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

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。大量研究表明，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（如胰高血糖素和儿茶酚胺）之间的平衡决定；然而，炎症对胰高血糖素和儿茶酚胺敏感性的潜在影响尚未研究。此外，介导肝脂肪变性炎症调节的信号通路定义不清。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是一种普遍表达的丝氨酸/苏氨酸激酶，由一组细胞因子激活，是激活非典型NF- B2通路所必需的，但不是典型的IKK /NF- B1通路。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被研究。我们观察到NIK增强了胰高血糖素增加cAMP水平和肝葡萄糖生成（HGP）的能力，但不直接调节胰岛素信号。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阴性小鼠出现胰高血糖素抵抗，并保护其免受饮食性高血糖和肝脂肪变性。NIK的缺失减少了肝细胞的脂肪生成并增加了氧化。肥胖患者肝脏NIK异常激活；肥胖小鼠和酒精性脂肪性肝病或丙型肝炎患者肝脏中CREB和活化NF- B2水平升高。肥胖与与NIK结合的Cdc37（一种Hsp90伴侣）升高有关。我们认为，由于NIK伴侣（Cdc37/Hsp90）、NIK E3连接酶（cIAP1/2）和肝细胞-库普诺夫细胞串音的失调，肝脏NIK在肥胖中异常激活。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Aim 1中，我们将确定肝脏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）降解来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是否可以预防2型糖尿病。在Aim 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NF- B2抑制-氧化，以及肝细胞特异性缺失NIK是否保护肝脏脂肪变性。在Aim 3中，我们将确定肥胖是否与Cdc37/Hsp90伴侣机制、cIAP1/2 E3连接酶活性和肝细胞-库普诺夫细胞串聊的失调有关，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通路为肝脂肪变性和2型糖尿病提供新的治疗方法。

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. PUBLIC HEALTH RELEVANCE: The prevalence of type 2 diabetes and fatty liver diseases continues to rise rapidly, devastating millions of American life. Unfortunately, our ability to tret these diseases is limited because their molecular mechanisms remain largely unknown. In the proposed study, we will determine how inflammation and cellular stress promote type 2 diabetes and fatty liver diseases, focusing on a protein kinase called NIK. The outcome of this project is expected to lead to new treatments of these two common diseases.