Hormonal control of NASH development and progression

NASH 发生和进展的激素控制

• 批准号: 10454874
• 负责人: Rhonda D Kineman
• 金额: --
• 依托单位: JESSE BROWN VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10454874
• 关键词: Address; Adult; Alanine Transaminase; Cardiovascular Diseases; Cirrhosis; Clinical; Clinical Research; Coupled; Data; Defect; Development; Diabetes Mellitus; Diet; Disease Progression; Economic Burden; Evaluation; Fatty Liver; Fatty acid glycerol esters; Female; Fibrosis; Functional disorder; Future; Gas Chromatography; Gene Expression; General Population; Glucose; Goals; Growth; Growth Hormone Receptor; Hepatic; Hepatocyte; Hormonal; Human; IGF1 gene; Indirect Calorimetry; Inflammation; Injury; JAK2 gene; Lead; Lipids; Literature; Liver; Liver Failure; Malignant neoplasm of liver; Mediating; Medical; Metabolic; Metabolic dysfunction; Mus; Obesity; Obesity associated liver disease; Pathology; Persons; Pharmaceutical Preparations; Plasma; Play; Population; Prevalence; Primary carcinoma of the liver cells; Production; Publishing; Receptor Signaling; Regulation; Reporting; Resistance development; Risk; Role; STAT5B gene; Signal Pathway; Signal Transduction; Slice; Somatotropin; Steatohepatitis; Testing; Therapeutic; Therapeutic Effect; Time; Transcriptional Activation; Western Blotting; Wild Type Mouse; adeno-associated viral vector; base; cardiovascular risk factor; cost; delivery vehicle; diabetic; diabetic patient; drug development; effective therapy; experimental study; glucose tolerance; growth hormone deficiency; hepatocellular injury; hormonal signals; hormone resistance; hormone therapy; innovation; insulin sensitivity; knock-down; lipid biosynthesis; liquid chromatography mass spectroscopy; liver function; liver injury; liver transplantation; male; mortality; mouse model; new therapeutic target; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; obese patients; obese person; patient population; prevent; receptor; simple steatosis; transcription factor; transgene delivery; vector; vector control

SUMMARY/ABSTRACT Non-alcoholic fatty liver disease (NAFLD) represents a spectrum of pathologies ranging from simple steatosis to non-alcoholic steatohepatitis (NASH – steatosis with hepatocellular injury) with or without fibrosis. NAFLD is prevalent in obese and diabetic patients, and represents an independent risk factor for cardiovascular disease and mortality. Within the VA patient population, the prevalence of obesity/diabetes/NASH is higher than in the general population and represents a major clinical and economic burden. There are no proven medical therapies to prevent and treat NASH. Therefore, it is important to understand the mechanisms that contribute to NASH development, with the goal to identify novel targets for future drug development. The current application overviews published clinical and experimental evidence that growth hormone (GH) suppresses hepatic fat accumulation and prevents liver injury. Our published and unpublished data indicate GH mediates these effects directly at the level of the hepatocyte by enhancing STAT5B activity. Studies are outlined that will use hepatocyte-specific adenoviral-associated vector (AAV) delivery of transgenes in adult mice to test the HYPOTHESIS- Reduction in hepatocyte-specific GHR-mediated activation of the transcription factor, STAT5B, directly contributes to adult-onset NASH development and selective enhancement of hepatocyte-STAT5B activity will prevent and reverse NASH. The following Specific Aims (SA) will test this hypothesis. SA1- Determine if augmenting hepatocyte STAT5B activity can slow or prevent diet-induced steatosis and NASH development in the presence or absence of hepatocyte GHR-signaling and IGF1 production. SA2- Determine if the reduction in hepatic pSTAT5B, observed in diet-induced fatty livers, is due to the development of hepatic GH resistance. SA3 - Determine if enhancing the activity of hepatocyte STAT5B can reverse established diet- induced NASH. Endpoints examined include: 1) histopathologic assessment of hepatic steatosis and injury; 2) determination of hepatic lipid content and composition by gas chromatography- and liquid chromatography mass spectroscopy; 3) activation status of hepatic GH receptor-mediated downstream signals by Western blot analysis; 4) evaluation of hepatic expression of genes important in lipid and glucose processing by qPCR and Western blot analysis; 5) assessment of whole body insulin sensitivity and glucose tolerance, as well as, glucose/lipid utilization by indirect calorimetry. Completion of these studies will provide new information regarding how GH directly controls hepatocyte function to inhibit steatosis and prevent liver injury. This information could reveal novel drug targets to treat NASH.

总结/摘要 非酒精性脂肪性肝病（NAFLD）代表了从单纯脂肪变性到 非酒精性脂肪性肝炎（NASH -脂肪变性伴肝细胞损伤）伴或不伴纤维化。NAFLD是 在肥胖和糖尿病患者中普遍存在，是心血管疾病的独立危险因素 and mortality.在VA患者人群中，肥胖/糖尿病/NASH的患病率高于VA患者人群。 一般人群，并代表了主要的临床和经济负担。没有经过验证的医学疗法 预防和治疗NASH。因此，重要的是要了解导致NASH的机制 开发，目标是为未来的药物开发确定新的靶点。当前应用程序 综述已发表的临床和实验证据表明，生长激素（GH）抑制肝脂肪 积累，防止肝损伤。我们已发表和未发表的数据表明，生长激素介导这些影响 直接在肝细胞水平通过增强STAT 5 B活性。研究概述，将使用 肝细胞特异性腺病毒相关载体（AAV）在成年小鼠中递送转基因，以测试 假设-肝细胞特异性GHR介导的转录因子STAT 5 B活化减少， 直接促进成人型NASH的发展和肝细胞-STAT 5 B的选择性增强 预防和逆转NASH。以下具体目标（SA）将检验这一假设。SA 1- 确定增强肝细胞STAT 5 B活性是否可以减缓或预防饮食诱导的脂肪变性和NASH 在存在或不存在肝细胞GHR信号传导和IGF 1产生的情况下发育。SA 2-确定是否 在饮食诱导的脂肪肝中观察到的肝脏pSTAT 5 B的减少是由于肝脏GH的发展。 阻力SA 3-确定增强肝细胞STAT 5 B的活性是否可以逆转已建立的饮食- 诱发NASH。检查的终点包括：1）肝脂肪变性和损伤的组织病理学评估; 2） 用气相色谱和液相色谱质谱法测定肝脂质含量和组成 3）通过Western blot检测肝脏GH受体介导的下游信号的激活状态 4）通过qPCR评估在脂质和葡萄糖加工中重要的基因的肝表达， Western印迹分析; 5）评估全身胰岛素敏感性和葡萄糖耐量，以及， 通过间接量热法测定葡萄糖/脂质利用率。这些研究的完成将提供有关以下方面的新信息： GH如何直接控制肝细胞功能，以抑制脂肪变性和防止肝损伤。该信息可以 揭示了治疗NASH的新药物靶点。