Zinc Transporter ZIP14 Functions in Hepatic Zinc, Iron and Glucose Homeostasis during the Innate Immune Response (Endotoxemia)

PLOS ONE, Dec 2019

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 Zn2+ and non-transferrin-bound Fe2+ in vitro. Using a Zip14−/− mouse model we demonstrated that ZIP14 was essential for control of phosphatase PTP1B activity and phosphorylation of c-Met during liver regeneration. In the current studies, a global screening of ZIP transporter gene expression in response to LPS-induced endotoxemia was conducted. Following LPS, Zip14 was the most highly up-regulated Zip transcript in liver, but also in white adipose tissue and muscle. Using ZIP14−/− mice we show that ZIP14 contributes to zinc absorption from the gastrointestinal tract directly or indirectly as zinc absorption was decreased in the KOs. In contrast, Zip14−/− mice absorbed more iron. The Zip14 KO mice did not exhibit hypozincemia following LPS, but do have hypoferremia. Livers of Zip14−/− mice had increased transcript abundance for hepcidin, divalent metal transporter-1, ferritin and transferrin receptor-1 and greater accumulation of iron. The Zip14−/− phenotype included greater body fat, hypoglycemia and higher insulin levels, as well as increased liver glucose and greater phosphorylation of the insulin receptor and increased GLUT2, SREBP-1c and FASN expression. The Zip14 KO mice exhibited decreased circulating IL-6 with increased hepatic SOCS-3 following LPS, suggesting SOCS-3 inhibited insulin signaling which produced the hypoglycemia in this genotype. The results are consistent with ZIP14 ablation yielding abnormal labile zinc pools which lead to increased SOCS-3 production through G-coupled receptor activation and increased cAMP production as well as signaled by increased pSTAT3 via the IL-6 receptor, which inhibits IRS 1/2 phosphorylation. Our data show the role of ZIP14 in the hepatocyte is multi-functional since zinc and iron trafficking are altered in the Zip14−/− mice and their phenotype shows defects in glucose homeostasis.

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Zinc Transporter ZIP14 Functions in Hepatic Zinc, Iron and Glucose Homeostasis during the Innate Immune Response (Endotoxemia)

Iron and Glucose Homeostasis during the Innate Immune Response (Endotoxemia). PLoS ONE 7(10): e48679. doi:10.1371/journal.pone.0048679 Zinc Transporter ZIP14 Functions in Hepatic Zinc, Iron and Glucose Homeostasis during the Innate Immune Response (Endotoxemia) Tolunay Beker Aydemir 0 Shou-Mei Chang 0 Gregory J. Guthrie 0 Alyssa B. Maki 0 Moon-Suhn Ryu 0 Afife Karabiyik 0 Robert J. Cousins 0 Pratibha V. Nerurkar, College of Tropical Agriculture and Human Resources, University of Hawaii, United States of America 0 1 Food Science and Human Nutrition Department and Center for Nutritional Sciences, College of Agricultural and Life Sciences, University of Florida, Gainesville, Florida, United States of America, 2 Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida , Gainesville, Florida , United States of America 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 Zn2+ and non-transferrin-bound Fe2+ in vitro. Using a Zip142/2 mouse model we demonstrated that ZIP14 was essential for control of phosphatase PTP1B activity and phosphorylation of c-Met during liver regeneration. In the current studies, a global screening of ZIP transporter gene expression in response to LPS-induced endotoxemia was conducted. Following LPS, Zip14 was the most highly upregulated Zip transcript in liver, but also in white adipose tissue and muscle. Using ZIP142/2 mice we show that ZIP14 contributes to zinc absorption from the gastrointestinal tract directly or indirectly as zinc absorption was decreased in the KOs. In contrast, Zip142/2 mice absorbed more iron. The Zip14 KO mice did not exhibit hypozincemia following LPS, but do have hypoferremia. Livers of Zip142/2 mice had increased transcript abundance for hepcidin, divalent metal transporter-1, ferritin and transferrin receptor-1 and greater accumulation of iron. The Zip142/2 phenotype included greater body fat, hypoglycemia and higher insulin levels, as well as increased liver glucose and greater phosphorylation of the insulin receptor and increased GLUT2, SREBP-1c and FASN expression. The Zip14 KO mice exhibited decreased circulating IL-6 with increased hepatic SOCS-3 following LPS, suggesting SOCS-3 inhibited insulin signaling which produced the hypoglycemia in this genotype. The results are consistent with ZIP14 ablation yielding abnormal labile zinc pools which lead to increased SOCS-3 production through G-coupled receptor activation and increased cAMP production as well as signaled by increased pSTAT3 via the IL-6 receptor, which inhibits IRS 1/2 phosphorylation. Our data show the role of ZIP14 in the hepatocyte is multi-functional since zinc and iron trafficking are altered in the Zip142/2 mice and their phenotype shows defects in glucose homeostasis. - Funding: Research described in this report was funded by United States National Institutes of Health Grants DK31127 and DK 94244 (R.J.C.), CALS Alumni Fellowships (A.B. M. and M.-S.R.) and limited support from Boston Family Endowment Funds of the University of Florida. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. Control of mammalian zinc homeostasis is maintained through zinc transporter activity. There are 24 zinc transporters that handle uptake, efflux and intracellular trafficking [1,2]. Expression and function of some of these genes respond to a variety of physiological stimuli and/or dietary conditions, whereas others appear to be constitutively expressed. Some of these zinc transporters may exhibit loose selectivity and thus could contribute to the cellular distribution of other metals such as iron, manganese and cadmium [35]. This possibility would be influenced upon dietary intake levels of the normal metal substrate and environmental exposure of toxic metals or concurrent pathophysiological conditions. The evidence that these transporters participate in the transport of multiple cations is based on in vitro data and have not been tested in integrative systems. Inflammation is initiated by pro-inflammatory cytokines that have profound effects of nutrient metabolism and utilization. During the acute phase response the liver prioritizes nutrient flows toward production of acute phase proteins and alters utilization of substrates for energy [6]. Trace elements are among those nutrients that exhibit atypical metabolic profiles during inflammation and infectious episodes [7,8]. Using a global screening approach for the ZnT and Zip transporter genes, we identified that in the liver of mice treated with turpentine to create a sterile abscess, or lipopolysaccharide (LPS) to mimic initiation of innate immunity, Zip14 was the gene most profoundly up-regulated by these pr (...truncated)


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Tolunay Beker Aydemir, Shou-Mei Chang, Gregory J. Guthrie, Alyssa B. Maki, Moon-Suhn Ryu, Afife Karabiyik, Robert J. Cousins. Zinc Transporter ZIP14 Functions in Hepatic Zinc, Iron and Glucose Homeostasis during the Innate Immune Response (Endotoxemia), PLOS ONE, 2012, 10, DOI: 10.1371/journal.pone.0048679