Function of Metal Transporter ZIP14 as Regulated by Proinflammatory Stimuli

锌是维持身体健康所必需的微量元素。锌转运体控制膳食锌的吸收和消除以及细胞功能。这个项目的重点是ZIP14，一种锌转运蛋白，对饮食因素、感染和损伤产生的促炎刺激作出反应。ZIP14通过其锌转运能力在细胞信号通路的控制中发挥作用，如蛋白激酶、蛋白磷酸酶和转录因子的调控。在这个项目中，我们确定了小鼠中Zip14基因敲除导致的表型的关键方面。这些包括：肝脏再生缺陷，肠道屏障功能减弱，低级别慢性炎症，血清IL-6水平升高，脂肪细胞肥大，胰岛素抵抗增加，血清瘦素水平升高。ZIP14基因敲除表型的某些方面随着年龄的增长而增加，有些方面是性别特异性的。总的来说，ZIP14的功能似乎是通过锌的运输来控制炎症。糖尿病和肥胖是两个严重的世界性医学问题。这些代谢紊乱的特征是胰岛素抵抗和低度炎症；它们与小鼠的Zip14基因敲除表型相同。这个更新项目的假设是，ZIP14功能障碍导致肠道屏障功能减弱而产生低度促炎状态，导致低度慢性炎症、脂肪组织胰岛素抵抗和肝脏内质网应激。该项目将利用全身和组织特异性Zip14敲除小鼠模型。有三个相互关联的具体目标：1。评估ZIP14维持肠道屏障功能、限制内毒素血症及其对高膳食脂肪和锌治疗干预的反应的机制。2. 评估ZIP14和靶向锌转运对脂肪组织和骨骼肌炎症信号传导的影响，以及促炎介质对ZIP14基因调控的影响。3. 描述Zip14基因敲除小鼠肝脏内质网应激及内质网应激对Zip14基因调控的影响。严谨的配套实验将利用Caco-2、HepG2、AML12、3T3-L1等细胞进行机制研究。该项目的目标是阐明锌如何通过靶向运输活动影响代谢紊乱，并阐明新的治疗选择。

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.