Figure 4 - available via license: Creative Commons Attribution 4.0 International
Content may be subject to copyright.
Zip14 2 / 2 mice exhibit normal iron absorption but altered iron homeostasis. (A) WT and Zip14 2 / 2 mice were administered LPS
Source publication
ZIP14 (slc39A14) is a zinc transporter induced in response to pro-inflammatory stimuli. ZIP14 induction accompanies the reduction in serum zinc (hypozincemia) of acute inflammation. ZIP14 can transport Zn(2+) and non-transferrin-bound Fe(2+) in vitro. Using a Zip14(-/-) mouse model we demonstrated that ZIP14 was essential for control of phosphatase...
Similar publications
Acyl-CoA:glycerol-sn-3-phosphate acyltransferase (GPAT) is an enzyme responsible for the rate-limiting step in the synthesis of glycerophospholipids and triacylglycerol (TAG). The enzymes of mammalian species are classified into four isoforms; GPAT1 and GPAT2 are localized in the mitochondrial outer membrane, whereas GPAT3 and GPAT4 are localized i...
Obesity is prevalent in modern society because of a lifestyle consisting of high dietary fat and sucrose consumption combined with little exercise. Among the consequences of obesity are the emerging epidemics of hepatic steatosis and nonalcoholic fatty liver disease (NAFLD). Sterol regulatory element-binding protein-1c (SREBP-1c) is a transcription...
Aim:
Expression of liver low-density lipoprotein receptor (LDLR), a determinant regulator in cholesterol homeostasis, is tightly controlled at multiple levels. The aim of this study was to examine whether proteasome inhibition could affect LDLR expression and LDL uptake in liver cells in vitro.
Methods:
HepG2 cells were examined. Real-time PCR and...
Over the past two decades, a striking increase in the number of people with metabolic syndrome (MS) has taken place worldwide. With the elevated risk of not only diabetes but also cardiovascular morbidity and mortality, there is urgent need for strategies to prevent this emerging global epidemic. The present study was undertaken to investigate the...
This study was designed to determine how estrogens withdrawal during a high-fat (HF) diet regimen affects liver triacylglycerol (TAG) and cholesterol accumulation. Female Sprague-Dawley rats were submitted to a HF (42% energy as fat) or a standard (SD) diet for 6 weeks before being either ovariectomized (Ovx) or sham operated (Sham). Thereafter, Ov...
Citations
... Downregulation of SLC39A14 has been reported in pancreatic islets of patients with T2D (23) as well as mouse models of HFD-induced or db/db-induced obesity (19). Third, our previous studies observed hyperinsulinemia in mice with whole body knockout of Slc39a14 (Zip14 KO) (24)(25)(26). However, whether the hyperinsulinemia phenotype of whole body Zip14 KO mice was due to b cell-specific effects or secondary effects of whole body KO of Zip14 remains unclear. ...
... To generate whole body ZIP14 knockout mice, heterozygous (ZIP14 þ /À ) mice of the C57BL/6;129S5 strain were originally obtained from the Mutant Mouse Research Resource Consortium at The University of California-Davis, and a breeding colony was established at Cornell University (25,27). Transposagen Biopharmaceuticals generated floxed ZIP14 mice. ...
... We were able to show that ZIP14 was highly expressed in pancreatic islets and largely colocalized with INS þ cells (Fig. 1A). This pattern of staining in the mouse pancreas is in agreement with our previous findings (25). Next, we gave wild-type mice a glucose challenge by oral gavage to examine whether pancreatic ZIP14 responds to glucose stimuli. ...
Metal transporter SLC39A14/ZIP14 is downregulated in pancreatic islets of patients with T2D and mouse models of HFD- or db/db-induced obesity. However, the function of ZIP14-mediated intracellular zinc trafficking in β cells is unknown. Our analyses revealed that SLC39A14 is the only Zn transporter expressed abundantly in human β cells besides SLC30A8. Within the β cells, ZIP14 is localized on the endoplasmic reticulum and serves as a negative regulator of insulin secretion, providing a potential therapeutic target for T2D.
... Inflammatory mediators may contribute to reducing serum Zn levels. Indeed, IL-6 can upregulate the Zn importer ZIP-14 in the liver, thus reducing Zn amounts in the serum and increasing the hepatic Zn content ( Figure 2) [63,64]. In addition, in vivo experiments suggested that oral Zn supplementation could be beneficial in RA patients. ...
