Introduction
Significance of zinc in human health
Micro-deficiencies and prevalence of zinc deficiency
Zinc uptake, absorption, and regulators of its bioavailability
Zinc: location, dietary sources, and intake recommendation
Compartments | Levels of zinc |
---|---|
70–250 µg/dL [1] 109–130 µg/dL [30] *62.13–117.72 µg/dL (conversion based on 9.5–18 µM [31]) *78.48 µg/dL–104.64 µg/dL (conversion based on 12–6 µM [29]) 60–120 µg/dL, (59–125 μg/dL for male and 50–103 μg/dL for female) in Bangladesh sample population [32] | |
Tissues | Muscles store about 50 to 60% of the zinc found in the body [3, 29], followed by bones which have about 30 to 36.7% [3, 29], then skin (4.2%) and liver (3.4%) [29] Prostate, pancreas, and bone, have high zinc concentration ranging from 100 to 250 µg/g [33] Heart, brain, and plasma, have comparatively lower concentration, ranging from 1 to 23 µg/g [33] |
Intracellular distribution | 30–40% in nucleus, 50% in cytoplasm, and remaining 10–20% associated with membrane organelles [34, 35] Mitochondria (0.14 pM), the mitochondrial matrix (0.2 pM), the endoplasmic reticulum (0.9 pM-5 nM), and the Golgi apparatus (0.2 pM) [28] |
Total levels in an adult body |
Zinc transporters: ZIPs and ZnTs
Transporter | Tissue and cellular distribution | Stimulus | Response | Mechanism of response |
---|---|---|---|---|
ZnT1 | Metal-response element-binding transcription factor-1 (MTF-1) binds to metal-response elements (MREs) in ZnT1 promoter [45] | |||
Zinc deficiency in HepG2 cells [45] | Decreased ZnT1 protein in HepG2 cells [45] | Endocytosis of cell surface ZnT1 with subsequent degradation via proteasomal or lysosomal pathways [45] | ||
T-cell stimulation by phytohaemagglutinin (immune activation) [47] | Downregulation of ZnT1 mRNA expression in T-cells [47] | – | ||
ZnT2 | Vesicles, secretory granules [43] Retina, mammary glands, small intestine, pancreas, kidney, prostate [44] Two variants: | High zinc levels in mammary glands, prostate, pancreas, small intestine, kidney, and retina [44] | Upregulation of ZnT2 mRNA [44] | |
Glucocorticoid hormone in pancreatic acinar cells [44] | Upregulation of ZnT2 transcription [44] | |||
Prolactin in mammary epithelial cells [44] | Upregulation of ZnT2 transcription [50] | Prolactin induced JAK2/STAT5 signalling pathway [50] | ||
ZnT3 | Protein detected in brain, retina, and pancreas. RNA detected in testis, duodenum, airways and adipose tissue [52] | Downregulation of ZnT3 mRNA expression [54] | Angiotensin II leads to reactive oxidative species which is thought to downregulate ZnT3 [54] | |
ZnT4 | Ubiquitous, with greater abundance in the brain and digestive tract [44] Trans-golgi network, cytoplasmic vesicles, endosomes, lysosomes, and Golgi apparatus [44] | Increased extracellular zinc [43] | Expression may not be affected but ZnT4 trafficking is induced [43] | Trafficking occurs from trans-golgi network to cytoplasmic vesicular compartment in cultured NRK cells [43] |
T-cell stimulation by phytohaemagglutinin (immune activation) [47] | Downregulation of ZnT4 mRNA expression in T-cells [47] | – | ||
Lipopolysaccharide in dendritic cells [46] | Upregulated expression of ZnT4 mRNA transcripts [46] | This is mediated via Toll/interleukin-1 receptor (TRIF) and myeloid differentiation primary response 88 (MyD88) protein in Toll like receptor (TLR) signalling [46] | ||
Granulocyte–macrophage colony-stimulating factor in macrophages [44] | Upregulation of ZnT4 mRNA expression [44] | – | ||
Increased ZnT4 expression [44] | – | |||
ZnT5 | ZnT5 mRNA was found in human endocrine pancreas, prostate and testis [55]. Also found in small intestine [56] Two variants: Variant A is located at the Golgi apparatus [57] | High or low zinc levels [43] | Increased expression [43] Decreased expression [43] | Increased mRNA stability [43] |
Lipopolysaccharide in mice liver [59] | Increased ZnT5 mRNA [59] | – | ||
ZnT6 | Protein detected in mouse brain, lung, small intestine, and kidney [60] | T-cell stimulation by phytohaemagglutinin (immune activation) [47] | Downregulation of ZnT6 mRNA expression in T-cells [47] | – |
Lipopolysaccharide in dendritic cells [46] | Upregulation in ZnT6 mRNA expression [46] | Mediated through the Toll/interleukin-1 receptor (TRIF) and myeloid differentiation primary response 88 (MyD88) protein in Toll-like receptor (TLR) signalling [46] | ||
