The Physiological, Biochemical, and Molecular Roles of Zinc Transporters in Zinc Homeostasis and Metabolism

2015 ◽  
Vol 95 (3) ◽  
pp. 749-784 ◽  
Author(s):  
Taiho Kambe ◽  
Tokuji Tsuji ◽  
Ayako Hashimoto ◽  
Naoya Itsumura
Keyword(s):  
Zinc Transporter ◽  
Zinc Homeostasis ◽  
Zinc Transporters ◽  
Whole Body ◽  
Biological Processes ◽  
Transport Mechanisms ◽  
Intercellular Signaling ◽  
Zip Transporters ◽  
Related Proteins ◽  
Made In

Zinc is involved in a variety of biological processes, as a structural, catalytic, and intracellular and intercellular signaling component. Thus zinc homeostasis is tightly controlled at the whole body, tissue, cellular, and subcellular levels by a number of proteins, with zinc transporters being particularly important. In metazoan, two zinc transporter families, Zn transporters (ZnT) and Zrt-, Irt-related proteins (ZIP) function in zinc mobilization of influx, efflux, and compartmentalization/sequestration across biological membranes. During the last two decades, significant progress has been made in understanding the molecular properties, expression, regulation, and cellular and physiological roles of ZnT and ZIP transporters, which underpin the multifarious functions of zinc. Moreover, growing evidence indicates that malfunctioning zinc homeostasis due to zinc transporter dysfunction results in the onset and progression of a variety of diseases. This review summarizes current progress in our understanding of each ZnT and ZIP transporter from the perspective of zinc physiology and pathogenesis, discussing challenging issues in their structure and zinc transport mechanisms.

Does Zinc Absorption Reflect Zinc Status?

2010 ◽  
Vol 80 (45) ◽  
pp. 300-306 ◽  
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.

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

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
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.

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

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.

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

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.

scholarly journals Zinc Homeostasis in Bone: Zinc Transporters and Bone Diseases

2020 ◽  
Vol 21 (4) ◽  
pp. 1236 ◽  
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.

scholarly journals The role of zinc transporter proteins as predictive and prognostic biomarkers of hepatocellular cancer

PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e12314
Author(s):  
Ceylan V. Bitirim
Keyword(s):  
Tumor Progression ◽  
Zinc Deficiency ◽  
Zinc Level ◽  
Zinc Transporter ◽  
Tumor Formation ◽  
Zinc Homeostasis ◽  
Zinc Transporters ◽  
Transporter Proteins ◽  
Grade Ii ◽  
Cellular Zinc

Identification of the key processes involved in the tumor progression, malignancy and the molecular factors which are responsible for the transition of the cirrhotic cells to the tumor cells, contribute to the detection of biomarkers for diagnosis of hepatocellular carcinoma (HCC) at an early stage. According to clinical data, HCC is mostly characterized by a significant decrease in zinc levels. It is strongly implied that zinc deficiency is the major event required in the early stages of tumor formation and development of malignancy. Due to this reason, the definition of the molecular players which have a role in zinc homeostasis and cellular zinc level could give us a clue about the transition state of the cirrhosis to hepatic tumor formation. Despite the well-known implications of zinc in the development of HCCthe correlation of the expression of zinc transporter proteins with tumor progression and malignancy remain largely unknown. In the present study, we evaluated in detail the relationship of zinc deficiency on the prognosis of early HCC patients. In this study, we aimed to test the potential zinc transporters which contribute tothe transformation of cirrhosis to HCCand the progression of HCC. Among the 24 zinc transporter proteins, the proteins to be examined were chosen by using Gene Expression Profiling Interactive Analysis (GEPIA) webpage and RNA-seq analysis using TCGA database. ZIP14 and ZIP5 transporters were found as common differentially expressed genes from both bioinformatic analyses. ZnT1, ZnT7 and ZIP7 transporters have been associated with tumor progression. Relative abundance of ZnT1, ZIP5 and ZIP14 protein level was determined by immunohistochemistry (IHC) in surgically resected liver specimens from 16 HCC patients at different stages. IHC staining intensity was analyzed by using ImageJ software and scored with the histological scoring (H-score) method. The staining of ZnT1 was significantly higher in Grade III comparing to Grade II and Grade I. On the contrary, ZIP14 staining decreased almost 10-foldcomparing to Grade Iand Grade II. ZIP5 staining was detected almost 2-fold higher in cirrhosis than HCC. But ZnT1 staining was observed almost 3-fold lower in cirrhosis comparing to HCC. Intracellular free zinc level was measured by flow cytometry in Hep40 and Snu398 cells using FluoZin-3 dye. The intracellular free zinc level was almost 9-fold decreased in poor differentiated Snu398 HCC cells comparing to well differentiated Hep40 HCC cells.This report establishes for the first time the correlation between the expression pattern of ZIP14, ZnT1 and ZIP5 and significant zinc deficiency which occurs concurrently with the advancing of malignancy. Our results provide new molecular insight into ZnT1, ZIP14 and ZIP5 mediated regulation of cellular zinc homeostasis and indicate that zinc transporters might be important factors and events in HCC malignancy, which can lead to the development of early biomarkers.

