In-KO) mice demonstrated a critical role for intestinal ZIP14 in controlling systemic manganese homeostasis because Zip14 -In-KO mice developed increased manganese in both the blood and the brain [ 26 , 27 ]. However, the brain manganese loading observed in Zip14 -In-KO mice was much less severe when compared with that seen in Zip14 −/− mice of a similar age [ 26 , 28 ]. We hypothesized that, since hepatic ZIP14 was intact in Zip14 -In-KO mice, excess manganese resulting from increased manganese absorption could be partially removed through hepatobiliary excretion, leading to less severe manganese loading in Zip14 -In-KO mice.…”

Section: Introductionmentioning

confidence: 99%

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The Combined Inactivation of Intestinal and Hepatic ZIP14 Exacerbates Manganese Overload in Mice

Fung

Zhao

2022

IJMS

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ZIP14 is a newly identified manganese transporter with high levels of expression in the small intestine and the liver. Loss-of-function mutations in ZIP14 can lead to systemic manganese overload, which primarily affects the central nervous system, causing neurological disorders. To elucidate the roles of intestinal ZIP14 and hepatic ZIP14 in maintaining systemic manganese homeostasis, we generated mice with single-tissue or two-tissue Zip14 knockout, including intestine-specific (Zip14-In-KO), liver-specific (Zip14-L-KO), and double (intestine and liver) Zip14-knockout (Zip14-DKO) mice. Zip14flox/flox mice were used as the control. Tissue manganese contents in these mice were compared using inductively coupled plasma mass spectrometry (ICP-MS) analysis. We discovered that although the deletion of intestinal ZIP14 only moderately increased systemic manganese loading, the deletion of both intestinal and hepatic ZIP14 greatly exacerbated the body’s manganese burden. Our results provide new knowledge to further the understanding of manganese metabolism, and offer important insights into the mechanisms underlying systemic manganese overload caused by the loss of ZIP14.

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Genetic control of MRI contrast using the manganese transporter Zip14

Rallapalli,

McCall,

Koretsky

2024

Magnetic Resonance in Med

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PurposeGene‐expression reporter systems, such as green fluorescent protein, have been instrumental to understanding biological processes in living organisms at organ system, tissue, cell, and molecular scales. More than 30 years of work on developing MRI‐visible gene‐expression reporter systems has resulted in a variety of clever application‐specific methods. However, these techniques have not yet been widely adopted, so a general‐purpose expression reporter is still required. Here, we demonstrate that the manganese ion transporter Zip14 is an in vivo MRI‐visible, flexible, and robust gene‐expression reporter to meet this need.MethodsPlasmid constructs consisting of a cell type–specific promoter, gene coding for human Zip14, and a histology‐visible tag were packaged into adeno‐associated viruses. These viruses were intracranially injected into the mouse brain. Serial in vivo MRI was performed using a vendor‐supplied 3D‐MPRAGE sequence. No additional contrast agents were administered. Animals were sacrificed after the last imaging timepoint for immunohistological validation.ResultsNeuron‐specific overexpression of Zip14 produced substantial and long‐lasting changes in MRI contrast. Using appropriate viruses enabled both anterograde and retrograde neural tracing. Expression of Zip14 in astrocytes also enabled MRI of glia populations in the living mammalian brain.ConclusionsThe flexibility of this system as an MRI‐visible gene‐expression reporter will enable many applications of serial, high‐resolution imaging of gene expression for basic science and therapy development.

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Restriction of Manganese Intake Prevents the Onset of Brain Manganese Overload in Zip14−/− Mice

Cited by 5 publications

References 33 publications

The Regulation of ZIP8 by Dietary Manganese in Mice

The Regulation of ZIP8 by Dietary Manganese in Mice

The Combined Inactivation of Intestinal and Hepatic ZIP14 Exacerbates Manganese Overload in Mice

Genetic control of MRI contrast using the manganese transporter Zip14

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