Role of NF-kB-induce kinase (NIK) in liver diseases

NF-kB 诱导激酶 (NIK) 在肝脏疾病中的作用

• 批准号: 10017957
• 负责人: LIANGYOU RUI
• 金额: $ 43.72万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-13 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10017957
• 关键词: Alcoholic Liver Diseases; Alcohols; Attenuated; Automobile Driving; Behavior; Bile Duct Epithelium; Biliary; Biliary cirrhosis; Binding; Cell Differentiation process; Cells; Cessation of life; Cholangiocarcinoma; Development; Diet; Disease; Disease Progression; Ductal Epithelial Cell; Enzymes; Etiology; Fatty Liver; Feedback; Fibroblasts; Fibrosis; Goals; Hepatic; Hepatic Stellate Cell; Hepatocyte; Hepatotoxicity; High Fat Diet; Human; Immune; Impairment; Inflammation; Injury; Janus kinase; Knowledge; Kupffer Cells; Light; Lipids; Liver; Liver Failure; Liver Fibrosis; Liver diseases; Longevity; MAP3K14 gene; Malignant Neoplasms; Mitochondria; Molecular; Mus; Myofibroblast; NF-kappa B; Outcome; Pathogenicity; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Phosphotransferases; Prevention strategy; Quality of life; Reaction; Resistance; Risk Factors; Role; STAT3 gene; Shapes; Testing; Therapeutic; Toxin; acute liver injury; bile duct; cell injury; cholangiocyte; combat; effective therapy; hepatocyte injury; hepatotoxin; injured; kinase inhibitor; liver inflammation; liver injury; liver metabolism; macrophage; nonalcoholic steatohepatitis; novel; organ growth; overexpression; prevent; programs; recombinase-mediated cassette exchange; recruit; release factor; response; sensor; small molecule; treatment strategy

Abstract (Description) Liver diseases, including nonalcoholic steatohepatitis (NASH) and alcoholic liver disease (ALD), are devastating and reduce lifespan and quality of life. Hepatocyte and cholangiocyte (bile duct epithelial cells) injury and death are hallmarks of all liver diseases. In NASH and ALD, excessive lipid accumulation (steatosis) induces hepatocyte injury. Damaged hepatocytes and cholangiocytes activate Kupffer cells and macrophages (Ф cells), leading to liver inflammation. Damaged hepatocytes and cholangiocytes also stimulate, in concert with activated Ф cells, differentiation of hepatic stellate cells and portal fibroblasts into active myofibroblasts that are responsible for liver fibrosis. In order to prevent/treat NASH and ALD, it is imperative to understand the liver injury-sensing machinery that orchestrates the destructive programs responsible for liver damage, inflammation, and fibrosis. Excitingly, we found that NF-κB-inducing kinase (NIK, also called MAP3K14) is a critical component of the machinery. NIK is known to activate the noncanonical NF-κB2 pathway and promote immune organ development. Abnormally-activated NIK promotes cancer development. However, NIK function in the liver is poorly defined. We found that hepatic NIK is highly activated in mice and humans with NASH, ALD, and drug-induced liver injury. Similarly, biliary NIK is also highly activated in biliary injury. To assess the role of liver NIK, we deleted NIK specifically in hepatocytes and cholangiocytes using inducible loxp/Cre systems. We showed that liver-specific deletion of NIK protects against high fat diet-induced liver steatosis and hepatotoxin-induced liver injury and inflammation; conversely, hepatocyte-specific overexpression of NIK induces liver injury, inflammation, and fibrosis. Furthermore, cholangiocyte-specific deletion of NIK attenuates toxin-induced bile duct proliferation and biliary fibrosis. Remarkably, treatment with small molecule NIK inhibitors substantially attenuates hepatotoxin-induced liver injury. At the molecular level, we found that NIK suppresses the STAT3 pathway that promotes hepatocyte survival. A subset of NIK localizes to mitochondria and binds to Drp1, a master regulator of mitochondrial fission. In light of these exciting findings, we hypothesize that liver NIK is a central component of the liver injury-sensing machinery. It shapes hepatocyte and cholangiocyte behavior, at least in part, through regulating the STAT3 and Drp1/mitochondria pathways. Furthermore, intrinsic NIK induces hepatocytes and cholangiocytes to release factors that stimulate Ф cells, and activated Ф cells further activate hepatic and biliary NIK through positive feedback loops, thereby driving liver disease progression. We will test these hypotheses in three Aims. Aim 1: Assess the role of hepatic NIK in NASH and ALD. Aim 2: Define the role of biliary NIK in bile duct proliferation and biliary fibrosis. Aim 3: Delineate the underlying molecular mechanisms responsible for the pathogenic actions of hepatic and biliary NIK. The outcomes are expected to define a critical pathogenic role of liver NIK and provide proof of concept evidence for the therapeutic potential of NIK inhibitors for NASH and ALD.

