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

• 批准号: 8677879
• 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
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8677879
• 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

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（由申请人提供）：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，炎症诱导胰岛素抵抗，导致2型糖尿病。血糖水平由胰岛素和反调节激素（例如胰高血糖素和儿茶酚胺）之间的平衡决定;然而，尚未研究炎症对胰高血糖素和儿茶酚胺敏感性的潜在影响。此外，介导肝脏脂肪变性的炎症调节的信号传导途径尚不清楚。我们的初步研究表明，NF-B诱导激酶（NIK）不仅是胰高血糖素/儿茶酚胺敏感性的新调节剂，而且还定义了调节脂肪生成和脂肪酸氧化的新途径。NIK是一种广泛表达的Ser/Thr激酶，由一组细胞因子激活，是激活非经典NF- B2途径所必需的，但不是经典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，但其在代谢中的作用尚未研究。我们观察到NIK增强胰高血糖素增加cAMP水平和肝葡萄糖产生（HGP）的能力，但不直接调节胰岛素信号传导。NIK使CREB磷酸化并增加其稳定性。CREB介导胰高血糖素/儿茶酚胺刺激HGP，也促进脂肪生成。NIK基因敲除小鼠产生胰高血糖素抗性，并免受饮食性高血糖症和肝脂肪变性的影响。在肝细胞中，NIK的缺失降低了脂肪生成并增加了氧化。肥胖者肝脏NIK异常激活;肥胖小鼠和酒精性脂肪肝或丙型肝炎患者肝脏CREB和激活的NF- B2水平升高。肥胖与结合NIK的Cdc 37（一种Hsp 90辅助分子伴侣）的增加有关。我们认为，肝脏NIK异常激活肥胖由于NIK分子伴侣（Cdc 37/Hsp 90），NIK E3连接酶（cIAP 1/2），和肝细胞库普弗细胞串扰的失调。肥胖相关的NIK过度活化通过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NIK细胞是否通过增加CREB稳定性和降低cAMP（胰高血糖素和儿茶酚胺的第二信使）降解自主促进胰高血糖素/儿茶酚胺敏感性，以及肝细胞特异性缺失NIK是否保护2型糖尿病。在目标2中，我们将确定肝NIK是否通过CREB直接促进脂肪生成并通过NF- B2抑制氧化，以及肝细胞特异性缺失NIK是否保护肝脂肪变性。在目标3中，我们将确定肥胖是否与Cdc 37/Hsp 90分子伴侣机制、cIAP 1/2 E3连接酶活性和肝细胞-枯否细胞串扰的失调相关，以及这三个因素是否驱动NIK过度活跃。该结果有望通过靶向NIK途径为肝脂肪变性和2型糖尿病带来新的治疗方法。