Notch, Type 2 Diabetes and NAFLD

Notch、2 型糖尿病和 NAFLD

• 批准号: 10557969
• 负责人: Utpal Pajvani
• 金额: $ 9.05万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10557969
• 关键词: Acute; Address; Affect; Cells; Chronic Disease; Compensatory Hyperinsulinemia; Data; Decision Making; Development; Diet; Elements; Etiology; FOXO1A gene; Fasting; Fatty Liver; Fibrosis; Genetic; Genetic Transcription; Glucose Intolerance; Goals; Grant; Hepatic; Hepatocyte; High Fat Diet; Hyperglycemia; ITGAM gene; Immune; In Vitro; Inflammatory; Insulin; Insulin Receptor; Insulin Resistance; Kinetics; Knockout Mice; Kupffer Cells; Ligands; Light; Liver; Mediating; Messenger RNA; Metabolic; Methylation; Modeling; Modernization; Molecular; Mus; Myelogenous; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; PTPRC gene; Pathogenicity; Pathology; Pathway interactions; Patients; Phagocytes; Pharmaceutical Preparations; Pharmacology; Phenotype; Phosphoric Monoester Hydrolases; Phosphorylation; Process; Protein Family; Proteins; Public Health; Receptor Activation; Regenerative response; Reporting; Signal Transduction; Stimulus; Suggestion; Testing; Therapeutic; Tissues; Translations; chronic liver disease; combat; comorbidity; demethylation; design; feeding; gain of function; glucose production; glucose tolerance; improved; inhibitor; jagged1 protein; lipid biosynthesis; liver inflammation; liver transplantation; loss of function; mRNA Stability; macrophage; mouse model; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; notch protein; novel; novel therapeutic intervention; obese patients; obese person; overexpression; pandemic disease; response; response to injury; stem; tool

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.

抽象的 肥胖流行带来了多种伴随的代谢合并症，包括 2 型糖尿病 （T2D）和非酒精性脂肪肝病（NAFLD）。 T2D 和 NAFLD 均未得到充分治疗 目前可用的治疗方法；尽管多种药物被批准用于治疗 T2D，但很少有药物能解决根本问题 问题——胰岛素抵抗。此外，目前还没有批准用于治疗 NAFLD 的药物，NAFLD 是慢性疾病的主要原因。 肝脏疾病和肝移植增长最快的原因。显然，潜在治疗方法的范围更广 必须采取措施才能遏制与肥胖相关的疾病的流行。 Notch 是一个高度保守的蛋白质家族，对细胞命运决策至关重要，但人们对其知之甚少 成熟组织中的缺口作用。我们已经证明，Notch 信号传导在正常肝脏中以低水平存在，但是 在饮食诱导或遗传性肥胖小鼠模型的肝脏中显着增加，在肥胖中也有类似情况 患有 T2D 或 NAFLD 的患者。在肝细胞和免疫细胞中发现了 Notch 信号增强，但并未发现 其他非实质肝细胞。接下来，为了测试因果关系，我们生成了缺乏肝细胞 Notch 信号传导的小鼠 – 这些小鼠在受到高脂肪饮食喂养的挑战时，表现出葡萄糖耐量的改善和类似的结果 肝脏脂肪变性减少。相反，具有组成性肝细胞Notch活性的小鼠表现出葡萄糖 即使喂养正常的食物，也会出现不耐受和脂肪肝。我们在 Notch 损失中观察到类似的效果 - 和 功能获得小鼠喂食了一种新型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信号传导的激活，以及这种适应不良反应的下游效应器，最终 目的是改善肥胖引起的代谢并发症。在目标 1 中，我们将确定 Jag1 是否增加 和 Notch1 在信号发送和接收肝细胞中的表达，可能是由于 Fto 的平行增加 胰岛素抵抗肝脏中的 FoxO1 和 FoxO1 活性，协调肝脏 Notch 活性及其下游的增加 肥胖的病理学。在目标 2 中，我们测试了 Notch 活性如何导致脂肪肝，假设 Notch- 诱导的 PHLPP2 降解允许不受控制的胰岛素作用和持续的从头脂肪生成。最后，在 目标 3，我们阐明了肝脏中 Notch 活性额外增加的机制和影响 肥胖中的巨噬细胞。实现该应用程序的目标将确定其基本机制 肥胖症中肝脏 Notch 信号传导增加，描绘了 Notch 诱导的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。