Dysregulated metal homeostasis is associated with many pathological conditions, including arthritic diseases. Osteoarthritis and rheumatoid arthritis are the two most prevalent disorders that damage the joints and lead to cartilage and bone destruction. Recent studies show that the levels of zinc (Zn) and copper (Cu) are generally altered in the serum of arthritis patients. Therefore, metal dyshomeostasis may reflect the contribution of these trace elements to the disease’s pathogenesis and manifestations, suggesting their potential for prognosis and treatment. Carnosine (Car) also emerged as a biomarker in arthritis and exerts protective and osteogenic effects in arthritic joints. Notably, its zinc(II) complex, polaprezinc, has been recently proposed as a drug-repurposing candidate for bone fracture healing. On these bases, this review article aims to provide an overview of the beneficial roles of Cu and Zn in bone and cartilage health and their potential application in tissue engineering. The effects of Car and polaprezinc in promoting cartilage and bone regeneration are also discussed. We hypothesize that polaprezinc could exchange Zn for Cu, present in the culture media, due to its higher sequestering ability towards Cu. However, future studies should unveil the potential contribution of Cu in the beneficial effects of polaprezinc.
... In a humanized mouse model of the ZIP8 variant, enhanced disease susceptibility was reported in chemically induced colitis (15,16). We have previously shown that deletion of Zip14, the phylogenetically closest relative of Zip8 (17), induced spontaneous intestinal permeability with low-grade chronic inflammation (metabolic endotoxemia), enlarged islets with mild compensatory hyperinsulinemia, and greater body fat with insulin resistance in adipose tissue (6,(18)(19)(20). Importantly, antibiotic treatment reversed the adipocyte phenotype suggesting a potential gut microbial role in the metabolic alterations in the WBKO mice (19). ...
... We found significantly higher levels of FITCdextran in the serum of mice that received the fecal slurry from Zip14 KO mice (Fig. 5B), indicating that the ZIP14shaped microbiome contributed to the development of intestinal permeability. Furthermore, the mice that received the fecal slurry from Zip14 KO were mildly hypoglycemic ( Fig. 5C) with significantly greater percent body fat (Fig. 5D) and lower percent lean mass (Fig. 5E), recapitulating the metabolic phenotype of Zip14 KO mice (20). Collectively, these data indicated that the microbiome shaped by the loss of Zip14 could influence metabolic phenotypes in the host. ...
... ZIP14, besides Zn, can transport Mn and Fe (46). We and others have previously shown that Zn and Mn homeostasis were altered in Zip14 KO mice at a steady state (18,20,42,64), whereas ZIP14-related alterations in iron transport were largely observed in iron overload (65). As both Zn and Mn are essential for microbial growth, the changes we observe in gut microbiome composition could be caused by either Zn-or Mn-deficient intestine of Zip14 KO mice. ...
Metal transporter SLC39A14/ZIP14 is localized on the basolateral side of the intestine, functioning to transport metals from blood to intestine epithelial cells. Deletion of Slc39a14/Zip14 causes spontaneous intestinal permeability with low-grade chronic inflammation, mild hyperinsulinemia, and greater body fat with insulin resistance in adipose. Importantly, antibiotic treatment reverses the adipocyte phenotype of Slc39a14/Zip14 knockout (KO), suggesting a potential gut microbial role in the metabolic alterations in the Slc39a14/Zip14 KO mice. Here, we investigated the hypothesis that increased intestinal permeability and subsequent metabolic alterations in the absence of Zip14 could be in part due to alterations in gut microbial composition. Dietary metals have been shown to be involved in the regulation of gut microbial diversity and composition. However, studies linking the action of intestinal metal transporters to gut microbial regulation are lacking. We showed the influence of deletion of metal transporter Slc39a14/Zip14 on gut microbiome composition and how ZIP14-linked changes to gut microbiome community composition are correlated with changes in host metabolism. Deletion of Slc39a14/Zip14 generated Zn-deficient epithelial cells and luminal content in the entire intestinal tract; a shift in gut microbial composition that partially overlapped with changes previously associated with obesity and inflammatory bowel disease (IBD); increased the fungi/bacteria ratio in the gut microbiome; altered the host metabolome; and shifted host energy metabolism toward glucose utilization. Collectively, our data suggest a potential pre-disease microbial susceptibility state dependent on host gene Slc39a14/Zip14 that contributes to intestinal permeability, a common trait of IBD, and metabolic disorders such as obesity and type-2 diabetes.
