A Brief Overview from the Physiological and Detrimental Roles of Zinc Homeostasis via Zinc Transporters in the Heart

In the last years, research has shown that zinc ions play an essential role in the physiology of brain function. Zinc acts as a potent neuromodulatory agent and signaling ions, regulating healthy brain development and the function of both neurons and glial cells. Therefore, the concentration of zinc within the brain and its cells is tightly controlled. Zinc transporters are key regulators of (extra-) cellular zinc levels, and deregulation of zinc homeostasis and zinc transporters has been associated with neurodegenerative and neuropsychiatric disorders. However, to date, the presence of specific family members and their subcellular localization within brain cells have not been investigated in detail. Here, we analyzed the expression of all zinc transporters (ZnTs) and Irt-like proteins (ZIPs) in the rat brain. We further used primary rat neurons and rat astrocyte cell lines to differentiate between the expression found in neurons or astrocytes or both. We identified ZIP4 expressed in astrocytes but significantly more so in neurons, a finding that has not been reported previously. In neurons, ZIP4 is localized to synapses and found in a complex with major postsynaptic scaffold proteins of excitatory synapses. Synaptic ZIP4 reacts to short-term fluctuations in local zinc levels. We conclude that ZIP4 may have a so-far undescribed functional role at excitatory postsynapses.

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Cooperation of metallothionein and zinc transporters for regulating zinc homeostasis in human intestinal Caco-2 cells

Nutrition Research ◽

10.1016/j.nutres.2008.02.011 ◽

2008 ◽

Vol 28 (6) ◽

pp. 406-413 ◽

Cited By ~ 25

Author(s):

Hui Shen ◽

Haihong Qin ◽

Junsheng Guo

Keyword(s):

Zinc Homeostasis ◽

Zinc Transporters

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The Role of Zinc and Zinc Homeostasis in Macrophage Function

Journal of Immunology Research ◽

10.1155/2018/6872621 ◽

2018 ◽

Vol 2018 ◽

pp. 1-11 ◽

Cited By ~ 28

Author(s):

Hong Gao ◽

Wei Dai ◽

Lu Zhao ◽

Junxia Min ◽

Fudi Wang

Keyword(s):

Immune System ◽

Innate Immune System ◽

Growth And Development ◽

Innate Immune ◽

Zinc Homeostasis ◽

Zinc Transporters ◽

Essential Trace Element ◽

Macrophage Function ◽

Living Organisms

Zinc has long been recognized as an essential trace element, playing roles in the growth and development of all living organisms. In recent decades, zinc homeostasis was also found to be important for the innate immune system, especially for maintaining the function of macrophages. It is now generally accepted that dysregulated zinc homeostasis in macrophages causes impaired phagocytosis and an abnormal inflammatory response. However, many questions remain with respect to the mechanisms that underlie these processes, particularly at the cellular and molecular levels. Here, we review our current understanding of the roles that zinc and zinc transporters play in regulating macrophage function.

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Does Zinc Absorption Reflect Zinc Status?

International Journal for Vitamin and Nutrition Research ◽

10.1024/0300-9831/a000037 ◽

2010 ◽

Vol 80 (45) ◽

pp. 300-306 ◽

Cited By ~ 18

Author(s):

Janet C. King

Keyword(s):

Physiological State ◽

Absorption Efficiency ◽

Zinc Homeostasis ◽

Zinc Transporters ◽

Whole Body ◽

Zinc Absorption ◽

Zinc Status ◽

Dietary Zinc ◽

Zinc Intake ◽

Supplemental Zinc

Unlike iron, zinc absorption is influenced by dietary zinc intake, not zinc status. As dietary zinc increases, the total amount of absorbed zinc increases while the percent absorbed declines. The gastrointestinal tract maintains whole-body zinc homeostasis by adjusting endogenous zinc losses to the amount absorbed. At intakes below about 9 mg/day, zinc absorption occurs primarily by a saturable (carrier) process involving ZIP4, ZnT1, and other transporters. There is no evidence that past zinc intakes, or status, influences zinc absorption. Instead, current zinc intake is the chief determinant of zinc absorption. Supplemental zinc taken with water in the post-absorptive state initially is absorbed more efficiently than food zinc, but absorption efficiency declines within 24 hours presumably due to down-regulation of the zinc transporters. More research is needed to understand the effect of physiological state on zinc absorption.

