Hormonal Regulation of Liver Metabolism

肝脏代谢的激素调节

基本信息

批准号：
10357761
负责人：
Rhonda D Kineman
金额：
$ 35.87万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
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 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10357761
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 Persons 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

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.

摘要/摘要非酒精性脂肪肝疾病（NAFLD）抑制剂肝脏中过多的脂肪积累（脂肪变性）通常具有炎症/纤维化（非酒精性脂肪性肝炎）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迄今为止，心血管疾病都没有倾斜的医疗疗法。有效的治疗方法，要了解控制肝脂肪积累的基本机制和肝脏损害。（GH） - 信号在NAFLD中降低，而GH的增加可以在人类和小鼠中重塑，这是我们最近的工作重点是确定GH如何介导我们的效果。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支持从头脂肪生成（DNL），GH的动作以前没有得到欣赏。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。如果GHR信号直接抑制肝 DNL并防止NAFLD进展。 DNL并通过在缺乏的小鼠中表达STAT5B（STAT5BCA）组成型活性形式来预防NAFLD 肝细胞GHR。将在肝细胞GHR和IGF1结合敲低的小鼠中表达 STAT5B是IGF1-IGF1-IGF1B，Expt SA1B，将确定是否需要GHR介导的STAT5B激活才能控制 DNL，通过在成年人的肝细胞中表达突变的GHR缺乏内源性GHR，其中突变受体无法激活STAT5B，但可以在A中活跃其他JAK2依赖性和独立途径小鼠的子集，肝细胞IGF1表达将被重新定为损失。向增强糖酵解驱动的DNL的信号。当胰岛素和肝脏输入肝脏输入为通过评估糖酵解，TCA中间和新脂肪的[1-13C]葡萄糖富集来控制在缺乏肝细胞GHR的小鼠中，酸在高胰岛素 - 血糖夹子条件下，没有或使用STAT5BCA。通过生成成人发病的小鼠，增强HEPATOTICTE GHR损失后的DNL，脂肪变性和肝损伤， CREBPα和GHR的肝细胞敲低将增强我们的基本了解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。