scholarly journals The Effects of Short-Term Zinc Feeding on Zinc Absorption and Zinc Transporter Expression in the Small Intestine of Mice

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 1827-1827
Author(s):  
Cassandra Olson ◽  
Alyssa Kelley ◽  
James McClung ◽  
Stephen Hennigar
Keyword(s):  
Small Intestine ◽  
Zinc Transporter ◽  
Zinc Homeostasis ◽  
Zinc Transporters ◽  
Zinc Absorption ◽  
Intestinal Segment ◽  
Deficient Diet ◽  
Us Government ◽  
Zinc Deficient Diet ◽  
Transporter Expression

Abstract Objectives Zinc homeostasis is primarily maintained by zinc transporters that regulate zinc uptake and efflux in the small intestine; however, no study to date has comprehensively examined zinc transporter expression in the small intestine of mice fed varying levels of dietary zinc. The objective of this study was to determine the effects of zinc absorption and zinc transporter expression in the small intestine of mice fed varying levels of zinc for one week. Methods Seven-week-old male C57BL/6 J mice were randomized to either a standard AIN-93 G diet containing 30 ppm zinc (zinc adequate) or modified AIN-93 G diets containing <1 ppm (zinc deficient) or 100 ppm zinc (zinc supplemented) for one week (n = 5–10/diet). Mice were given an oral gavage containing a slurry of zinc deficient feed and 10 μg 67 Zn; plasma isotope appearance was determined 6-h later by ICP-MS. Gene expression of Slc39a1–14 and Slc30a1–10 was determined in each intestinal segment (duodenum, jejunum, and ileum) by RT-qPCR. Results Plasma and liver zinc concentrations were not different after one week of feeding (P > 0.05 for both). Plasma appearance of 67 Zn was greater in mice fed the zinc deficient (mean ± SD: 0.36 ± 0.03 ng/mL) compared to the zinc adequate (0.22 ± 0.03 ng/mL) and zinc supplemented (0.22 ± 0.03 ng/mL, P < 0.0001 for both) diets. With the exception of Slc39a12, Slc30a3, and Slc30a8, the remaining zinc transporters were expressed across all diets and intestinal segments. Expression of Slc39a1, Slc39a4, Slc39a5, Slc39a7, Slc39a9, Slc39a11, Slc39a14, Slc30a2, Slc30a4, Slc30a5, Slc30a6, and Slc30a9 changed with diet (Pdiet < 0.05 for all); expression of Slc39a3, Slc39a7, Slc39a9 and Slc30a5 changed by intestinal segment (Psegment < 0.05 for all). Of those transporters expressed, Slc39a4 was positively associated with plasma appearance of 67 Zn (r = 0.645, P < 0.0001) and increased 7-fold in mice consuming the zinc deficient diet compared to the zinc adequate and zinc supplemented diets (P < 0.0001 for both). Conclusions Although most zinc transporters are expressed in the small intestine and likely function in concert, fluctuations in fractional zinc absorption are positively correlated with Slc39a4 expression in the small intestine. Funding Sources The views expressed herein are those of the authors and do not reflect official policy of the Army, DoD, or US Government. Supported by MRDC.