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Function, Structure, and Transport Aspects of ZIP and ZnT Zinc Transporters in Immune Cells

Journal of Immunology Research ◽

10.1155/2018/9365747 ◽

2018 ◽

Vol 2018 ◽

pp. 1-9 ◽

Cited By ~ 13

Author(s):

Bum-Ho Bin ◽

Juyeon Seo ◽

Sung Tae Kim

Keyword(s):

Immune Cells ◽

Drug Targets ◽

Therapeutic Potential ◽

Family Members ◽

Zinc Transporter ◽

Zinc Homeostasis ◽

Zinc Transporters ◽

Function Structure ◽

Rich Domain ◽

Zip Family

Zinc is an important trace metal in immune systems, and zinc transporters are involved in many immune responses. Recent advances have revealed the structural and biochemical bases for zinc transport across the cell membrane, with clinical implications for the regulation of zinc homeostasis in immune cells like dendritic cells, T cells, B cells, and mast cells. In this review, we discuss the function, structure, and transport aspects of two major mammalian zinc transporter types, importers and exporters. First, Zrt-/Irt-like proteins (ZIPs) mediate the zinc influx from the extracellular or luminal side into the cytoplasm. There are 14 ZIP family members in humans. They form a homo- or heterodimer with 8 transmembrane domains and extra-/intracellular domains of various lengths. Several ZIP members show specific extracellular domains composed of two subdomains, a helix-rich domain and proline-alanine-leucine (PAL) motif-containing domain. Second, ZnT (zinc transporter) was initially identified in early studies of zinc biology; it mediates zinc efflux as a counterpart of ZIPs in zinc homeostasis. Ten family members have been identified. They show a unique architecture characterized by a Y-shaped conformation and a large cytoplasmic domain. A precise, comprehensive understanding of the structures and transport mechanisms of ZIP and ZnT in combination with mice experiments would provide promising drug targets as well as a basis for identifying other transporters with therapeutic potential.

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Curcumin Reduces Hepatic and White Adipose Tissue Inflammation and Expression of Specific Zinc Transporters in Diet-Induced Obese Mice

Current Developments in Nutrition ◽

10.1093/cdn/nzab037_035 ◽

2021 ◽

Vol 5 (Supplement_2) ◽

pp. 325-325

Author(s):

Tariful Islam ◽

Geetika Katasani ◽

Iurii Koboziev ◽

Kembra Albracht-Schulte ◽

Shane Scoggin ◽

...

Keyword(s):

Adipose Tissue ◽

White Adipose Tissue ◽

Inflammatory Markers ◽

Zinc Homeostasis ◽

Metabolic Effects ◽

Zinc Transporters ◽

Whole Body ◽

Mrna Levels ◽

Alcoholic Fatty Liver ◽

Anti Inflammatory

Abstract Objectives Obesity is a complex metabolic disease, that is often associated with non-alcoholic fatty liver disease (NAFLD). Inflammation is a common feature of both diseases. Curcumin, a traditionally used spice in Asia, exerts anti-inflammatory effects in liver and white adipose tissue (WAT) of diet-induced obese (DIO) mice. However, mechanisms involved in these beneficial effects remain obscure. Zinc is an important micronutrient involved in inflammatory responses. Whole-body zinc homeostasis plays a critical role in decreasing tissue specific inflammation. Zinc homeostasis is maintained mainly by zinc transporters known as ZnT (zinc transporters) and Zip (Zrt and Irt-like proteins) family. We propose that zinc transporters may contribute to curcumin's protective metabolic effects. Thus, the objective of this research was to determine curcumin's effects on inflammatory markers and zinc transporters in liver and WAT from DIO mice. Methods Male B6 mice were fed a HFD (45% kcal fat) or HFD supplemented with 0.4% (w/w) curcumin (HFC) for fourteen weeks. Serum triglycerides (TG) and free fatty acid (FFA) levels were measured. mRNA levels for inflammatory markers and zinc transporters were determined in WAT and liver by qRT-PCR. Results No significant changes were observed in body weight, serum TG and FFA levels with curcumin supplementation. However, gene expression of inflammatory markers, including Stat1, and Nf-KB subunit p65 were significantly reduced in liver and WAT from HFC group compared to HF (P < 0.05). Furthermore, curcumin reduced hepatic zinc transporters Zip10, Zip14, ZnT10 but increased ZnT9 expression. In WAT, curcumin significantly reduced mRNA levels for Zip1, Zip14, ZnT1, and ZnT7 (P < 0.05). Conclusions Our results indicate that zinc transporters may in part mediate the anti-inflammatory properties of curcumin, particularly Zip14, in WAT and liver of DIO mice. Future mechanistic studies are necessary to establish whether zinc transporters are required for curcumin's anti-inflammatory effects in obesity and associated NAFLD. Funding Sources AHA grant# 19AIREA34450279.

