Notch, Type 2 Diabetes and NAFLD

摘要 肥胖症的流行带来了多种伴随而来的代谢并发症，包括2型糖尿病 (T2D)和非酒精性脂肪性肝病(NAFLD)。T2D和NAFLD都没有得到充分的治疗 目前可用的治疗方法；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，没有任何药物被批准用于治疗NAFLD，这是慢性脂肪肝的主要原因 肝脏疾病和肝移植增长最快的原因。显然，潜在疗法的更广泛网络 必须铸造，以遏制与肥胖相关的疾病的浪潮。 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，但人们对此知之甚少。 在成熟组织中的缺口作用。我们已经证明Notch信号在正常肝脏中存在于低水平，但是 在饮食诱导或遗传肥胖的小鼠模型中，肝脏显著增加，肥胖也是如此 T2D或NAFLD患者。在肝细胞和免疫细胞中发现Notch信号增加，但没有 其他非实质性肝细胞。接下来，为了检验因果关系，我们产生了缺乏肝细胞Notch信号的小鼠 -这些小鼠在接受高脂饮食挑战时，表现出更好的糖耐量和平行的 减少肝脏脂肪变性。相反，具有固有肝细胞Notch活性的小鼠表现出葡萄糖 不耐受和脂肪肝，即使在正常饮食的情况下也是如此。我们在凹槽损耗中观察到了类似的影响--以及 功能增强的小鼠喂食了一种新的引发纤维化的饮食。在这里，我们将研究潜在的机制 肝脏Notch信号的激活，以及这种适应不良反应的下游效应器，最终 目的改善肥胖引起的代谢并发症。在目标1中，我们将确定是否增加了Jag1 和Notch1在信号发送和接收肝细胞中的表达，可能是由于FTO平行增加所致 和FoxO1在胰岛素抵抗的肝脏中的活性，协调肝脏Notch活性的增加和下游 肥胖症的病理学。在目标2中，我们测试Notch活动如何导致脂肪肝，假设Notch- 诱导的PHLPP2降解允许不受抑制的胰岛素作用和持续的从头脂肪生成。最后，在 目的3，我们阐明了肝脏Notch活性增加的机制和影响 巨噬细胞与肥胖。实现此应用程序的目标将确定 肥胖中肝脏Notch信号的增加，描述了Notch诱导脂肪生成的机制决定因素 并可能揭示Notch抑制剂治疗T2D和NAFLD的潜在用途。

Abstract 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 have shown that Notch signaling is present at low levels in normal liver, but increased markedly in livers from diet-induced or genetic mouse models of obesity, and similarly in obese patients with T2D or NAFLD. Increased Notch signaling was found in hepatocytes and immune cells, but not other nonparenchymal liver cells. Next, to test causality, 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. Conversely, mice with constitutive hepatocyte Notch activity showed glucose intolerance and fatty liver even when fed normal chow diet. We observed similar effects in Notch loss- and gain-of-function mice fed a novel fibrosis-provoking diet. Here, we will examine the mechanisms underlying activation of hepatic Notch signaling, and downstream effectors of this maladaptive response, with ultimate objective to ameliorate obesity-induced metabolic complications. In Aim 1, we will determine if increased Jag1 and Notch1 expression in signal-sending and -receiving hepatocytes, potentially due to parallel increase in Fto and FoxO1 activity in the insulin-resistant liver, coordinate increased liver Notch activity and downstream pathology in obesity. In Aim 2, we test how Notch activity leads to fatty liver, with the hypothesis that Notch- induced PHLPP2 degradation allows unchecked insulin action and persistent de novo lipogenesis. Finally, in Aim 3, we elucidate mechanism and repercussions of the additional increased Notch activity in hepatic macrophages in obesity. Achieving the goals of this application will identify the underlying mechanism of increased liver Notch signaling in obesity, delineate mechanistic determinants of Notch-induced lipogenesis, and may uncover the potential use of Notch inhibitors for treatment of T2D and NAFLD.