Hepatocyte Notch Signaling Regulates NASH

 描述(申请人提供)：肥胖大流行带来了多种伴随而来的代谢共病，包括2型糖尿病(T2D)和非酒精性脂肪性肝病(NAFLD)，这可能是21世纪决定性的卫生和公共政策问题。非酒精性脂肪肝是慢性肝病的头号病因，在某些人群中的患病率接近30%，但实际上可能被认为是非酒精性脂肪性肝炎(NASH)的“疾病前”状态。NASH的定义是肝细胞损伤和相关的炎症和纤维化，易患肝硬变和肝细胞癌，是肝移植增长最快的原因。NASH没有得到批准的药物治疗--随着肥胖相关NASH的患病率持续上升，可供移植的肝脏仍然有限，这一未得到满足的需求变得更加迫切。Notch是一个高度保守的蛋白质家族，对细胞命运的决定至关重要，但人们对Notch在成熟组织中的作用知之甚少。我们的初步特征表明，在正常生理条件下，Notch信号在低水平存在，但在饮食诱导或遗传性肥胖小鼠模型或患有T2D或NAFLD的肥胖患者的肝脏中显著增加。令人惊讶的是，在NASH患者或与人类NASH相似的饮食小鼠模型中，肝脏Notch活性仍然较高。在患者个体水平上，或在脂肪性肝炎小鼠模型中，Notch活性指标与NASH的生化(ALT水平)和病理(NAFLD活动评分)指标呈显著正相关。这些结果提示，肝脏中的Notch活性可能是肝细胞损伤的生物标志物，也可能是NASH的病因。在这一应用中，我们将研究NASH中肝脏Notch信号激活的潜在机制，以及它作为肥胖诱导NASH的新治疗靶点的潜力。在目标1中，我们将确定对肝细胞Notch信号的遗传或药物抑制是否可以防止高脂肪/高碳水化合物喂养引起的小鼠脂肪性肝炎和纤维化。在目标2中，我们将确定哪个细胞和通过哪个配体在脂肪性肝炎中传播Notch信号，并确定我们是否可以利用这一知识来设计安全和特异的Notch抑制剂来治疗NASH。实现这项应用的目标将确定Notch信号在肥胖引起的肝病中增加的潜在机制，并有可能重新使用现有的Notch抑制剂作为治疗NASH的新颖和独特的药物疗法。

 DESCRIPTION (provided by applicant): The obesity pandemic brings with it multiple attendant metabolic comorbidities, including Type 2 Diabetes (T2D) and Non-Alcoholic Fatty Liver Disease (NAFLD), which are likely to be the defining health and public policy issues of the 21st century. NAFLD is the number one cause for chronic liver disease, with prevalence approaching 30% in certain populations, but may in fact be considered a "pre-disease" state for Non-Alcoholic Steatohepatitis (NASH). NASH, which is defined by hepatocyte damage and associated inflammation and fibrosis, predisposes to cirrhosis and hepatocellular cancer, and is the fastest-growing reason for liver transplantation. NASH has no approved pharmacotherapy - as the prevalence of obesity-related NASH continues to rise, and available livers for transplantation remain limiting, this unmet need grows more urgent. Notch is a highly conserved family of proteins critical for cell fate decision-making, but less is known about Notch action in mature tissue. Our initial characterization demonstrated that Notch signaling is present at low levels in normal physiologic conditions, but increases markedly in livers from diet-induced or genetic mouse models of obesity, or obese patients with T2D or NAFLD. Surprisingly, hepatic Notch activity is higher still in patients with NASH, or in dietary mouse models which approximate human NASH. At the level of individual patient, or in mouse models of steatohepatitis, markers of Notch activity show significant positive correlations with biochemical (ALT levels) and pathologic (NAFLD Activity Score) markers of NASH. These results suggest that Notch activity in liver may be either a biomarker of hepatocyte damage, or may be causative to NASH. In this application, we will examine the mechanisms underlying activation of hepatic Notch signaling in NASH and its potential as a novel therapeutic target for obesity-induced NASH. In Aim 1, we will determine whether genetic or pharmacologic inhibition of hepatocyte Notch signaling prevents steatohepatitis and fibrosis induced by high-fat/high-carb feeding in mice. In Aim 2, we will determine which cell, and by which ligand, propagates the Notch signal in steatohepatitis, and determine whether we can exploit this knowledge to design safe and specific Notch inhibitors for treatment of NASH. Achieving the goals of this application will identify the underlying mechanism of increased Notch signaling in obesity-induced liver disease, as well as potentially repurpose existing Notch inhibitors as novel and unique pharmacotherapy for NASH.