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Role of inflammation and cellular stress in the pathogenesis of type 2 diabetes

炎症和细胞应激在 2 型糖尿病发病机制中的作用

基本信息

批准号：
8845196
负责人：
LIANGYOU RUI
金额：
$ 38.1万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8845196
关键词：
Alcoholic Fatty Liver American B-Lymphocytes Binding Blood Glucose CREB1 gene Catecholamines Cell Cycle Cells Cellular Stress Chronic Complex Cyclic AMP Cyclic AMP-Dependent Protein Kinases Cyclic Nucleotides Data Development Diet Disease Dominant-Negative Mutation Equilibrium Fatty Liver Genetic Glucagon Glucocorticoids Glucose Intolerance Hepatic Hepatitis C Hepatocyte Hormones Human Hyperactive behavior Hyperglycemia Inflammation Insulin Insulin Resistance Knockout Mice Kupffer Cells Lead Life Link Liver Liver diseases MAP3K14 gene MAP4K4 gene Mediating Metabolic Metabolism Modeling Molecular Molecular Chaperones Mus Non-Insulin-Dependent Diabetes Mellitus Obese Mice Obesity Osteoclasts Outcome PDE 3B Pathogenesis Pathway interactions Phosphorylation Phosphotransferases Prevalence Production Protein Kinase Regulation Reporting Resistance Role Second Messenger Systems Signal Pathway T-Lymphocyte TNF receptor-associated factor 3 TRAF2 gene Testing Work chaperone machinery cytokine fatty acid oxidation glucose production hormone sensitivity insulin signaling lipid biosynthesis liver inflammation liver metabolism novel overexpression oxidation receptor response second messenger ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): The prevalence of type 2 diabetes is rising rapidly, devastating the lives of millions of Americans. Extensive studies demonstrate that inflammation induces insulin resistance, contributing to type 2 diabetes. Blood glucose levels are determined by a balance between insulin and counterregulatory hormones (e.g. glucagon and catecholamines); however, potential effects of inflammation on glucagon and catecholamine sensitivity have not been studied. Furthermore, signaling pathways that mediate inflammation regulation of hepatic steatosis are poorly defined. Our preliminary study suggests that NF- B-inducing kinase (NIK) is not only a novel regulator of glucagon/catecholamine sensitivity but also defines new pathways that regulate lipogenesis and fatty acid oxidation. NIK is a ubiquitously-expressed Ser/Thr kinase activated by a subset of cytokines, and is required for the activation of the noncanonical NF- B2, but not the canonical IKK /NF- B1, pathway. NIK regulates T cell, B cell, and osteoclast development, but its role in metabolism has not been studied. We observed that NIK enhanced the ability of glucagon to increase cAMP levels and hepatic glucose production (HGP) but did not directly regulate insulin signaling. NIK phosphorylated CREB and increased its stability. CREB mediates glucagon/catecholamine stimulation of HGP and also promotes lipogenesis. NIK null mice developed glucagon resistance and were protected from dietary hyperglycemia and hepatic steatosis. Deletion of NIK decreased lipogenesis and increased oxidation in hepatocytes. Hepatic NIK was aberrantly activated in obesity; CREB and activated NF- B2 levels were increased in the livers of mice with obesity and humans with alcoholic fatty liver disease or hepatitis C. Obesity was associated with an increase in Cdc37 (an Hsp90 cochaperone) that bound to NIK. We propose that hepatic NIK is abnormally activated in obesity due to dysregulation of NIK chaperones (Cdc37/Hsp90), NIK E3 ligases (cIAP1/2), and hepatocyte-Kupffer cell crosstalk. Obesity-associated NIK overactivation increases glucagon/catecholamine sensitivity, HGP, and lipogenesis through CREB, and decreases oxidation through NF- B2. In Aim 1, we will determine whether hepatic NIK cell-autonomously promotes glucagon/catecholamine sensitivity by increasing CREB stability and decreasing cAMP (a second messenger for glucagon and catecholamines) degradation, and whether hepatocyte-specific deletion of NIK protects against type 2 diabetes. In Aim 2, we will determine whether hepatic NIK directly promotes lipogenesis via CREB and suppresses -oxidation via NF- B2, and whether hepatocyte-specific deletion of NIK protects against hepatic steatosis. In Aim 3, we will determine whether obesity is associated with dysregulation of the Cdc37/Hsp90 chaperone machinery, cIAP1/2 E3 ligase activity, and hepatocyte-Kupffer cell crosstalk, and whether these three factors drive NIK hyperactivity. The outcome is expected to lead to new therapies for hepatic steatosis and type 2 diabetes by targeting the NIK pathways.

