Influence of ZIP14 (slc39A14) on intestinal zinc processing and barrier function

Guthrie, Gregory; Aydemir, Tolunay Beker; Troche, Catalina; Martin, Alyssa B; Chang, Soo-Eun; Cousins, Robert J.

doi:10.1152/ajpgi.00021.2014

Cited by 92 publications

(83 citation statements)

References 38 publications

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“…These in vitro data are compatible with the hypothesis that less functional cellular zinc is available in adipocytes of KO mice. This finding is indicative of the "zinc trap" hypothesis associated with Zip14 ablation that we advanced earlier (25) in mouse intestine. Zip14 siRNA clearly resulted in increased expression of Il-6 and Tnf␣ (P Ͻ 0.05) and to a lesser extent Il-1␤ (Fig.…”

Section: Zip14 Is Highly Expressed In Wat During Acute Inflammationsupporting

confidence: 67%

“…However, a prolonged inflammatory response will eventually lead to metabolic alterations within WAT. Acute inflammation impacts ZIP14 expression in a tissue-specific manner (3,25). From the experiments described to this point, it has been established that adipose ZIP14 is highly responsive to LPS.…”

Section: Discussionmentioning

confidence: 98%

“…Knockout (KO) of ZIP14 results in a variety of unique phenotypes. We have reported previously that mice lacking ZIP14 have impaired liver zinc uptake (3) and elevated levels of serum endotoxin (25). Previously, Aydemir et al (3) reported an increase in fat/lean ratios in Zip14-KO mice, a finding that led to our further investigation of ZIP14 in adipose function.…”

mentioning

confidence: 82%

“…It is apparent that ZIP14 is highly induced by endotoxin in WAT. Previously, we established that global Zip14-KO impaired intestinal barrier function, which precipitates systemic endotoxemia (25). Therefore, we hypothesized that systemic endotoxemia would enhance the inflammatory status of adipose tissue.…”

Section: Zip14 Is Highly Expressed In Wat During Acute Inflammationmentioning

confidence: 96%

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Zinc transporter Slc39a14 regulates inflammatory signaling associated with hypertrophic adiposity

Troche

Aydemir

Cousins

2016

American Journal of Physiology-Endocrinology and Metabolism

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Troche C, Beker Aydemir T, Cousins RJ. Zinc transporter Slc39a14 regulates inflammatory signaling associated with hypertrophic adiposity. Am J Physiol Endocrinol Metab 310: E258 -E268, 2016. First published December 8, 2015 doi:10.1152/ajpendo.00421.2015.-Zinc is a signaling molecule in numerous metabolic pathways, the coordination of which occurs through activity of zinc transporters. The expression of zinc transporter Zip14 (Slc39a14), a zinc importer of the solute carrier 39 family, is stimulated under proinflammatory conditions. Adipose tissue upregulates Zip14 during lipopolysaccharide-induced endotoxemia. A null mutation of Zip14 (KO) revealed that phenotypic changes in adipose include increased cytokine production, increased plasma leptin, hypertrophied adipocytes, and dampened insulin signaling. Adipose tissue from KO mice had increased levels of preadipocyte markers, lower expression of the differentiation marker (PPAR␥), and activation of NF-B and STAT3 pathways. Our overall hypothesis was that ZIP14 would play a role in adipocyte differentiation and inflammatory obesity. Global Zip14 KO causes systemic endotoxemia. The observed metabolic changes in adipose metabolism were reversed when oral antibiotics were administrated, indicating that circulating levels of endotoxin were in part responsible for the adipose phenotype. To evaluate a mechanism, 3T3-L1 cells were differentiated into adipocytes and treated with siRNA to knock down Zip14. These cells had an impaired ability to mobilize zinc, which caused dysregulation of inflammatory pathways (JAK2/STAT3 and NF-B). The Zip14 deletion may limit the availability of intracellular zinc, yielding the unique phenotype of inflammation coupled with hypertrophy. Taken together, these results suggest that aberrant zinc distribution observed with Zip14 ablation impacts adipose cytokine production and metabolism, ultimately increasing fat deposition when exposed to endotoxin. To our knowledge, this is the first investigation into the mechanistic role of ZIP14 in adipose tissue regulation and metabolism.

