Signaling Pathways Regulating the Activity of ChREBP by Glucose

葡萄糖调节 ChREBP 活性的信号通路

• 批准号: 7329243
• 负责人: ADAM J SHAYWITZ
• 金额: $ 5.48万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-26 至 2009-06-25
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7329243
• 关键词: 14-3-3 Proteins; Acetylation; Affect; Binding Proteins; Biochemical; Biological Assay; Blood Glucose; Carbohydrates; Cell Line; Cell Nucleus; Cells; Condition; Cultured Cells; Cyclic AMP-Dependent Protein Kinases; Cytosol; Defect; Diabetes Mellitus; Disease; Disruption; Elevation; Emerging Technologies; Engineering; Exhibits; Family; Fatty acid glycerol esters; Gene Family; Genes; Genetic; Glucose; Glucose Transporter; Glycolysis; Goals; Hepatocyte; Incidence; Injection of therapeutic agent; Label; Laboratories; Lead; Libraries; Lipids; Lipodystrophy; Liver; Location; Mass Spectrum Analysis; Metabolic; Metabolic Control; Metformin; Methylation; Modification; Monitor; Mus; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Organism; Oxidative Stress; Pharmaceutical Preparations; Phosphorylation; Phosphorylation Site; Phosphotransferases; Play; Post-Translational Protein Processing; Prevention; Protein Kinase; Proteins; Public Health; Pyruvate Kinase; RNA Interference; Rare Diseases; Rate; Regulation; Reporter; Reporting; Resources; Response Elements; Role; STK11 gene; Serum; Signal Pathway; Signal Transduction; System; Tail; Techniques; Testing; Time; Up-Regulation; Veins; activating transcription factor; base; carbohydrate binding protein; carbohydrate receptor; extracellular; glucose metabolism; glucose uptake; hormone regulation; in vivo; insight; interest; intracellular protein transport; lipid metabolism; man; mature animal; member; mutant; novel; programs; protein expression; protein function; protein localization location; research study; response; transcription factor; upstream kinase

DESCRIPTION (provided by applicant): Project Summary The overarching goal of the proposed project is to better understand the intracellular and extracellular signals that regulate fat storage in the mature animal. From an evolutionary perspective, the ability of an organism to store energy in the form of fat when resources are plentiful is critical for its survival in ensuing times when resources are scarce. However, inappropriate fat storage can lead to multiple metabolic problems in man, including both common diseases such as obesity and type 2 diabetes as well as rarer disorders such as the lipodystrophies. The carbohydrate response-element binding protein (ChREBP) is a protein recently identified as playing a critical role in conversion of carbohydrate into fats. This factor responds to changes in serum glucose levels by activating cellular programs of lipid synthesis and storage, and mice lacking ChREBP exhibit significant alterations in lipid and glucose metabolism. AMP-dependent protein kinase (AMPK) is another well-characterized protein that senses intracellular energy and glucose but appears to function in a manner opposite to ChREBP. We and others have previously reported that the commonly used diabetes medication metformin relies on AMPK for exerting its beneficial effect on blood glucose. We wish to test the hypothesis that AMPK plays either a direct or indirect role as a negative regulator of ChREBP and that elevation in glucose uptake reduces AMPK activity and thus circumvents the negative regulation. The aims of this proposed project are to first identify the specific modifications on ChREBP induced by changes in serum glucose and then to investigate whether these modifications are consistent with the known activity of AMPK. These modifications will be identified using the technique of mass spectrometry, an emerging technology with which our laboratory has proven expertise. We also will test whether conditions that either enhance or inhibit AMPK activity lead to functional changes in ChREBP within the cell. We will then test whether genetic disruption of AMPK function, both in cultured cells as well as in mice, leads to changes in ChREBP activity. Relevance Type 2 diabetes and obesity are growing public health concerns both characterized by disordered fat metabolism. Identification of the specific molecules controlling fat synthesis and storage will provide new insights into these disorders and may potentially produce novel pharmacologic targets for treatment.

描述（由申请人提供）：项目摘要拟议项目的总体目标是更好地了解调节成熟动物脂肪储存的细胞内和细胞外信号。从进化的角度来看，生物体在资源充足时以脂肪形式储存能量的能力对于其在随后资源稀缺时期的生存至关重要。然而，不适当的脂肪储存可能会导致人类出现多种代谢问题，包括肥胖和2型糖尿病等常见疾病以及脂肪营养不良等罕见疾病。碳水化合物反应元件结合蛋白（ChREBP）是一种最近被鉴定为在碳水化合物转化为脂肪的过程中发挥关键作用的蛋白质。该因子通过激活脂质合成和储存的细胞程序来响应血清葡萄糖水平的变化，缺乏 ChREBP 的小鼠表现出脂质和葡萄糖代谢的显着改变。 AMP 依赖性蛋白激酶 (AMPK) 是另一种特征明确的蛋白质，可感知细胞内能量和葡萄糖，但其功能似乎与 ChREBP 相反。我们和其他人之前曾报道过，常用的糖尿病药物二甲双胍依赖 AMPK 发挥其对血糖的有益作用。我们希望检验以下假设：AMPK 作为 ChREBP 的负调节剂发挥直接或间接作用，并且葡萄糖摄取的升高会降低 AMPK 活性，从而规避负调节。该项目的目的是首先确定血清葡萄糖变化引起的 ChREBP 特异性修饰，然后研究这些修饰是否与已知的 AMPK 活性一致。这些修饰将使用质谱技术来识别，这是一种新兴技术，我们的实验室拥有经过验证的专业知识。我们还将测试增强或抑制 AMPK 活性的条件是否会导致细胞内 ChREBP 的功能变化。然后，我们将测试培养细胞和小鼠中 AMPK 功能的遗传破坏是否会导致 ChREBP 活性的变化。相关性 2 型糖尿病和肥胖症日益引起公众健康关注，其特点是脂肪代谢紊乱。控制脂肪合成和储存的特定分子的识别将为这些疾病提供新的见解，并可能产生新的治疗药理学靶点。