Zinc is an essential micronutrient that is required to maintain health. Zinc transporters control absorption and elimination of dietary zinc and cellular functions. This project is focused on ZIP14, a zinc transporter that responds to proinflammatory stimuli produced by dietary factors, infection and injury. ZIP14, through its zinc transporting capacity has roles in control of cellular signaling pathways, e.g. protein kinases, protein phosphatases and transcription factor regulation. During this project we identified key aspects of the phenotype resulting from knockout of Zip14 in mice. These include: defective liver regeneration, diminished intestinal barrier function with low grade chronic inflammation and increased levels of serum IL-6, adipocyte hypertrophy with increased insulin resistance and increased levels of serum leptin. Some aspects of the ZIP14 knockout phenotype increase with age and some are gender-specific. Overall ZIP14 function, via zinc transport, appears to control inflammation. Two critical worldwide medical problems are diabetes and obesity. These metabolic disorders are characterized by insulin resistance and low-grade inflammation; they are shared with the Zip14 knockout phenotype in mice. The hypothesis for this renewal project is that ZIP14 dysfunction leads to low grade proinflammatory conditions produced by diminished intestinal barrier function that causes low grade chronic inflammation, insulin resistance in adipose tissue and ER stress in liver. The project will utilize whole-body and tissue-specific Zip14 knockout mouse models. There are three interconnected Specific Aims: 1. Evaluate the mechanism through which ZIP14 operates to maintain intestinal barrier function and limits endotoxemia and its responsiveness to high dietary fat and therapeutic interventions with zinc. 2. Evaluate the influence of ZIP14 and targeted zinc transport on inflammatory signaling in adipose tissue and skeletal muscle and the influence of proinflammatory mediators on Zip14 gene regulation. 3. Characterize hepatic ER stress in Zip14 knockout mice and the influence of ER stress on Zip14 gene regulation. Rigorous companion experiments will utilize Caco-2, HepG2, AML12, 3T3-L1 and other cells for mechanistic studies. The goal of the project is to clarify how zinc, through targeted transport activity, can influence metabolic disorders and illuminate new therapeutic options.
Zinc provided from the diet performs many functions that influence well-being. Health benefits include control of inflammation, resistance to infections and regulation of metabolic disorders such as diabetes and obesity. A zinc transporter that regulates body zinc pathways during inflammation is the focus of this project and is therefore relevant to the NIH?s overarching mission in seeking to enhance health, lengthen life, and reduce illness and disability.
|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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