... 47,48 Notably, proinflammatory cytokines were capable of enhancing the Zip-14 expression, that is a Zn transporter, and eliminating serum Zn in the liver during inflammation. 49 Last, both infection and inflammatory cascade induce oxidative stress, and in consequence raise serum Cu-ceruloplasmin levels. Likewise, many physiological and pathological pertubations pertaining to the redox state of human systemic albumin substantially affect its binding properties. ...
Background
Sleep disturbance and trace elements imbalance are common features in patients with decompensated cirrhosis, partially sharing similar mechanistic contributors and linking to adverse outcomes. However, there is a paucity of data concerning their relationship.
Objectives
To investigate the association between serum trace elements levels and sleep quality in the context of cirrhosis.
Design
Cross-sectional study.
Methods
We consecutively enrolled 160 patients with decompensated cirrhosis. The sleep disturbance was determined by the Pittsburgh Sleep Quality Index (PSQI > 5). Serum trace elements [magnesium, calcium, iron, copper (Cu), zinc (Zn), lead, and manganese] was measured by inductively coupled plasma mass spectrometry. Association of examined trace elements levels and sleep disturbance was analyzed by multiple linear (global PSQI scores) and multivariate logistic (dichotomized PSQI categories) regression models, respectively.
Results
In total, 91 patients (56.88%) represented PSQI-defined sleep disturbance, characterized by female preponderance, lower body mass index levels, and higher serum Cu levels (all p < 0.05). Looking into its clinical relevance with debilitating conditions, we showed that Cu/Zn ratio (CZr) is significantly higher in cirrhosis with poor sleep quality (1.77 versus 1.48, p = 0.003). Diagnostic performance analysis indicated CZr > 1.62 to exhibit better discrimination relative to respective Cu. Both multiple linear (β = 0.355, p < 0.001) and multivariate logistic regression (odds ratio = 2.364, p = 0.019) identified higher CZr as an independent risk factor associated with sleep disturbance.
Conclusion
Our findings implied an association between higher CZr and the presence of sleep disturbance in patients with decompensated cirrhosis.
... Mainly, the two families of zinc transporters (SLC30/ZNT and SLC39/ZIP) maintain zinc homeostasis in the body, from intestinal absorption/excretion to the distribution of Zn to the target tissues, cells, or subcellular compartments. While the zinc status regulates some zinc transporters for maintaining homeostasis, others respond to cytokines, hormones, secondary messengers, and dietary components with consequent changes in zinc distribution (3)(4)(5)(6)(7). Therefore, zinc metabolism is very dynamic and requires careful assessment in normal-and pathophysiology. ...
Objective
Zinc is an essential micronutrient that is critical for many physiological processes, including glucose metabolism, regulation of inflammation, and intestinal barrier function. Further, zinc dysregulation is associated with an increased risk of chronic inflammatory diseases such as type II diabetes, obesity, and inflammatory bowel disease. However, whether altered zinc status is a symptom or cause of disease onset remains unclear. Common symptoms of these three chronic diseases include the onset of increased intestinal permeability and zinc dyshomeostasis. The specific focus of this work is to investigate how dietary sources of intestinal permeability, such as high sucrose consumption, impact transporter-mediated zinc homeostasis and subsequent zinc-dependent physiology contributing to disease development.
Method
We used in vivo subchronic sucrose treatment, ex vivo intestinal organoid culture, and in vitro cell systems. We analyze the alterations in zinc metabolism and intestinal permeability and metabolic outcomes.
Results
We found that subchronic sucrose treatment resulted in systemic changes in steady-state zinc distribution and increased ⁶⁵Zn transport (blood-to-intestine) along with greater ZIP14 expression at the basolateral membrane of the intestine. Further, sucrose treatment enhanced cell survival of intestinal epithelial cells, activation of the EGFR-AKT-STAT3 pathway, and intestinal permeability.