scholarly journals Expression Analysis of Zinc Transporters in Nervous Tissue Cells Reveals Neuronal and Synaptic Localization of ZIP4

2021 ◽  
Vol 22 (9) ◽  
pp. 4511
Author(s):  
Chiara A. De Benedictis ◽  
Claudia Haffke ◽  
Simone Hagmeyer ◽  
Ann Katrin Sauer ◽  
Andreas M. Grabrucker
Keyword(s):  
Brain Function ◽  
Zinc Homeostasis ◽  
Zinc Transporters ◽  
Excitatory Synapses ◽  
Short Term ◽  
Synaptic Localization ◽  
Zinc Levels ◽  
Rat Astrocyte ◽  
Cellular Zinc ◽  
The Brain

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.

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

2008 ◽  
Vol 28 (6) ◽  
pp. 406-413 ◽  
Author(s):  
Hui Shen ◽  
Haihong Qin ◽  
Junsheng Guo
Keyword(s):  
Zinc Homeostasis ◽  
Zinc Transporters

scholarly journals Growth and zinc homeostasis in the severely Zn-deficient rat

1984 ◽  
Vol 52 (3) ◽  
pp. 545-560 ◽  
Author(s):  
R. Giugliano ◽  
D. J. Millward
Keyword(s):  
Body Weight ◽  
Growth Rates ◽  
Control Diet ◽  
Rate Of Change ◽  
Zinc Homeostasis ◽  
Whole Body ◽  
Zn Deficiency ◽  
Control Groups ◽  
Body Weights ◽  
Cyclic Changes

1. Male weanling rats were fed on diets either adequate (55 mg/kg), or severely deficient (0.4 mg/kg) in zinc, either ad lib. or in restricted amounts in four experiments. Measurements were made of growth rates and Zn contents of muscle and several individual tissues.2. Zn-deficient rats exhibited the expected symptoms of deficiency including growth retardation, cyclic changes in food intake and body-weight.3. Zn deficiency specifically reduced whole body and muscle growth rates as indicated by the fact that (a) growth rates were lower in ad lib.-fed Zn-deficient rats compared with rats pair-fed on the control diet in two experiments, (b) Zn supplementation increased body-weights of Zn-deficient rats given a restricted amount of diet at a level at which they maintained weight if unsupplemented, (c) Zn supplementation maintained body-weights of Zn-deficient rats fed a restricted amount of diet at a level at which they lost weight if unsupplemented (d) since the ratio, muscle mass:body-weight was lower in the Zn-deficient rats than in the pair-fed control groups, the reduction in muscle mass was greater than the reduction in body-weight.4. Zn concentrations were maintained in muscle, spleen and thymus, reduced in comparison to some but not all control groups in liver, kidney, testis and intestine, and markedly reduced in plasma and bone. In plasma, Zn concentrations varied inversely with the rate of change of body-weight during the cyclic changes in body-weight.5. Calculation of the total Zn in the tissues examined showed a marked increase in muscle Zn with a similar loss from bone, indicating that Zn can be redistributed from bone to allow the growth of other tissues.6. The magnitude of the increase in muscle Zn in the severely Zn-deficient rat, together with the magnitude of the total losses of muscle tissue during the catabolic phases of the cycling, indicate that in the Zn-deficient rat Zn may be highly conserved in catabolic states.

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