摘要（说明） 肝脏疾病，包括非酒精性脂肪性肝炎（NASH）和酒精性肝病（ALD）， 毁灭性的，减少寿命和生活质量。肝细胞和胆管细胞（胆管上皮细胞） 损伤和死亡是所有肝脏疾病的标志。在NASH和ALD中，过度脂质蓄积（脂肪变性） 诱导肝细胞损伤。受损的肝细胞和胆管细胞激活枯否细胞和巨噬细胞 （肝细胞），导致肝脏炎症。受损的肝细胞和胆管细胞也刺激， 用活化的成纤维细胞，肝星状细胞和门静脉成纤维细胞分化为活性肌成纤维细胞 导致肝纤维化为了预防/治疗NASH和ALD，必须了解 肝损伤--协调造成肝损伤的破坏性程序的感测机制， 炎症和纤维化。令人兴奋的是，我们发现NF-κ B诱导激酶（NIK，也称为MAP 3 K14）是一种抑制NF-κ B诱导的激酶。 机器的关键部件。已知NIK可激活非经典NF-κB2通路，并促进 免疫器官发育。异常激活的NIK促进癌症发展。然而，NIK功能 肝脏中的脂肪定义不明确。我们发现肝脏NIK在患有NASH的小鼠和人类中高度活化， ALD和药物性肝损伤。同样，胆汁NIK在胆汁损伤中也高度活化。评估 肝脏NIK的作用，我们删除NIK特异性在肝细胞和胆管细胞使用诱导型loxp/Cre 系统.我们发现，肝脏特异性NIK缺失可防止高脂饮食诱导的肝脏脂肪变性， 肝毒素诱导的肝脏损伤和炎症;相反，NIK的肝细胞特异性过表达 诱导肝损伤、炎症和纤维化。此外，胆管细胞特异性NIK缺失减弱了 毒素诱导的胆管增生和胆管纤维化。值得注意的是，用小分子NIK治疗 抑制剂基本上减弱了肝毒素诱导的肝损伤。在分子水平上，我们发现NIK 抑制促进肝细胞存活的STAT 3通路。NIK的一个子集定位于线粒体 并与线粒体分裂的主要调节因子Drp 1结合。根据这些令人兴奋的发现，我们 假设肝脏NIK是肝脏损伤感知机制的中心组成部分。它塑造肝细胞 和胆管细胞的行为，至少部分，通过调节STAT 3和Drp 1/线粒体途径。 此外，内源性NIK诱导肝细胞和胆管细胞释放刺激胰岛细胞的因子， 激活的NIK细胞通过正反馈回路进一步激活肝和胆的NIK， 肝病进展。我们将在三个目标中检验这些假设。目的1：评估肝脏NIK的作用 NASH和ALD。目的2：明确胆汁NIK在胆管增生和胆管纤维化中的作用。目标三： 描述导致肝脏和胆汁致病作用的潜在分子机制 尼克这些结果预计将确定肝脏NIK的关键致病作用，并提供概念证明 NIK抑制剂对NASH和ALD的治疗潜力的证据。