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 肥胖大流行带来了多种服务的代谢合并症，包括2型糖尿病 （T2D）和非酒精性脂肪肝病（NAFLD）。 T2D和NAFLD的处理不足 尽管多种药物已被批准用于T2D，但很少有人解决基础 问题 - 胰岛素抵抗。此外，没有批准NAFLD的药物，这是慢性的主要原因 肝病和肝移植最快的原因。显然，用于潜在治疗的更广泛的网络 必须施放才能阻止与肥胖相关疾病的潮流。 Notch是对细胞命运决策至关重要的高度组成的蛋白质家族，但对 成熟组织中的缺口作用。我们已经表明，正常肝脏中的凹槽信号在低水平上存在，但是 肥胖的饮食诱导或遗传小鼠模型的生活显着增加，并且在肥胖中类似 T2D或NAFLD的患者。在肝细胞和免疫细胞中发现缺口信号增加，但没有 其他非副作用肝细胞。接下来，为了测试因果关系，我们产生了缺乏肝细胞凹口信号传导的小鼠 - 这些小鼠在用高脂饮食喂养挑战时，表现出改善的葡萄糖耐受性和相似之处 肝脂肪变性减少。相反，具有组成型肝细胞缺口活性的小鼠显示葡萄糖 即使喂养正常的食物饮食，摄取和脂肪肝也是如此。我们观察到在缺口损失和 喂养一种新型纤维化饮食的功能收益小鼠。在这里，我们将检查基础机制 肝脏缺口信号传导的激活和这种不良适应反应的下游效应，并具有最终 改善对象性诱导的代谢并发症的目标。在AIM 1中，我们将确定JAG1是否增加 以及信号量和 - 接种肝细胞中的Notch1表达，可能是由于FTO平行的增加 和FOXO1活性在胰岛素耐药性肝脏中，坐标增加肝脏缺口和下游 肥胖症中的病理学。在AIM 2中，我们测试了Notch活性如何导致脂肪肝，并假设Notch- 诱导的PHLPP2降解允许未检查的胰岛素作用和持续的从头脂肪生成。最后，在 AIM 3，我们阐明了肝运动中增加缺口活性的机制和影响 肥胖中的巨噬细胞。实现此应用程序的目标将确定 肥胖症中肝脏缺口信号的增加，描绘了缺口诱导的脂肪形成的机械决定因素， 并且可能会发现缺口抑制剂用于治疗T2D和NAFLD的潜在用途。