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）：这是一项题为“肝胰岛素抵抗和代谢疾病”的新提案，它基于过去5年在我们的实验室中与LDKO（肝特异性IRS1 - / - “ IRS2 - / - ”的工作中进行的工作，全身的代谢失调，包括肝和周围胰岛素抵抗，高血糖，中度高胰岛素血症和进行性NAFLD（非酒精性脂肪肝病） 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着重于由于长期活化的FOXO1导致的线粒体功能障碍，从而增加了数百个基因的表达，包括Hemeoxygogyasy-1（由HMOX1编码）和环磷脂D（由PPIF编码）。为了询问分子机制，我们建议在开始（10周龄）和NAFLD的纳米粒子递送靶向靶向的siRNA来抑制肝FOXO1，HMOX1或PPIF的表达。为了在我们的实验室中启用这项技术，我们已经与东北大学药学院的Amiji集团建立了“财团协议”。 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线粒体功能并减弱肝炎症，NASH及其在持续性肝胰岛素抵抗期间向HCC的发展。 ii）研究LDKO小鼠中骨骼肌胰岛素抵抗，以建立肝炎与骨骼肌胰岛素胰岛素作用和代谢失调之间的关系。 iii）使用在肝线粒体功能障碍和NAFLD抑制FOXO1，HMOX1或PPIF之前和之后，使用磷材料特异性单克隆抗体的LDKO-肌肉中IRS1的Ser/Thr磷酸化。 由于LDKO-小鼠与ob/ob-ciper遇到的基于下丘脑的肥胖的主要作用并不复杂，因此我们的实验正专注于肝胰岛素抵抗与NAFLD之间的关系，以及它与全身性胰岛素抵抗和糖尿病的发展。