Hepatic insulin resistance and metabolic disease

肝脏胰岛素抵抗与代谢疾病

• 批准号: 8829241
• 负责人: Morris F. White
• 金额: $ 45.99万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8829241
• 关键词: 1-Phosphatidylinositol 3-Kinase; Adipose tissue; Adult; Age; Age-Months; Agreement; Alcohols; Apoptosis; Attenuated; Benign; Bladder; Cells; Ceramides; Characteristics; Data; Defect; Diabetes Mellitus; Disease; Disease Progression; Dysplasia; Etiology; Functional disorder; Gene Expression; Gene Targeting; Genes; Genetic; Genomics; Health; Hepatic; Histopathology; Homeostasis; Hyperglycemia; Hyperinsulinism; Hyperlipidemia; Hypothalamic structure; IRS1 gene; Inflammation; Insulin; Insulin Resistance; Investigation; Knock-in Mouse; Laboratories; Leptin; Libraries; Life; Lipids; Liver; Liver diseases; Mediating; Metabolic; Metabolic Diseases; Metabolism; Mitochondria; Molecular; Monoclonal Antibodies; Morbidity - disease rate; Mus; Muscle; Natural regeneration; Necrosis; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Peripheral; Pharmacy Schools; Phosphorylation; Plant Roots; Primary carcinoma of the liver cells; Production; Proteins; Regulation; Resistance; Resolution; Role; Signal Transduction; Site; Skeletal Muscle; Small Interfering RNA; Structure of beta Cell of islet; Technology; Tissues; Triglycerides; Universities; Work; adenoviral-mediated; base; cyclophilin D; design; heme oxygenase-1; innovation; insulin secretion; insulin signaling; mitochondrial dysfunction; mortality; mutant; nanoparticle; non-alcoholic fatty liver; nonalcoholic steatohepatitis; prevent; research study; targeted delivery; treatment strategy

DESCRIPTION (provided by applicant): This is a new proposal entitled "Hepatic insulin resistance and metabolic disease" that is based upon work conducted in our laboratory during the past 5 years with LDKO (hepatic-specific Irs1-/-"Irs2-/-) and LTKO (hepatic-specific Irs1-/-"Irs2-/-"FoxO1-/-) mice. LDKO-mice display systemic metabolic dysregulation, including hepatic and peripheral insulin resistance, hyperglycemia, moderate hyperinsulinemia, and progressive NAFLD (nonalcoholic fatty liver disease). The etiology of NAFLD is rooted in insulin resistance, obesity, hyperlipidemia, and diabetes. As LTKO-mice display normal nutrient homeostasis, we posit that activated hepatic FoxO1, rather than the mere accumulation of hepatic triglyceride, promotes inflammation that progresses to life- threatening necrosis/apoptosis and cycles of regeneration that culminate with damage-characteristic of the progression of NAFLD to NASH (nonalcoholic steatohepatitis) and HCC (hepatocellular carcinoma). To investigate the underlying pathophysiology, we focus upon mitochondrial dysfunction that develops as a result of chronically activated FoxO1 that increases the expression of hundreds of genes, including hemeoxygenase- 1 (encoded by Hmox1) and cyclophilin D (encoded by Ppif). To interrogate the molecular mechanisms, we propose to use nanoparticle delivery of targeted siRNA to suppress the expression of hepatic FoxO1, Hmox1, or Ppif during initiation (10 weeks of age) and progression (10 months of age) of NAFLD. To enable this technology in our laboratory, we have formed a 'Consortium Agreement' with the Amiji group in the School of Pharmacy at Northeastern University. The mouse-based experiments will investigate the relation between FoxO1-mediated hepatic mitochondrial dysfunction and progressive NAFLD/NASH upon systemic inflammation and muscle insulin action that contributes to diabetes in the following Specific Aims: i) Investigate FoxO1-mediated mitochondrial dysfunction in LDKO-mice by modulating the expression of FoxO1, Hmox1 or Ppif to restore mitochondrial function and attenuate hepatic inflammation, NASH and its progression to HCC during persistent hepatic insulin resistance. ii) Investigate skeletal muscle insulin resistance in LDKO-mice to establish the relation between hepatic inflammation and dysregulated skeletal muscle insulin action and metabolism. iii) Quantify Ser/Thr-phosphorylation of IRS1 in muscle of LDKO-mice using a library of phosphosite-specific monoclonal antibodies before and after resolution of hepatic mitochondrial dysfunction and NAFLD by suppression of FoxO1, Hmox1 or Ppif. Since the LDKO-mice are uncomplicated by the dominant effects of hypothalamic-based obesity encountered with ob/ob-mice, our experiments focus squarely upon the relation between hepatic insulin resistance and NAFLD, and its progression to systemic insulin resistance and diabetes.

描述（由申请人提供）：这是一个名为“肝脏胰岛素抵抗和代谢性疾病”的新提案，基于我们实验室过去5年对LDKO（肝脏特异性Irs1-/-“Irs2-/-”）和LTKO（肝脏特异性Irs1-/-“Irs2-/-”fox01 -/-）小鼠的研究。ldko小鼠表现出全身性代谢失调，包括肝脏和外周胰岛素抵抗、高血糖、中度高胰岛素血症和进行性NAFLD（非酒精性脂肪性肝病）。NAFLD的病因是胰岛素抵抗、肥胖、高脂血症和糖尿病。由于ltko -小鼠表现出正常的营养平衡，我们假设激活的肝脏FoxO1，而不仅仅是肝脏甘油三酯的积累，促进炎症发展为危及生命的坏死/凋亡和再生周期，最终以损伤告终，这是NAFLD发展为NASH（非酒精性脂肪性肝炎）和HCC（肝细胞癌）的特征。为了研究潜在的病理生理学，我们重点研究了长期激活FoxO1导致的线粒体功能障碍，FoxO1增加了数百个基因的表达，包括血红素加氧酶- 1（由Hmox1编码）和亲环蛋白D（由Ppif编码）。为了探究其分子机制，我们建议使用纳米颗粒递送靶向siRNA来抑制NAFLD发病（10周龄）和进展（10月龄）期间肝脏fox01、Hmox1或Ppif的表达。为了在我们的实验室中实现这项技术，我们已经与东北大学药学院的Amiji小组达成了“联盟协议”。小鼠实验将研究fox01介导的肝脏线粒体功能障碍与进行性NAFLD/NASH在全身性炎症和肌肉胰岛素作用下导致糖尿病的关系，具体目的如下：i)通过调节FoxO1、Hmox1或Ppif的表达，研究FoxO1介导的ldko小鼠线粒体功能障碍，以恢复线粒体功能，减轻肝脏炎症、NASH及其向HCC的进展。ii)研究ldko -小鼠骨骼肌胰岛素抵抗，建立肝脏炎症与骨骼肌胰岛素作用和代谢失调之间的关系。iii)在通过抑制FoxO1、Hmox1或Ppif解决肝脏线粒体功能障碍和NAFLD前后，使用磷酸位点特异性单克隆抗体文库，定量ldko -小鼠肌肉中IRS1的Ser/ thr磷酸化。由于ldko -小鼠不受ob/ob-小鼠所遇到的下丘脑肥胖的主要影响，因此我们的实验直接关注肝脏胰岛素抵抗与NAFLD之间的关系，以及其向全身性胰岛素抵抗和糖尿病的进展。