Zinc is an essential micronutrient that is required to maintain health. The underlying mechanisms are unknown, but evidence is emerging that zinc has roles in control of signaling pathways, e.g. protein kinases, protein phosphatases and transcription factor phosphorylation. The role is similar to that of calcium where the intracellular ion concentration controls functions. Cells use 24 different zinc transporter proteins derived from two gene families to direct zinc ions to intracellular sites. Some zinc transporter genes respond to the dietary zinc supply and participate in homeostasis, whereas a few others are regulated by cytokines and hormones. We have identified two zinc transporter genes Zip8 and Zip14, which respond to proinflammatory cytokines. ZIP8 mediated transport of Zn2+ from lysosomes of activated T cells maintains CREB in its phosphorylated forum enabling enhanced IFNy transcription. We have demonstrated that Zip14 is induced in hepatocytes upon stimulation by IL6, IL12 and nitric oxide. ZIP14 stimulates Zn2+ transport and has functional outcomes such as interaction with the metal responsive transcription factor, MTF1. The focus of this proposal is to explore the physiologic role of ZIP14 using Zip14 knockout mice. Our hypothesis for this project is that Zip14 is up-regulated by pro-inflammatory conditions and transports zinc for functions in liver, the gastrointestinal tract, and muscle. We will test our hypothesis through three interconnected specific aims: 1. Characterize the phenotype of the Zip14-/- mouse including the effects of Zip14 deletion on metal transport in vivo and in primary cells. 2. Evaluate the involvement of ZIP14 in murine liver regeneration and during inflammatory responses. 3. Physiologic consequences of Zip14 Deletion and Expression in signaling pathways in liver, gastrointestinal tract and muscle during inflammation. The rationale for these experiments is that the ZIP14 (SLC39A14) transporter is responsive to proinflammatory stimuli and hence is dysregulated in many pathophysiologic conditions producing altered zinc signaling. These may benefit from zinc supplementation or drugs designed to influence ZIP14 activity.

Public Health Relevance

There is strong evidence for the biochemical roles of zinc, however, we do not have a clear understanding of how these functions maintain health. Research from this project is relevant to NIH's mission as it addresses how humans acquire and utilize zinc in an integrative manner, via regulated expression of zinc transporters, to effectively maximize functions of this micronutrient in the promotion of health. This project will examine the expression and function of a zinc transporter (ZIP14) that is dramatically up-regulated by pro-inflammatory conditions using a gene knockout model. We will examine how ZIP14 expression in the gastrointestinal tract, liver and muscle influences metal ion transport and specific cell signaling pathways. Since ZIP14 is increased during inflammation zinc supplementation or drugs targeting ZIP14 activity may influence related to inflammation.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Integrative Nutrition and Metabolic Processes Study Section (INMP)
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Maruvada, Padma
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University of Florida
Schools of Earth Sciences/Natur
United States
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Kim, Min-Hyun; Aydemir, Tolunay B; Kim, Jinhee et al. (2017) Hepatic ZIP14-mediated zinc transport is required for adaptation to endoplasmic reticulum stress. Proc Natl Acad Sci U S A 114:E5805-E5814
Aydemir, Tolunay Beker; Kim, Min-Hyun; Kim, Jinhee et al. (2017) Metal Transporter Zip14 (Slc39a14) Deletion in Mice Increases Manganese Deposition and Produces Neurotoxic Signatures and Diminished Motor Activity. J Neurosci 37:5996-6006
Aydemir, Tolunay Beker; Troche, Catalina; Kim, Min-Hyun et al. (2016) Hepatic ZIP14-mediated Zinc Transport Contributes to Endosomal Insulin Receptor Trafficking and Glucose Metabolism. J Biol Chem 291:23939-23951
Troche, Catalina; Aydemir, Tolunay Beker; Cousins, Robert J (2016) Zinc transporter Slc39a14 regulates inflammatory signaling associated with hypertrophic adiposity. Am J Physiol Endocrinol Metab 310:E258-68
Aydemir, Tolunay Beker; Troche, Catalina; Kim, Jinhee et al. (2016) Aging amplifies multiple phenotypic defects in mice with zinc transporter Zip14 (Slc39a14) deletion. Exp Gerontol 85:88-94
Wessels, Inga; Cousins, Robert J (2015) Zinc dyshomeostasis during polymicrobial sepsis in mice involves zinc transporter Zip14 and can be overcome by zinc supplementation. Am J Physiol Gastrointest Liver Physiol 309:G768-78
Guthrie, Gregory J; Aydemir, Tolunay B; Troche, Catalina et al. (2015) Influence of ZIP14 (slc39A14) on intestinal zinc processing and barrier function. Am J Physiol Gastrointest Liver Physiol 308:G171-8
Martin, Alyssa B; Aydemir, Tolunay Beker; Guthrie, Gregory J et al. (2013) Gastric and colonic zinc transporter ZIP11 (Slc39a11) in mice responds to dietary zinc and exhibits nuclear localization. J Nutr 143:1882-8
Aydemir, Tolunay Beker; Chang, Shou-Mei; Guthrie, Gregory J et al. (2012) Zinc transporter ZIP14 functions in hepatic zinc, iron and glucose homeostasis during the innate immune response (endotoxemia). PLoS One 7:e48679
Aydemir, Tolunay Beker; Sitren, Harry S; Cousins, Robert J (2012) The zinc transporter Zip14 influences c-Met phosphorylation and hepatocyte proliferation during liver regeneration in mice. Gastroenterology 142:1536-46.e5

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