Conclusion
Our work suggests that subchronic high sucrose consumption alters systemic and intestinal zinc homeostasis linking diet-induced changes in zinc homeostasis to the intestinal permeability and onset of precursors for chronic disease.
... Zinc homeostasis shows rapid and dynamic changes in response to in ammation during an acute-phase response in mammals. It is well known that zinc concentration transitorily is decreased in blood after the administration of several chemical and biological in ammatory agents, such as dibutyryl-cAMP, glucocorticoids hormones, IL-1b, lipopolysaccharide (LPS) and turpentine [1,2,3,4,5]. This hypozincemia results from zinc uptake by different cells, mainly by hepatocytes [2]. ...
... Results obtained in this work agree with other research that reported the upregulation of Zip14 after an in ammatory process. Due to different in ammatory stimuli, the expression of Zip14 is regulated by IL-6, Zip14 gene is considered such as an acute phase reactant [4,5,16,17,18,19]. ...
Objective
Study the signaling pathways involved in hepatic Zip14 expression in rats undergoing abdominal surgery.
Animals
Twenty-five Wistar rats received specific IL-6 and IL-1β signaling pathway inhibitors, were subjected to abdominal surgical stress, and sacrificed at 9-h. Rats administered with the vehicle used with each inhibitor served as controls.
Methods
mRNA-Zip14 transporter was analyzed using real-time RT-PCR, and protein levels were determined by western blot and immunohistochemistry. Intracellular zinc levels were determined by zinquin and dithizone stains.
Results
Rats administered with a pStat3 inhibitor and undergoing 9-h of abdominal surgery presented a decrease of Zip-14 mRNA and its protein level and an intracellular reduction of zinc. Jak2 inhibition decreased Zip-14 mRNA and its protein levels, but intracellular zinc levels did not show changes. Rats administered with an NF-kB inhibitor increased Zip14-mRNA levels without protein and intracellular zinc changes. Inhibition of JNK and MAPp38 did not change Zip-14 mRNA, but the protein level decreased and showed an increase in intracellular zinc.
Conclusion
Results suggest that after abdominal surgery, Zip-14 is one of the most essential zinc transporters involved in the hepatic redistribution of zinc. The main signaling pathway involved in Zip-14 expression is mediated by Jak 2/ stat3, which IL-6 activates.
... Transferrin and non-transferrin bound iron is primarily imported by lung epithelial and immune cells through transferrin receptor 1 (CD71) and divalent metal transporter 1 (DMT1), respectively, with additional iron import also facilitated through the zinc uptake receptors ZRT/IRT-like protein 8 and 14 (ZIP8 and ZIP14) and low-density lipoprotein-related protein 1 (LRP1) [46][47][48][49] (Figure 1). Lung resident macrophages and neutrophils can also import iron through natural resistance-associated macrophage protein 1 (NRAMP1). ...
Chronic obstructive pulmonary disease (COPD) is a debilitating lung disease characterised by airflow limitation, chronic bronchitis, emphysema and airway remodelling. Cigarette smoke is considered the primary risk factor for the development of COPD; however, genetic factors, host responses and infection also play an important role. Accumulating evidence highlights a role for iron dyshomeostasis and cellular iron accumulation in the lung as a key contributing factor in the development and pathogenesis of COPD. Recent studies have also shown that mitochondria, the central players in cellular iron utilisation, are dysfunctional in respiratory cells in individuals with COPD, with alterations in mitochondrial bioenergetics and dynamics driving disease progression. Understanding the molecular mechanisms underlying the dysfunction of mitochondria and cellular iron metabolism in the lung may unveil potential novel investigational avenues and therapeutic targets to aid in the treatment of COPD.
... Whole Body Zip14−/− (WB-KO) mice were developed, characterized, and backcrossed as reported previously [18]. Wild-type (WT) mice of the same strain were used as controls. ...