ZnT7 | In mice, protein was found in lung and small intestine. The mRNA was found in liver, kidney, spleen, heart, brain, small intestine, and lung, with abundant expression in small intestine and liver and less expression in heart [61] Early secretory pathway including Golgi apparatus [44] | T-cell stimulation by phytohaemagglutinin (immune activation) [47] | Downregulation of ZnT7 mRNA expression in T-cells [47] | – |
Granulocyte–macrophage colony-stimulating factor in macrophages [44] | Upregulation of ZnT7 mRNA expression [44] | – | ||
ZnT8 | Downregulation of ZnT8 protein [64] | – | ||
ZnT10 | Early/recycling endosomes, Golgi apparatus but can localise to plasma membrane under high extracellular zinc concentrations [44] | IL-6 in human SH-SY5Y neuroblastoma cells [44] | Decrease in both ZnT10 mRNA and protein levels [66] | |
Downregulation of ZnT10 mRNA expression [54] | Angiotensin II leads to reactive oxidative species which is thought to downregulate ZnT10 [54] | |||
High manganese intake in mice [67] | Increased ZnT10 protein levels in liver and small intestine in male mice [67] | – | ||
High extracellular zinc levels in human 5Y5Y neuroblastoma cells [68] | Downregulation of ZnT10 mRNA [68] | A zinc responsive element (ZRE) may be involved in ZnT10 downregulation [68] |
Transporter | Tissue and cellular distribution | Stimulus | Response | Putative mechanism of response |
---|---|---|---|---|
ZIP1 | Ubiquitous, [69] Plasma membrane [44] Intracellular vesicles [69] | Zinc deficiency in vitro [70] | Increased mouse ZIP1 protein expression in transfected Human embryonic kidney cells (HEK293) [70] (ZIP1 expression was unaffected by zinc in vivo [71]) | |
Cell differentiation of pluripotent mesenchymal stem cells into osteoblast-like cells [73] | Increased ZIP1 protein expression [73] | – | ||
ZIP2 | Dendritic cells, ovaries, skin, liver [79] Plasma membrane [79] | – | ||
Granulocyte macrophage-colony stimulating factor in macrophages [44] | Upregulation of ZIP2 mRNA in macrophages [44] | – | ||
Keratinocyte differentiation [44] | Upregulation of ZIP2 mRNA in differentiating keratinocytes [44] | – | ||
Macrophage polarisation to M2 [75] | Increased ZIP2 mRNA levels [75] | – | ||
ZIP3 | Widespread [69] Plasma membrane but can localise to intracellular compartments after zinc treatment [44] | Zinc deficiency in zebrafish gill [76] | Increased ZIP3 mRNA [76] | – |
Zinc deficiency in vitro [70] | Increased cell surface mouse ZIP3 expression in transfected cells [70] | Reduced rates of ZIP3 endocytosis due to zinc limitation [70] | ||
Prolactin in secretory mammary epithelial cells [77] | Upregulation of ZIP3 mRNA and protein levels [77] | – | ||
ZIP4 | Small intestine and epidermis [79] Plasma membrane [79] | Downregulation of ZIP4 protein [44] | Endocytosis and degradation ubiquitin-proteasomal and lysosomal degradation pathways [44] Zinc repletion can lead to endocytosis and degradation of ZIP4 and ZIP4 mRNA destabilisation [71] | |
Non-transcriptional: ZIP4 mRNA stabilisation [44] | ||||
ZIP5 | ||||
Dietary zinc deficiency in mice [71] | Downregulation of ZIP5 translation [71] | ZIP5 mRNA is associated with polysomes and ZIP5 protein is endocytosed and degraded in enterocytes, acinar cells, and endoderm cells [71] | ||
ZIP6 | Plasma membrane [44] | Lipopolysaccharide in dendritic cells [46] | Downregulation of ZIP6 mRNA expression [46] | Mediated through Toll/interleukin-1 receptor (TRIF) in Toll like receptor (TLR) signalling [46] |
Lipopolysaccharide in mice liver [59] | Increased ZIP6 mRNA [59] | – | ||
Macrophage polarisation to M2 [75] | Increased ZIP6 mRNA [75] | – | ||
ZIP7 | Endoplasmic reticulum and golgi apparatus [44] | Supplemental zinc [43] | Protein abundance of ZIP7 repressed by supplemental zinc [43] | – |
Cellular zinc levels [81] | ZIP7 expression inversely correlate with cellular zinc levels in CLN6 neurons [81] | |||
Macrophage polarisation to M2 [75] | Increased ZIP7 mRNA levels [75] | – | ||
ZIP8 | Plasma membrane (apical in polarised cells) and lysosome [44] | T-cell activation in vitro [83] | Upregulation of ZIP8 expression in human T-cells [83] | – |
Lipopolysaccharide in primary human lung epithelia, monocytes and macrophages [84] | Upregulation of ZIP8 at transcriptional level [84] | NF-κB-dependent mechanism [84] | ||
TNF-alpha in primary human lung epithelia, monocytes and macrophages [84] | Upregulation of ZIP8 at transcriptional level [84] | NF-κB-dependent mechanism [84] | ||
Iron loading in rat H4IIE hepatoma cells [85] | Increase in total and cell surface ZIP8 levels [85] | – | ||
ZIP9 | Widely distributed [79] Plasma membrane, golgi apparatus [44] | Macrophage polarisation to M2 [75] | Increased ZIP9 mRNA levels [75] | – |
