Notch, Type 2 Diabetes and NAFLD

 描述(申请人提供)：肥胖大流行带来多种伴随的代谢共病，包括2型糖尿病(T2D)和非酒精性脂肪性肝病(NAFLD)。T2D和NAFLD都不能用目前可用的治疗方法进行充分的治疗；尽管多种药物被批准用于T2D，但很少有药物能解决潜在的问题--胰岛素抵抗。此外，没有药物被批准用于治疗NAFLD，NAFLD是慢性肝病的主要原因，也是肝移植增长最快的原因。显然，必须为潜在的治疗方法撒下更大的网，以遏制肥胖相关疾病的浪潮。Noch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 对Notch在成熟组织中的作用知之甚少。我们发现，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肥胖小鼠模型的肝脏中显著增加，类似地，在患有T2D或NAFLD的肥胖患者中也是如此。由于Notch已被证明与肝脏糖异生的关键转录调节因子FoxO1和调节胰岛素介导的脂肪生成的mTORC1相互作用，我们假设Notch在生理性和病理性的糖脂代谢中发挥积极作用。我们产生了缺乏肝细胞Notch信号的小鼠--当接受高脂饮食喂养时，这些小鼠表现出糖耐量的改善和肝脏脂肪变性的平行减少。在验证性研究中，我们发现Notch抑制剂对肥胖小鼠的治疗重现了我们的遗传功能丧失模型，表明Notch可能既是肥胖相关病理中的一个机械节点，也是一个真正的治疗靶点。在这一应用中，我们将研究肝脏Notch信号激活的潜在机制，以及它作为肥胖引起的代谢并发症的新治疗靶点的潜力。在目标1中，我们将确定肝细胞Notch信号如何与胰岛素/FoxO1和营养素/mTORC1信号通路结合来调节肝脏的胰岛素敏感性和甘油三酯水平。在目标2中，我们研究了Notch稳定和激活mTORC1的机制。在目标3中，我们将研究Notch信号是如何传递的--即通过什么配体，由肝脏中的哪种细胞类型表达--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抑制剂来治疗代谢性疾病。这项应用的成功完成将确定肥胖中不适当的Notch信号的潜在机制，并可能重新使用现有的Notch抑制剂治疗胰岛素抵抗/T2D和NAFLD。

 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). Both T2D and NAFLD are inadequately treated with currently available therapy; although multiple medications are approved for T2D, few address the underlying problem-insulin resistance. In addition, no medications are approved for NAFLD, the leading cause of chronic liver disease and fastest-growing reason for liver transplantation. Clearly, a wider net for potential therapeutics must be cast in order to stem the tide of obesity-related illness. Notch is a highly conserved family of proteins critical for cell fate decision-making, but less is known about Notch action in mature tissue. We showed 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, and similarly in obese patients with T2D or NAFLD. As Notch has been shown to interact with FoxO1, the key transcriptional regulator of hepatic gluconeogenesis, and mTORC1, which regulates insulin-mediated lipogenesis, we hypothesized that Notch plays an active role in physiologic and pathologic glucose and lipid metabolism. We generated mice lacking hepatocyte Notch signaling- these mice, when challenged with high- fat diet feeding, showed improved glucose tolerance and a parallel decrease in hepatic steatosis. In proof-of- principle studies, we found that Notch inhibitor treatment of obese mice recapitulated our genetic loss-of- function model, suggesting Notch may be both a mechanistic node in obesity-related pathology as well as a bona fide therapeutic target. In this application, we will examine the mechanisms underlying activation of hepatic Notch signaling and its potential as a novel therapeutic target for obesity-induced metabolic complications. In Aim 1, we will determine how hepatocyte Notch signaling integrates with the insulin/FoxO1 and nutrient/mTORC1 pathways to modulate hepatic insulin sensitivity and triglyceride levels. In Aim 2, we study the mechanism by which Notch stabilizes and activates mTORC1. In Aim 3, we will study how the Notch signal is transduced - i.e., by what ligand, expressed by which cell type in the liver - and determine whether we can exploit this knowledge to design safe and specific Notch inhibitors for treatment of metabolic disease. Successful completion of this application will identify the underlying mechanism of inappropriate Notch signaling in obesity, as well as potentially repurpose existing Notch inhibitors for treatment of insulin resistance/T2D and NAFLD.