Integration of non-coding RNAs and miRNAs with physiological processes in animals, including nutrient metabolism, is an important new focus. Twenty-three transporter proteins control cellular zinc homeostasis. The transporter Zip14 (Slc39a14) responds to proinflammatory stimuli. Using enterocyte-specific Zip14 knockout mice and RNA-sequencing and quantitative polymerase chain reaction (qPCR), we conducted transcriptome profiling of proximal small intestine, where Zip14 is highly expressed, using RNA from whole intestine tissue, isolated intestinal epithelial cells (IECs) and intestinal organoids. H19, U90926, Meg3, Bvht, Pvt1, Neat1 and miR-7027 were among the most highly expressed genes. Enterocyte-specific deletion of Zip14 demonstrated tissue specific expression, as such these changes were not observed with skeletal muscle. Chromatin immunoprecipitation (ChIP) assays of chromatin from isolated intestinal epithelial cells showed that enterocyte-specific Zip14 deletion enhanced binding of proinflammatory transcription factors (TFs) signal transducer and activator of transcription 3 (STAT3) and nuclear factor kappa beta (NF-ĸβ) to promoters of H19, Meg3 and U90926. We conclude enterocyte-specific ablation of Zip14 restricts changes in those RNAs to the intestine. Binding of proinflammatory TFs, NF-ĸβ and STAT3 to the H19, Meg3 and U90926 promoters is consistent with a model where Zip14 ablation, leads to increased TF occupancy, allowing epigenetic regulation of specific lncRNA genes.
... This is primarily facilitated by upregulation of the zinc transporter ZIP 14, which is induced in an IL-6-dependent manner. This occurs rapidly within only a few hours and leads to zinc accumulation in the liver and hypozincemia in the serum, respectively [99,100]. ...
During the last few decades, the micronutrient zinc has proven to be an important metal ion for a well-functioning immune system, and thus also for a suitable immune defense. Nowadays, it is known that the main cause of zinc deficiency is malnutrition. In particular, vulnerable populations, such as the elderly in Western countries and children in developing countries, are often affected. However, sufficient zinc intake and homeostasis is essential for a healthy life, as it is known that zinc deficiency is associated with a multitude of immune disorders such as metabolic and chronic diseases, as well as infectious diseases such as respiratory infections, malaria, HIV, or tuberculosis. Moreover, the modulation of the proinflammatory immune response and oxidative stress is well described. The anti-inflammatory and antioxidant properties of zinc have been known for a long time, but are not comprehensively researched and understood yet. Therefore, this review highlights the current molecular mechanisms underlying the development of a pro-/ and anti-inflammatory immune response as a result of zinc deficiency and zinc supplementation. Additionally, we emphasize the potential of zinc as a preventive and therapeutic agent, alone or in combination with other strategies, that could ameliorate infectious diseases.
... Metallothionein is normally found in the cytoplasm, known as defense proteins that work to reduce metal toxicity, etc., and its localization to the nucleus occurs with cell proliferation and differentiation [24]. Zinc, cadmium, corticosteroids, endotoxin, reactive oxygen species, TNFα, IL-6, and interferon are known as metallothionein-inducing substances [25][26][27]. Metallothionein has antioxidant, cytoprotective, and hepatocyte regeneration-promoting effects on hepatocytes, but in the presence of zinc deficiency, the free radical scavenging effect of metallothionein is reduced and oxidative stress is enhanced, resulting in prolonged inflammation and inhibition of apoptosis [28]. Zinc deficiency is also thought to be associated with an increased risk of liver carcinogenesis and development of liver fibrosis [29]. ...
Zinc is an essential trace element for the maintenance of life because it acts as a center of activity or cofactor for hundreds of enzymes. Zinc deficiency causes a variety of symptoms, including anemia, dermatitis, stomatitis, alopecia, bedsores, decreased appetite, impaired growth, gonadal dysfunction, susceptibility to infection, and taste disorders, etc. In March 2017, zinc acetate hydrate, which had been approved for Wilson disease in Japan, received an additional indication for hypozincemia. Hypozincemia is frequently observed in patients with chronic liver disease (CLD), especially cirrhosis, and it has recently been shown that hypozincemia is closely related to the development of liver fibrosis and increased risk of liver carcinogenesis, in addition to the appearance of various subjective symptoms. Moreover, hypozincemia in CLD may be associated with sarcopenia (i.e., decrease in muscle strength and muscle mass) and frailty (i.e., vulnerability), which receive much attention these days. It is assumed that treatment with zinc acetate hydrate will become widespread in patients with CLD. Zinc acetate hydrate may also have potential for improving sarcopenia in patients with CLD. This review primarily outlines the significance of zinc in patients with CLD.
