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

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)， 破坏和降低寿命和生活质量。肝细胞和胆管细胞(胆管上皮细胞) 受伤和死亡是所有肝病的特征。在NASH和ALD中，脂肪过度堆积(脂肪变性) 导致肝细胞损伤。受损的肝细胞和胆管细胞激活枯否细胞和巨噬细胞 (Ф细胞)，导致肝脏炎症。受损的肝细胞和胆管细胞也会协同刺激 活化的Ф细胞诱导肝星状细胞和门脉成纤维细胞分化为活性肌成纤维细胞 对肝纤维化负有责任。为了预防/治疗NASH和ALD，必须了解 肝脏损伤感应器，负责协调导致肝脏损伤的破坏性程序， 炎症和纤维化。令人兴奋的是，我们发现核因子-丝裂原活化蛋白B诱导激酶(NIK，又称κ3K14)是一种 机械的关键部件。已知NIK激活非规范的NF-κB2途径，并促进 免疫器官发育。异常激活的Nik促进癌症的发展。但是，Nik函数 在肝脏中的定义并不明确。我们发现肝脏NIK在患有NASH的小鼠和人类中高度激活， ALD和药物性肝损伤。同样，胆汁NIK在胆道损伤中也高度激活。要评估 肝脏Nik的作用，我们使用诱导性loxP/Cre在肝细胞和胆管细胞中特异性地删除了Nik 系统。我们发现，肝脏特异性缺失的Nik基因可以预防高脂饮食诱导的肝脏脂肪变性。 肝毒素诱导的肝损伤和炎症；反之，肝细胞特异性过表达Nik 导致肝脏损伤、炎症和纤维化。此外，NIK的胆管细胞特异性缺失可减弱 毒素诱导的胆管增殖和胆管纤维化。值得注意的是，用小分子Nik治疗 抑制剂可显著减轻肝毒素所致的肝损伤。在分子水平上，我们发现尼克 抑制促进肝细胞存活的STAT3途径。NIK的一个子集定位于线粒体 并与线粒体分裂的主要调节者Drp1结合。鉴于这些令人振奋的发现，我们 假设肝脏NIK是肝脏损伤感知机制的中心组件。它塑造了肝细胞 和胆管细胞的行为，至少部分是通过调节STAT3和Drp1/线粒体通路。 此外，固有的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细胞通过正反馈环进一步激活肝脏和胆汁NIK，从而推动 肝脏疾病的进展。我们将在三个目标上检验这些假设。目标1：评估肝脏NIK的作用 在纳什和阿尔德。目的2：明确胆汁Nik在胆管增殖和胆管纤维化中的作用。目标3： 阐明导致肝脏和胆道疾病的潜在分子机制 尼克。这些结果有望确定肝脏NIK的关键致病作用，并提供概念上的证据 NIK抑制剂对NASH和ALD治疗潜力的证据。

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.