Hormonal Regulation of Liver Metabolism

肝脏代谢的激素调节

基本信息

  • 批准号:
    10093021
  • 负责人:
  • 金额:
    $ 36.52万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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.
总结/摘要 非酒精性脂肪性肝病(NAFLD)代表了肝脏中脂肪过度积累的一系列表现。 (脂肪变性)而不伴有或伴有炎症/纤维化(非酒精性脂肪性肝炎- NASH)。NAFLD通常 在肥胖和2型糖尿病中观察到,但也在与糖尿病相关的非肥胖患者中观察到。 心血管疾病到目前为止,还没有经过证实的医学疗法可以逆转NAFLD。为了发展 为了获得有效的治疗方法,关键是要了解控制肝脏脂肪堆积的基本机制, 相关的肝损伤。由于临床和实验研究都表明肝生长激素 在NAFLD中,(GH)-信号传导减少,增加GH可以减少人类和小鼠的NAFLD,我们最近的研究表明, 工作集中在确定GH如何介导这些作用。我们使用了独特的小鼠模型, 成年期肝细胞GH受体(GHR)的丢失,并证实GH信号通过以下途径控制脂肪变性: 抑制从头脂肪生成(DNL),以前没有认识到GH的作用。其他初步数据, 结合已发表的报告,我们提出了以下假设:GH通过以下途径直接控制肝细胞DNL: GHR/Stat 5 b介导的糖酵解调节,保护肝脏免受损伤。具体目标(SA) 将检验这个假设。SA 1-确定GHR是否通过Stat 5发出信号,以直接抑制肝脏 DNL和防止NAFLD进展。实验SA 1A将确定增强Stat 5 b活性是否可以抑制 DNL和预防NAFLD通过表达Stat 5 b的组成型活性形式(Stat 5 bCA)在缺乏DNL的小鼠中, 肝细胞GHR。由于Stat 5 b增强肝脏IGF 1表达并提高循环IGF 1水平,因此Stat 5 bCA 将在肝细胞GHR和IGF 1联合敲低的小鼠中表达,以确定 Stat 5 b不依赖于IGF 1。实验SA 1B将确定是否需要GHR介导的Stat 5 b激活来控制 DNL,通过在缺乏内源性GHR的成年小鼠的肝细胞中表达突变型GHR, 突变型受体不能激活Stat 5 b,但可以激活其他JAK 2依赖性和非依赖性途径。中 在小鼠亚组中,将重建肝细胞IGF 1表达,以防止由于IGF 1引起的继发性变化 损失SA 2-确定肝细胞GHR/Stat 5 b信号传导的丧失是否独立于经典胰岛素发挥作用 信号以增强糖酵解驱动的DNL。实验SA 2A将确定肝细胞GHR损失和 当胰岛素和碳水化合物输入肝脏时,Stat 5 b活性的恢复调节糖酵解通量和DNL。 通过评估糖酵解、TCA中间体和新形成的脂肪酸的[1- 13 C]葡萄糖富集, 酸,在高胰岛素-高血糖钳夹条件下,在缺乏肝细胞GHR的小鼠中, 关于Stat 5 bCA实验SA 2B将确定糖酵解介导的转录因子Chrebp β是否需要 增强DNL,脂肪变性和肝细胞GHR损失后的肝损伤,通过产生成年发病的小鼠, Chrebpα和GHR两者的肝细胞敲低。完成这些研究将加强我们的基本 了解GH直接控制肝细胞碳水化合物/脂质代谢的机制, 保护肝脏免受损伤,最终目标是揭示治疗NAFLD的新的“可药物化”目标。

项目成果

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Rhonda D Kineman其他文献

Rhonda D Kineman的其他文献

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{{ truncateString('Rhonda D Kineman', 18)}}的其他基金

BLRD Research Career Scientist Award Application
BLRD 研究职业科学家奖申请
  • 批准号:
    10514612
  • 财政年份:
    2020
  • 资助金额:
    $ 36.52万
  • 项目类别:
BLRD Research Career Scientist Award Application
BLRD 研究职业科学家奖申请
  • 批准号:
    10337062
  • 财政年份:
    2020
  • 资助金额:
    $ 36.52万
  • 项目类别:
Hormonal Regulation of Liver Metabolism
肝脏代谢的激素调节
  • 批准号:
    10357761
  • 财政年份:
    2019
  • 资助金额:
    $ 36.52万
  • 项目类别:
Hormonal Regulation of Liver Metabolism
肝脏代谢的激素调节
  • 批准号:
    9902412
  • 财政年份:
    2019
  • 资助金额:
    $ 36.52万
  • 项目类别:
Hormonal control of NASH development and progression
NASH 发生和进展的激素控制
  • 批准号:
    10454874
  • 财政年份:
    2019
  • 资助金额:
    $ 36.52万
  • 项目类别:
Hormonal control of NASH development and progression
NASH 发生和进展的激素控制
  • 批准号:
    10265382
  • 财政年份:
    2019
  • 资助金额:
    $ 36.52万
  • 项目类别:
Hormonal control of NASH development and progression
NASH 发生和进展的激素控制
  • 批准号:
    9906041
  • 财政年份:
    2019
  • 资助金额:
    $ 36.52万
  • 项目类别:
Hormonal control of NASH development and progression
NASH 发生和进展的激素控制
  • 批准号:
    10588460
  • 财政年份:
    2019
  • 资助金额:
    $ 36.52万
  • 项目类别:
Low-intensity vibration to improve healing of chronic wounds
低强度振动可促进慢性伤口的愈合
  • 批准号:
    10264788
  • 财政年份:
    2018
  • 资助金额:
    $ 36.52万
  • 项目类别:
Low-intensity vibration to improve healing of chronic wounds
低强度振动可促进慢性伤口的愈合
  • 批准号:
    10681198
  • 财政年份:
    2018
  • 资助金额:
    $ 36.52万
  • 项目类别:

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