Hormonal Regulation of Liver Metabolism

肝脏代谢的激素调节

• 批准号: 10093021
• 负责人: Rhonda D Kineman
• 金额: $ 36.52万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 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 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10093021
• 关键词: Adipose tissue; Adult; Age; Automobile Driving; Biochemical Pathway; Carbohydrates; Cardiovascular Diseases; Clinical; Clinical Research; Closure by clamp; Coupled; Data; Diet; Disease Progression; Drug Targeting; Economic Burden; Exhibits; Fatty Acids; Fatty Liver; Fatty acid glycerol esters; Fibrosis; Fructose; Future; Glucokinase; Glucose; Glycolysis; Goals; Growth Hormone Receptor; Hepatic; Hepatocyte; Human; Hyperglycemia; IGF1 gene; Impairment; Inflammation; Injury; Insulin; Insulin Resistance; Insulin-Like Growth Factor I; JAK2 gene; Lipids; Lipolysis; Liver; Mediating; Medical; Molecular; Mus; Non obese; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathway interactions; Patients; Production; Publishing; Receptor Signaling; Regulation; Reporting; Resistance; Signal Pathway; Signal Transduction; Somatotropin; Testing; Triglycerides; Work; clinically relevant; cost; effective therapy; experimental study; growth hormone deficiency; hormonal signals; hormone regulation; insulin signaling; knock-down; lipid biosynthesis; lipid metabolism; liver injury; liver metabolism; mouse model; mutant; new therapeutic target; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; prevent; receptor; reconstitution; restoration; transcription factor

Summary/Abstract Non-alcoholic fatty liver disease (NAFLD) represents a spectrum of excess fat accumulation in the liver (steatosis) without or with inflammation/fibrosis (non-alcoholic steatohepatitis - NASH). NAFLD is commonly observed in obesity and type 2 diabetes, but is also observed in non-obese patients associated with cardiovascular disease. To date, there are no proven medical therapies to reverse NAFLD. In order to develop effective treatments, it is critical to understand the basic mechanisms controlling hepatic fat accumulation and associated liver damage. Since both clinical and experimental studies demonstrate hepatic growth hormone (GH)-signaling is reduced in NAFLD and increasing GH can reduce NAFLD both in humans and mice, our recent work has focused on determining how GH mediates these effects. We have used unique mouse models with adult-onset loss of the hepatocyte GH receptor (GHR) and demonstrated GH signaling controls steatosis by suppressing de novo lipogenesis (DNL), an action of GH not previously appreciated. Additional preliminary data, coupled with published reports, led us to formulate the HYPOTHESIS: GH directly controls hepatocyte DNL via GHR/Stat5b-mediated regulation of glycolysis, to protect the liver from injury. The following Specific Aims (SA) will test this hypothesis. SA1 - Determine if the GHR signals through Stat5 to directly suppress hepatic DNL and prevent NAFLD progression. Expt SA1A, will determine if enhancing Stat5b activity can suppress DNL and prevent NAFLD by expressing a constitutively active form of Stat5b (Stat5bCA) in mice lacking the hepatocyte GHR. Since Stat5b enhances hepatic IGF1 expression and raises circulating IGF1 levels, Stat5bCA will be expressed in mice with combined knockdown of hepatocyte GHR and IGF1, to determine what actions of Stat5b are IGF1-independent. Expt SA1B, will establish if GHR-mediated Stat5b activation is required to control DNL, by expressing a mutant GHR in the hepatocyte of adult mice lacking the endogenous GHR, where this mutant receptor cannot activate Stat5b, but can active other JAK2-dependent and independent pathways. In a subset of mice, hepatocyte IGF1 expression will be reconstituted, to prevent secondary changes due to IGF1 loss. SA2 – Determine if loss of hepatocyte GHR/Stat5b signaling acts independent of canonical insulin signaling to augment glycolysis-driven DNL. Expt SA2A, will determine if hepatocyte GHR loss and restoration of Stat5b activity regulates glycolytic flux and DNL when insulin and carbohydrate input to the liver is controlled, by assessing [1-13C] glucose enrichment of glycolytic, TCA intermediates and newly formed fatty acids, under hyperinsulinemic-hyperglycemic clamp conditions, in mice lacking the hepatocyte GHR, without or with Stat5bCA. Expt SA2B, will establish if the glycolysis-mediated transcription factor, Chrebp, is required to enhance DNL, steatosis and liver injury after hepatocyte GHR loss, by generating mice with adult-onset, hepatocyte knockdown of both Chrebpα and GHR. Completion of these studies will enhance our basic understanding of the mechanisms by which GH directly controls hepatocyte carbohydrate/lipid metabolism and protects the liver against injury, with the ultimate goal of unveiling novel “druggable” targets to treat NAFLD.

