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，基于过去 5 年我们实验室对 LDKO（肝特异性 Irs1-/-"Irs2-/-）和 LTKO（肝特异性 Irs1-/-"Irs2-/-"FoxO1-/-）小鼠进行的工作。LDKO-小鼠展示 全身代谢失调，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（非酒精性脂肪肝）。 NAFLD 的病因根源于胰岛素抵抗、肥胖、高脂血症和糖尿病。由于 LTKO 小鼠表现出正常的营养稳态，我们假设激活 肝脏 FoxO1 不仅仅是肝脏甘油三酯的积累，它会促进炎症发展为危及生命的坏死/细胞凋亡和再生周期，最终导致 NAFLD 进展为 NASH（非酒精性脂肪性肝炎）和 HCC（肝细胞癌）的损伤特征。为了研究潜在的病理生理学，我们 重点关注因长期激活 FoxO1 而导致的线粒体功能障碍，FoxO1 会增加数百个基因的表达，包括 hemeoxygenase-1（由 Hmox1 编码）和 cyclophilin D（由 Ppif 编码）。为了探究分子机制，我们建议使用纳米颗粒递送靶向 siRNA 来抑制肝脏 FoxO1 的表达， NAFLD 起始（10 周龄）和进展（10 个月龄）期间的 Hmox1 或 Ppif。为了在我们的实验室中实现这项技术，我们与东北大学药学院的 Amiji 小组签订了“联盟协议”。基于小鼠的实验将研究 FoxO1 介导的肝线粒体功能障碍与全身炎症引起的进行性 NAFLD/NASH 之间的关系 和肌肉胰岛素作用有助于糖尿病，具体目标如下： i) 通过调节 FoxO1、Hmox1 或 Ppif 的表达来研究 LDKO 小鼠中 FoxO1 介导的线粒体功能障碍，以恢复线粒体功能并减轻肝脏炎症、NASH 及其在持续性肝胰岛素抵抗期间向 HCC 的进展。 ii) 研究骨骼 LDKO 小鼠的肌肉胰岛素抵抗，以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) 在肝线粒体功能障碍和 NAFLD 解决之前和之后，使用磷酸位点特异性单克隆抗体文库量化 LDKO 小鼠肌肉中 IRS1 的 Ser/Thr 磷酸化 抑制 FoxO1、Hmox1 或 Ppif。 由于 LDKO 小鼠不会受到 ob/ob 小鼠下丘脑肥胖的显着影响，因此我们的实验直接关注肝胰岛素抵抗和 NAFLD 之间的关系，及其向全身胰岛素抵抗和糖尿病的进展。