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.

摘要 肥胖症的流行带来了多种伴随的代谢合并症，包括2型糖尿病 (T2D)非酒精性脂肪肝（NAFLD）T2 D和NAFLD都没有得到充分的治疗， 目前可用的治疗;尽管多种药物被批准用于T2 D，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NAFLD，这是慢性炎症的主要原因。 肝病和肝移植增长最快的原因。显然，一个更广泛的潜在治疗方法 为了遏制肥胖相关疾病的浪潮，必须铸造。 Notch是一个高度保守的蛋白质家族，对于细胞命运决策至关重要，但人们对此知之甚少 成熟组织中的切口作用。我们已经表明，Notch信号在正常肝脏中以低水平存在，但 在饮食诱导或遗传性肥胖小鼠模型的肝脏中显著增加， T2 D或NAFLD患者。在肝细胞和免疫细胞中发现了Notch信号的增加， 其他非实质肝细胞。接下来，为了检验因果关系，我们产生了缺乏肝细胞Notch信号传导的小鼠， - 这些小鼠在高脂饮食喂养下表现出葡萄糖耐量的改善， 肝脂肪变性减少。相反，具有组成型肝细胞Notch活性的小鼠显示葡萄糖 不耐受和脂肪肝，即使当喂食正常的食物饮食。我们在Notch损失中观察到类似的效果， 功能获得小鼠喂食一种新的纤维化诱发饮食。在这里，我们将研究潜在的机制， 激活肝脏Notch信号传导，以及这种适应不良反应的下游效应物，最终导致 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Jag 1 和Notch 1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。 和FoxO 1活性，协调增加的肝脏Notch活性和下游 肥胖症的病理学在目标2中，我们测试Notch活性如何导致脂肪肝，假设Notch- 诱导的PHLPP 2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，阐明Notch活性增加的机制和影响， 巨噬细胞在肥胖中的作用实现本应用程序的目标将确定 肥胖症中增加的肝脏Notch信号传导，描绘Notch诱导的脂肪生成的机制决定因素， 并可能揭示Notch抑制剂用于治疗T2 D和NAFLD的潜在用途。