摘要/摘要 非酒精性脂肪肝病（NAFLD）代表肝脏中过量脂肪的积累 （脂肪变性）没有注射/纤维化（非酒精性脂肪性肝炎-NASH）。 NAFLD通常是 在肥胖症和2型糖尿病中观察到，但在与之相关的非肥胖患者中也观察到 心血管疾病。迄今为止，还没有可靠的医疗疗法来逆转NAFLD。为了发展 有效的治疗方法，了解控制肝脂肪积累的基本机制和 相关的肝损伤。由于临床和实验研究都证明了肝增长马 （GH） - 信号在NAFLD中减少，而GH的增加可以减少人类和小鼠的NAFLD，这是我们最近的 工作重点是确定GH如何介导这些影响。我们使用了独特的鼠标模型 成人发作的肝细胞GH受体（GHR）的丧失，并证明GH信号传导控制了脂肪变性 抑制从头脂肪形成（DNL），这是GH先前没有理解的作用。其他初步数据， 再加上已发表的报告，我们提出了假设：GH直接控制肝细胞DNL通过 GHR/STAT5B介导的糖酵解调节，以保护肝脏免受损伤。以下特定目标（SA） 将检验这一假设。 SA1-确定GHR是否通过STAT5信号直接抑制肝 DNL并防止NAFLD进展。 EXT SA1A，将确定增强STAT5B活动是否可以抑制 DNL和通过表达始终如一的STAT5B（STAT5BCA）的活性形式来预防NAFLD 肝细胞GHR。由于STAT5B增强了肝IGF1表达并提高循环IGF1水平，因此STAT5BCA 将在肝细胞GHR和IGF1结合敲低的小鼠中表达 STAT5B是无关的。 expt sa1b，将确定是否需要GHR介导的STAT5B激活才能控制 DNL，通过在缺乏内源性GHR的成年小鼠的肝细胞中表达一个突变的GHR， 突变接收器不能激活STAT5B，但是可以活跃其他JAK2依赖性和独立途径。在 小鼠的子集，将重组肝细胞IGF1表达，以防止因IGF1而引起的次要变化 损失。 SA2 - 确定肝细胞GHR/STAT5B信号的丧失是否独立于规范胰岛素 信号传导以增强糖酵解驱动的DNL。 expt sa2a，将确定肝细胞GHR是否损失和 当胰岛素和碳水化合物输入到肝脏时，STAT5B活性的恢复会调节糖酵解通量和DNL 通过评估[1-13C]糖酵解，TCA中间体和新形成的脂肪的评估[1-13C] 在缺乏肝细胞GHR的小鼠中，酸在高胰岛素 - 血糖夹子条件下，没有或 与STAT5BCA。 EXT SA2B将确定是否需要糖酵解介导的转录因子Chrebp 通过产生成人发病的小鼠，增强肝癌GHR损失后的DNL，脂肪变性和肝损伤 Chrebpα和GHR的肝细胞敲低。这些研究的完成将增强我们的基本 理解GH直接控制肝细胞碳水化合物/脂质代谢的机制和 保护肝脏免受伤害，其最终目标是揭示小说“可药”目标来治疗NAFLD。