ZIP10 | Plasma membrane [43] | Zinc deficiency in zebrafish gill [76] Zinc excess in vitro and in vivo [76] | Upregulation of ZIP10 mRNA [76] Downregulation of ZIP10 mRNA [76] | MTF-1 was suggested to be a negative regulator of ZIP10 expression [76] |
Zinc deficiency in mice brain and liver [86] | Upregulation of ZIP10 transcription [86] | During zinc sufficient conditions, zinc-activated MTF-1 physically blocks Pol II movement through the gene, leading to ZIP10 transcription downregulation [86] | ||
Lipopolysaccharide in dendritic cells [46] | Downregulation of ZIP10 mRNA transcript expression [46] | Mediated through Toll/interleukin-1 receptor (TRIF) in Toll-like receptor (TLR) signalling [46] | ||
Cytokines in early B cell developmental stages [87] | Upregulated ZIP10 transcription [87] | JAK/STAT pathway involving two STAT binding sites in the promoter [87] | ||
Thyroid hormone in intestine and kidney cells in a rat model of hypo- and hyperthyroidism [88] | Increased ZIP10 mRNA and protein levels in hyperthyroid rats and decreased ZIP10 mRNA in hypothyroid rats, when compared to euthyroid rats [88] | – | ||
ZIP11 | Suggested to localise to stomach and colon [82] | Possibly zinc-dependent [89] | ZIP11 expression only modestly decreased in mouse stomach but not large or small intestine in response to dietary zinc deficiency. Upon acute zinc repletion, expression levels were not restored [89] | The presence of many MREs upstream of the first exon of the ZIP11 gene would suggest that ZIP11 expression is upregulated in response to increasing zinc levels; however, this was not seen in practice [44] |
ZIP12 | Plasma membrane [44] | Hypoxia in pulmonary vascular smooth muscle cells [90] | Upregulation of ZIP12 mRNA expression [90] | The Slc39a12 gene contains a hypoxia response element (HRE) encoding HIF-1α- and HIF-2α-binding motifs and is located 1 kb downstream of the ZIP12 transcription start site [90] |
ZIP13 | High iron levels in Drosophila [91] | Upregulation of Drosophila ZIP13 levels [91] | Iron stabilises Drosophila ZIP13 protein, protecting it from degradation [91] | |
ZIP14 | Widespread, liver, bone, and cartilage [79] | Zinc deficiency in mouse liver [92] | Upregulation of ZIP14 expression [92] | Mediated through the UPR [92] |
IL-6 in mouse hepatocytes [59] | Increased ZIP14 mRNA and protein [59] | – | ||
Inflammation induced by turpentine [59] | Increased ZIP14 mRNA [59] | |||
Lipopolysaccharide in mice liver [59] | Increased ZIP14 mRNA [59] | |||
Nitric oxide (induced by IL-1β) in mice liver [93] | Increased ZIP14 transcription [93] | Nitric oxide increases binding of Activator Protein-1 (AP-1) to the ZIP14 promoter [93] | ||
High manganese intake in mice [67] | Upregulated liver ZIP14 expression in both male and female mice, but upregulated small intestine ZIP14 expression only in male mice [67] | – | ||
High extracellular glucose (medium) involving INS-1E cells [94] | Upregulation of ZIP14 mRNA expression [94] | – | ||
Iron loading in rat liver and pancreas, and in hypotransferrinemic mice liver [95] | Upregulated ZIP14 protein expression [95] | – |
Process of zinc uptake, absorption, and circulation
Variability in data regarding the proportion of zinc bound to albumin and α2-macroglobulin in systemic circulation
Regulators of zinc bioavailability
Zinc homeostasis at physiological level
Endogenous zinc secretion
Zinc homeostasis at the cellular level
Effect of high and low zinc on ZnTs: how zinc regulates ZnT expression
Effect of high and low zinc on ZIPs: how zinc regulates ZIP expression
Other regulators of ZnTs and ZIPs
Metallothioneins (MTs): at the interface of physiological and cellular zinc regulation
Acquired zinc deficiency: diagnosis and treatment
Condition/disease | Possible reason for low zinc level and the clinical status |
---|---|
Infection with HIV | Reduced absorption of zinc from foods. These patients often have diarrhoea, which causes excess zinc loss, resulting in low serum zinc [128] |
Chronic kidney disease | Serum zinc levels tend to be on the lower side due to inadequate dietary intake, malabsorption and zinc removal during haemodialysis [129] |
Liver diseases | |
Polycystic ovarian syndrome that increase oestrogen levels [132] | High levels of oestrogen can decrease plasma zinc levels and increase zinc in the liver [130] |
Sickle cell disease or beta thalassaemia | These patients require frequent blood transfusions, which lead to iron loading. The latter is tackled via iron chelation, but this could lead to zinc deficiency, a common complication of sickle cell treatment [133] |