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Section: Zip14 Is Highly Expressed In Wat During Acute Inflammationsupporting

confidence: 67%

Section: Discussionmentioning

confidence: 98%

mentioning

confidence: 82%

Section: Zip14 Is Highly Expressed In Wat During Acute Inflammationmentioning

confidence: 96%

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Zinc transporter Slc39a14 regulates inflammatory signaling associated with hypertrophic adiposity

Troche

Aydemir

Cousins

2016

American Journal of Physiology-Endocrinology and Metabolism

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“…expressed in the intestine (57), its expression is enriched on the basolateral membrane (25). Moreover, ZIP14-mediated iron uptake in vitro is optimal at pH 7.5 (Ref.…”

Section: G642 Role Of Intestinal Dmt1 In Metal Homeostasismentioning

confidence: 99%

Intestinal DMT1 is critical for iron absorption in the mouse but is not required for the absorption of copper or manganese

Shawki

Anthony

Nose

et al. 2015

American Journal of Physiology-Gastrointestinal and Liver Physi

120

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Divalent metal-ion transporter-1 (DMT1) is a widely expressed iron-preferring membrane-transport protein that serves a critical role in erythroid iron utilization. We have investigated its role in intestinal metal absorption by studying a mouse model lacking intestinal DMT1 (i.e., DMT1 int/int ). DMT1 int/int mice exhibited a profound hypochromicmicrocytic anemia, splenomegaly, and cardiomegaly. That the anemia was due to iron deficiency was demonstrated by the following observations in DMT1 int/int mice: 1) blood iron and tissue nonheme-iron stores were depleted; 2) mRNA expression of liver hepcidin (Hamp1) was depressed; and 3) intraperitoneal iron injection corrected the anemia, and reversed the changes in blood iron, nonheme-iron stores, and hepcidin expression levels. We observed decreased total iron content in multiple tissues from DMT1 int/int mice compared with DMT1 ϩ/ϩ mice but no meaningful change in copper, manganese, or zinc. DMT1 int/int mice absorbed 64 Cu and 54 Mn from an intragastric dose to the same extent as did DMT1 ϩ/ϩ mice but the absorption of 59 Fe was virtually abolished in DMT1 int/int mice. This study reveals a critical function for DMT1 in intestinal nonheme-iron absorption for normal growth and development. Further, this work demonstrates that intestinal DMT1 is not required for the intestinal transport of copper, manganese, or zinc. copper absorption; iron deficiency; iron-deficiency anemia; iron-refractive iron-deficiency anemia; manganese absorption; SLC11A2; zinc metabolism IRON DEFICIENCY is the most prevalent micronutrient deficiency worldwide (4, 50). Its deficiency leads to irondeficiency anemia, and to neurological and developmental disorders in children (3, 4). Since there exists no regulated mechanism for the excretion of iron, regulation of the whole body iron economy is achieved by tightly controlling absorption of the metal (21). Failure to regulate iron absorption in a manner appropriate to iron status is characteristic of several hereditary iron-overload disorders and iron-refractive iron-deficiency anemia (12,19,21).Divalent metal-ion transporter-1 (DMT1; reviewed in Ref. 52) is a widely expressed mammalian proton-coupled iron transporter (23,38). Mice in which the SLC11A2 gene coding for DMT1 was globally inactivated (i.e., SLC11A2 Ϫ/Ϫ ) exhibited a severe hypochromic-microcytic anemia and did not survive more than 7 days (22). A critical role for DMT1 in erythroid iron acquisition was confirmed by the following observations: 1) transfusion of red blood cells, but not parenteral iron injections, improved survival of SLC11A2 Ϫ/Ϫ mice; and 2) lethal dose-irradiated wild-type mice into which the investigators transplanted hematopoietic stem cells from SLC11A2 Ϫ/Ϫ mice exhibited defective erythropoiesis (22). The microcytic (mk) mouse and Belgrade (b) rat models, inbred strains that harbor a Gly185¡Arg mutation in DMT1 (17, 18), also exhibited an anemia phenotype. Parenteral iron injections partially improved the condition, and tissue or vesicle preparations from the m...

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Zinc Transport in the Mammalian Intestine

Hennigar

McClung

2018

Comprehensive Physiology

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Zinc homeostasis is primarily maintained in the proximal small intestine. Sophisticated transport mechanisms maintain zinc homeostasis by controlling the uptake and efflux of zinc in intestinal absorptive epithelial cells. Zrt‐irt‐like proteins (ZIPs) and zinc transporters (ZnTs) function in a coordinated manner to assimilate zinc from the lumen of the small intestine, subcellular compartments within the absorptive epithelial cell, and circulation. This manuscript details zinc transport mechanisms in the mammalian small intestine, along with factors that regulate these processes and consequences of dysregulated zinc transport. © 2019 American Physiological Society. Compr Physiol 9:59‐74, 2019.

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Influence of ZIP14 (slc39A14) on intestinal zinc processing and barrier function

Cited by 92 publications

References 38 publications

Zinc transporter Slc39a14 regulates inflammatory signaling associated with hypertrophic adiposity

Zinc transporter Slc39a14 regulates inflammatory signaling associated with hypertrophic adiposity

Intestinal DMT1 is critical for iron absorption in the mouse but is not required for the absorption of copper or manganese

Zinc Transport in the Mammalian Intestine

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