Function of Metal Transporter ZIP14 as Regulated by Proinflammatory Stimuli

锌是维持健康所必需的微量营养素。锌转运蛋白控制膳食锌的吸收和消除以及细胞功能。该项目的重点是ZIP 14，一种锌转运蛋白，对饮食因素，感染和损伤产生的促炎刺激做出反应。ZIP 14通过其锌转运能力在控制细胞信号传导途径中发挥作用，例如蛋白激酶、蛋白磷酸酶和转录因子调节。在这个项目中，我们确定了小鼠中Zip 14敲除所导致的表型的关键方面。其中包括：有缺陷的肝再生、肠屏障功能减弱伴轻度慢性炎症和血清IL-6水平升高、脂肪细胞肥大伴胰岛素抵抗增加和血清瘦素水平升高。ZIP 14敲除表型的某些方面随年龄增加而增加，有些方面具有性别特异性。ZIP 14的整体功能，通过锌转运，似乎控制炎症。糖尿病和肥胖症是两个严重的世界性医学问题。这些代谢紊乱的特征在于胰岛素抵抗和低度炎症;它们与小鼠中的Zip 14敲除表型共有。该更新项目的假设是，ZIP 14功能障碍导致由肠屏障功能减弱产生的低级促炎性病症，其导致低级慢性炎症、脂肪组织中的胰岛素抵抗和肝脏中的ER应激。该项目将利用全身和组织特异性Zip 14基因敲除小鼠模型。有三个相互关联的具体目标：1。评价ZIP 14维持肠道屏障功能和限制内毒素血症的机制及其对高膳食脂肪和锌治疗干预的反应。2.评估ZIP 14和靶向锌转运对脂肪组织和骨骼肌中炎症信号传导的影响，以及促炎介质对Zip 14基因调控的影响。3.描述Zip 14基因敲除小鼠的肝脏ER应激以及ER应激对Zip 14基因调控的影响。严格的伴随实验将利用Caco-2、HepG 2、AML 12、3 T3-L1和其他细胞进行机制研究。该项目的目标是阐明锌如何通过有针对性的转运活动影响代谢紊乱，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.