描述(申请人提供)：2型糖尿病的患病率正在迅速上升，摧毁了数百万美国人的生活。广泛的研究表明，炎症会导致胰岛素抵抗，从而导致2型糖尿病。血糖水平是由胰岛素和反调节激素(如高血糖素和儿茶酚胺)之间的平衡决定的；然而，炎症对高血糖素和儿茶酚胺敏感性的潜在影响尚未被研究。此外，介导肝脏脂肪变性炎症调节的信号通路还不清楚。我们的初步研究表明，核因子-B诱导激酶(NIK)不仅是一种新的胰高血糖素/儿茶酚胺敏感性调节因子，而且还定义了调节脂肪生成和脂肪酸氧化的新途径。NIK是一种普遍表达的丝氨酸/苏氨酸蛋白激酶，被一组细胞因子激活，它是激活非规范的NF-B2途径所必需的，而不是激活规范的IKK/NF-B1途径所必需的。NIK调节T细胞、B细胞和破骨细胞的发育，但其在新陈代谢中的作用尚未被研究。我们观察到，Nik增强了胰高血糖素增加cAMP水平和肝脏葡萄糖产生(HGP)的能力，但不直接调节胰岛素信号。NIK使CREB磷酸化，增加了其稳定性。CREB介导胰高血糖素/儿茶酚胺对HGP的刺激，并促进脂肪生成。Nik基因缺失的小鼠出现了对胰高血糖素的抵抗力，并受到保护，免受饮食中的高血糖和肝脏脂肪变性的影响。Nik的缺失减少了肝细胞中的脂肪生成，增加了肝细胞的氧化。肥胖小鼠和人类酒精性脂肪性肝病或丙型肝炎患者肝脏中的CREB和活化的核因子-B2水平升高，肥胖与与NIK结合的CDc37(一种Hsp90辅伴蛋白)的增加有关。我们认为，由于Nik伴侣(CDC37/Hsp90)、Nik E3连接酶(cIAP1/2)和肝细胞-Kupffer细胞串扰的调节失调，肝脏NIK在肥胖时被异常激活。肥胖相关的NIK过度激活通过CREB增加胰高血糖素/儿茶酚胺敏感性、HGP和脂肪生成，并通过NF-B2减少氧化。在目标1中，我们将确定肝脏Nik细胞是否通过增加CREB的稳定性和降低cAMP(胰高血糖素和儿茶酚胺的第二信使)降解来自主促进胰高血糖素/儿茶酚胺的敏感性，以及肝细胞特异性缺失的Nik是否对2型糖尿病具有保护作用。在目标2中，我们将确定肝脏NIK是否通过CREB直接促进脂肪生成并通过核因子-B2抑制氧化，以及肝细胞特异性缺失NIK是否对肝脏脂肪变性具有保护作用。在目标3中，我们将确定肥胖是否与CDC37/Hsp90伴侣机制失调、cIAP1/2 E3连接酶活性和肝细胞-库普弗细胞串扰有关，以及这三个因素是否导致Nik过度活动。这一结果有望通过靶向Nik通路而导致治疗肝脏脂肪变性和2型糖尿病的新疗法。