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Zinc Transporter ZIP12 Maintains Zinc Homeostasis and Protects Spermatogonia From Oxidative Stress During Spermatogenesis

10.21203/rs.3.rs-800872/v1 ◽

2021 ◽

Author(s):

Xinye Zhu ◽

Chengxuan Yu ◽

Wangshu Wu ◽

Lei Shi ◽

Chenyi Jiang ◽

...

Keyword(s):

Oxidative Stress ◽

Cell Viability ◽

Male Fertility ◽

Sperm Quality ◽

Zinc Level ◽

Zinc Transporter ◽

Zinc Homeostasis ◽

Mouse Testis ◽

Zinc Transporters ◽

Wide Range

Abstract Background: Overwhelming evidences now suggest oxidative stress is a major cause of sperm dysfunction and male infertility. Zinc is an important non-enzyme antioxidant with a wide range of biological functions and plays a significant role in preserving male fertility. Notably, zinc trafficking through the cellular and intracellular membrane is endorsed by precise families of zinc transporters, i.e. SLC39s/ZIPs and SLC30s/ZnTs. However, the expression and function of zinc transporters in the male germ cells were rarely reported. The aim of this study is to determine the crucial zinc transporter responsible for the maintenance of spermatogenesis.Methods: In the present study, we investigated the expression of all fourteen ZIP members in mouse testis and further analyzed the characteristic of ZIP12 expression in testis and spermatozoa by qRT-PCR, immunoblot and immunohistochemistry analyses. To explore the antioxidant role of ZIP12 in spermatogenesis, an obese mouse model fed with high-fat-diet was employed to confirm the correlation between ZIP12 expression level and sperm quality. Furthermore, ZIP12 expression in response to oxidative stress in a spermatogonia cell line, C18-4 cells, was determined and its function involved in regulating cell viability and apoptosis was investigated by RNAi experiment. Results: We initially found that ZIP12 expression in mouse testis was significantly high compared to other members of ZIPs and its mRNA and protein were intensively expressed in testis rather than the other tissues. Importantly, ZIP12 was intensively abundant in spermatogonia and spermatozoa, both in mice and humans. Moreover, ZIP12 expression in testis significantly decreased in obese mice, which associated with reduced sperm zinc content, excessive sperm ROS, poor sperm quality and male subfertility. Similarly, its expression in C18-4 cells significantly declined in response to oxidative stress. Additionally, reduced ZIP12 expression by RNAi associated with a decline in zinc level subsequently caused low cell viability and high cell apoptosis in C18-4 cells. Conclusions: The zinc transporter ZIP12 is intensively expressed in testis, especially in spermatogonia and spermatozoa. ZIP12 may play a key role in maintaining intracellular zinc level in spermatogonia and spermatozoa, by which it resists oxidative stress during spermatogenesis and therefore preserves male fertility.

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Zinc Homeostasis in Bone: Zinc Transporters and Bone Diseases

International Journal of Molecular Sciences ◽

10.3390/ijms21041236 ◽

2020 ◽

Vol 21 (4) ◽

pp. 1236 ◽

Cited By ~ 4

Author(s):

Tongling Huang ◽

Guoyong Yan ◽

Min Guan

Keyword(s):

Cell Types ◽

Bone Diseases ◽

Zinc Transporter ◽

Zinc Homeostasis ◽

Zinc Transporters ◽

Bone Homeostasis ◽

Microstructural Stability ◽

Physiological Processes ◽

Zip Family ◽

Intracellular Compartments

Zinc is an essential micronutrient that plays critical roles in numerous physiological processes, including bone homeostasis. The majority of zinc in the human body is stored in bone. Zinc is not only a component of bone but also an essential cofactor of many proteins involved in microstructural stability and bone remodeling. There are two types of membrane zinc transporter proteins identified in mammals: the Zrt- and Irt-like protein (ZIP) family and the zinc transporter (ZnT) family. They regulate the influx and efflux of zinc, accounting for the transport of zinc through cellular and intracellular membranes to maintain zinc homeostasis in the cytoplasm and in intracellular compartments, respectively. Abnormal function of certain zinc transporters is associated with an imbalance of bone homeostasis, which may contribute to human bone diseases. Here, we summarize the regulatory roles of zinc transporters in different cell types and the mechanisms underlying related pathological changes involved in bone diseases. We also present perspectives for further studies on bone homeostasis-regulating zinc transporters.

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