Mechanistic insights into the crosstalk between iron metabolism and diabetes

铁代谢与糖尿病之间相互作用的机制见解

• 批准号: 10597528
• 负责人: Peijian He
• 金额: $ 38.15万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10597528
• 关键词: Accounting; Acetylation; Address; Adult; Albumins; Attenuated; Autophagocytosis; Binding; Biopsy; Cessation of life; Cohort Studies; Complications of Diabetes Mellitus; Data; Dependence; Deposition; Development; Diabetes Mellitus; Diabetic mouse; Dietary Iron; Disease; Duodenum; Engineering; Enterocytes; Epithelial Cells; Ferritin; Foundations; Genetically Engineered Mouse; Goals; Hepatic; Hepatocyte; Hyperactivity; Hyperglycemia; Impairment; In Vitro; Incidence; Inflammation; Inherited; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; Intestines; Iron; Iron Overload; Knock-out; Lipid Peroxidation; Liver; Mediating; Membrane; Modality; Modeling; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; PRKCA gene; Pathogenesis; Pathologic; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phosphorylation; Play; Population; Prediabetes syndrome; Production; Protein Kinase C; Publishing; Reactive Oxygen Species; Regulation; Risk Factors; Role; SLC11A2 gene; Serum; Severities; Signal Transduction; Site; Streptozocin; Testing; Type 2 diabetic; Ubiquitination; United States; Up-Regulation; Work; blood glucose regulation; cost estimate; diabetic; diabetic patient; hepcidin; improved; in vivo; inhibitor; insight; insulin sensitivity; intestinal epithelium; iron absorption; iron metabolism; lenalidomide; liver inflammation; liver injury; loss of function; metal transporting protein 1; microscopic imaging; novel; protein activation; receptor; tissue injury; ubiquitin-protein ligase; uptake

In the United States 10.5% of the population has diabetes, accounting for over 3% of deaths and costs an estimated $327 billion in 2017. Iron overload is a strong risk factor both the incidence of diabetes and the progression of diabetic complications. Reduction of iron content improves diabetic complications and insulin sensitivity. Therefore, a better understanding of iron metabolism in diabetes as well as the precise mechanisms underlying the detrimental role of iron could identify novel treatment modalities for diabetic control. Our published work and new preliminary data have shown that hyperactive protein kinase Cα (PKCα) signaling associated with diabetes promotes dietary iron absorption by up-regulating iron importer divalent metal transporter 1 (DMT1) and exporter ferroportin (Fpn). The importance of PKCα in the regulation of intestinal iron absorption is supported by in vivo findings in PKCα-/- mice showing decreased Fpn expression and increased iron retention in intestinal epithelium as well as diminished liver and serum iron. Liver is the primary site of iron deposition, and plays a major role in systemic glucose homeostasis. We further observed that iron loading exacerbates diabetes-associated liver injury and inflammation through induction of hepatocyte ferroptosis. We hypothesize that PKCα is an important regulator of the crosstalk between diabetes and iron metabolism by mediating hyperglycemia-induced iron loading and exacerbated liver injury. We will utilize multiple genetically engineered mouse models, cultured intestinal epithelial cells, and intestinal biopsies of diabetic patients to address the following interconnected specific aims. Aim 1: To understand the mechanisms by which hyperglycemia-PKCα axis increases intestinal iron import. We will demonstrate that cereblon, a substrate receptor of E3 ubiquitin ligase, binds and mediates the ubiquitination of intestinal DMT1. Hyperactive PKCα inhibits DMT1-cereblon interaction and the ubiquitination/internalization of DMT1, enhancing membrane expression of DMT1 and iron uptake. Aim 2: To understand the mechanism by which hyperactive PKCα up-regulates Fpn stability and iron export in the intestine. We will identify a novel mechanism underlying the regulation of Fpn stability, wherein diabetes-induced activation of PKCα increases Fpn phosphorylation and acetylation counteracting hepcidin-induced ubiquitination and degradation of Fpn. Diabetic up-regulation of Fpn and its PKCα dependency will be also examined using duodenal biopsies of diabetic patients. Aim 3: To identify the mechanism by which iron loading exacerbates diabetic liver injury. We will establish that iron loading, in the context of diabetes-induced impairment in autophagy, induces hepatocytes ferroptosis as a novel mechanism exacerbating liver injury in diabetes. We will further test if the loss-of-function of PKCα alleviates liver injury through reduction of hepatic iron content. These studies will highlight the important role of PKCα in diabetes-induced iron loading and tissue injury as well as the precise molecular mechanisms, laying the foundation for the development of novel treatment modalities in diabetic control.

在美国，10.5%的人口患有糖尿病，占死亡人数的3%以上，2017年的成本估计为3270亿美元。铁超载是糖尿病发病率和糖尿病并发症进展的一个重要危险因素。减少铁含量可以改善糖尿病并发症和胰岛素敏感性。因此，更好地了解糖尿病中的铁代谢以及铁有害作用的确切机制可以确定糖尿病控制的新治疗方式。我们发表的工作和新的初步数据表明，与糖尿病相关的高活性蛋白激酶Cα (PKCα)信号通过上调铁进口二价金属转运蛋白1 （DMT1）和出口铁转运蛋白（Fpn）来促进膳食铁的吸收。PKCα-/-小鼠的体内研究结果支持了PKCα在调节肠道铁吸收中的重要性，PKCα-/-小鼠显示肠上皮中Fpn表达减少，铁潴留增加，肝脏和血清铁减少。肝脏是铁沉积的主要部位，在全身葡萄糖稳态中起着重要作用。我们进一步观察到，铁负荷通过诱导肝细胞铁下垂加重了糖尿病相关的肝损伤和炎症。我们假设PKCα通过介导高血糖诱导的铁负荷和加重肝损伤，是糖尿病和铁代谢之间串扰的重要调节因子。我们将利用多种基因工程小鼠模型、培养肠上皮细胞和糖尿病患者肠道活检来解决以下相互关联的特定目标。目的1：了解高血糖- pkc α轴增加肠道铁进口的机制。我们将证明E3泛素连接酶的底物受体小脑结合并介导肠道DMT1的泛素化。过度活跃的PKCα抑制DMT1-小脑相互作用和DMT1的泛素化/内化，增强DMT1的膜表达和铁摄取。目的2：了解过度活跃的PKCα上调肠内Fpn稳定性和铁输出的机制。我们将确定Fpn稳定性调控的新机制，其中糖尿病诱导的PKCα激活增加Fpn磷酸化和乙酰化，抵消hepcidin诱导的Fpn泛素化和降解。糖尿病对Fpn的上调及其对PKCα的依赖性也将通过糖尿病患者的十二指肠活检进行检查。目的3：确定铁负荷加重糖尿病肝损伤的机制。我们将证实，在糖尿病诱导的自噬损伤的背景下，铁负荷诱导肝细胞铁凋亡是一种加剧糖尿病肝损伤的新机制。我们将进一步测试PKCα的功能丧失是否通过降低肝铁含量来减轻肝损伤。这些研究将突出PKCα在糖尿病诱导的铁负荷和组织损伤中的重要作用及其精确的分子机制，为开发新的糖尿病控制治疗方式奠定基础。