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: 9750723
• 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 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9750723
• 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; 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（描述） 肝脏疾病，包括非酒精性脂肪性肝炎（NASH）和酒精性肝病（ALD） 破坏性并降低肝细胞和胆管细胞（胆管上皮细胞）的寿命和生活质量。 损伤和死亡是所有肝脏疾病的标志，在 NASH 和 ALD 中，脂质过度积累（脂肪变性）。 诱导肝细胞损伤 受损的肝细胞和胆管细胞激活库普弗细胞和巨噬细胞。 （Ф细胞），导致肝脏炎症，同时刺激肝细胞和胆管细胞。 活化的Ф细胞，使肝星状细胞和门脉成纤维细胞分化为活性肌成纤维细胞 为了预防/治疗 NASH 和 ALD，必须了解导致肝纤维化的因素。 肝损伤感知机制，协调导致肝损伤的破坏性程序， 令人兴奋的是，我们发现 NF-κB 诱导激酶（NIK，也称为 MAP3K14）是一种 NIK 是该机制的关键组成部分，可激活非经典 NF-κB2 通路并促进 异常激活的 NIK 会促进癌症的发展。 我们发现肝脏 NIK 在患有 NASH 的小鼠和人类中高度激活。 ALD 和药物引起的肝损伤类似，胆道 NIK 也在胆道损伤中高度激活。 为了了解肝脏 NIK 的作用，我们使用诱导型 loxp/Cre 特异性删除了肝细胞和胆管细胞中的 NIK 我们发现肝脏特异性缺失 NIK 可预防高脂肪饮食引起的肝脏脂肪变性和 肝毒素诱导的肝损伤和炎症；相反，NIK 的肝细胞特异性过度表达； 诱导肝损伤、炎症和纤维化此外，胆管细胞特异性缺失 NIK 会减弱。 毒素诱导的胆管增殖和胆道纤维化 值得注意的是，小分子 NIK 治疗。 我们发现 NIK 抑制剂可在分子水平上显着减轻肝毒素引起的肝损伤。 抑制促进肝细胞存活的 STAT3 通路 NIK 的一个子集定位于线粒体。 并与线粒体裂变的主要调节因子 Drp1 结合。鉴于这些令人兴奋的发现，我们 肝脏 NIK 是肝脏损伤感知机制的核心组成部分，它塑造肝细胞。 和胆管细胞行为，至少部分是通过调节 STAT3 和 Drp1/线粒体途径。 此外，内在的NIK诱导肝细胞和胆管细胞释放刺激Ф细胞的因子， 激活的Ф细胞通过正反馈回路进一步激活肝脏和胆道NIK，从而驱动 我们将在三个目标中检验这些假设：评估肝脏 NIK 的作用。 目标 2：明确胆道 NIK 在胆管增殖和胆道纤维化中的作用。 描述肝脏和胆道致病作用的潜在分子机制 NIK 的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 具有治疗潜力的证据。