Hormonal control of NASH development and progression

NASH 发生和进展的激素控制

• 批准号: 10265382
• 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/10265382
• 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; 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; Structure; Testing; Therapeutic; Therapeutic Effect; Time; Transcriptional Activation; Western Blotting; Wild Type Mouse; adeno-associated viral vector; base; cardiovascular risk factor; cost; 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; 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.

摘要/摘要 非酒精性脂肪性肝病 (NAFLD) 代表一系列病理学，从简单的脂肪变性到 伴有或不伴有纤维化的非酒精性脂肪性肝炎（NASH - 脂肪变性伴肝细胞损伤）。 常见于肥胖和糖尿病患者，是心血管疾病的独立危险因素 在 VA 患者群体中，肥胖/糖尿病/NASH 的患病率高于 VA 患者群体。 给一般人群带来重大的临床和经济负担 目前还没有经过证实的医疗疗法。 因此，了解 NASH 的发病机制非常重要。 开发，旨在确定未来药物开发的新靶标。 概述发表了生长激素 (GH) 抑制肝脂肪的临床和实验证据 我们已发表和未发表的数据表明 GH 介导这些作用。 通过增强 STAT5B 活性直接在肝细胞水平上进行研究概述了将使用的方法。 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 STAT5B 激活减少， 直接促进成人发病的 NASH 发展和肝细胞-STAT5B 的选择性增强 活动将预防和逆转 NASH，以下具体目标 (SA) 将检验该假设。 确定增强肝细胞 STAT5B 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 IGF1 产生的情况下发育 - 确定是否存在。 在饮食诱导的脂肪肝中观察到的肝脏 pSTAT5B 减少是由于肝脏 GH 的发展 SA3 - 确定增强肝细胞 STAT5B 的活性是否可以逆转既定饮食 - 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) 通过气相色谱和液相色谱质量法测定肝脂质含量和成分 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 评估脂质和葡萄糖加工中重要基因的肝脏表达 蛋白质印迹分析；5) 评估全身胰岛素敏感性和葡萄糖耐量，以及， 这些研究的完成将提供有关间接量热法的葡萄糖/脂质利用的新信息。 GH 如何控制肝细胞功能以直接抑制肝脏脂肪变性并预防损伤。 揭示治疗 NASH 的新药物靶点。