The Role of ChREBP in Fructose Induced Metabolic Disease

ChREBP 在果糖诱导的代谢性疾病中的作用

• 批准号: 8791897
• 负责人: MARK A HERMAN
• 金额: $ 37.85万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-15 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8791897
• 关键词: Ablation; Affect; Animal Model; Area; Binding Proteins; Biological; Body Composition; Body Weight; Carbohydrates; Cardiovascular Diseases; Clinical Data; Complex; Consumption; Coupled; Data; Development; Diabetes Mellitus; Diet; Dietary Intervention; Dietary Sucrose; Disease; Disease Resistance; Dyslipidemias; Elements; Endocrinology; Enzymes; Epidemic; Epidemiology; Fructose; Functional disorder; Genes; Genetic; Glucokinase; Glucose; Goals; Health; Hepatic; Hereditary fructose intolerance syndrome; Homeostasis; Human; Hypertension; Hypertriglyceridemia; Ingestion; Insulin Resistance; Intestines; Lipids; Liver; Liver diseases; Metabolic; Metabolic Diseases; Metabolic syndrome; Metabolism; Modeling; Molecular; Mus; Nutritional; Obesity; Physiological; Play; Population; Positioning Attribute; Prevention; Protein Isoforms; Regulatory Element; Reporting; Risk Factors; Role; Serum; Single Nucleotide Polymorphism; Small Intestines; Sucrose; Tissues; Triglycerides; blood glucose regulation; carbohydrate metabolism; carbohydrate receptor; computer studies; feeding; gain of function; gene therapy; genome wide association study; glucose production; in vivo; insight; insulin sensitivity; loss of function; mouse model; non-alcoholic fatty liver; novel; novel strategies; novel therapeutics; obesity treatment; overexpression; prevent; programs; research study; response; sugar; sweetened beverage; transcription factor

DESCRIPTION (provided by applicant): The metabolic syndrome is a cluster of disorders that includes obesity, dyslipidemia, hypertension, non- alcoholic fatty liver disease and insulin resistance, all of which predispose to the development of diabetes and cardiovascular disease. Epidemiological and clinical data indicate that increased sugar, and particularly fructose, ingestion is a major contributor to the development of the metabolic syndrome and progression to diabetes. The mechanisms by which fructose consumption causes metabolic dysfunction remain elusive. Carbohydrate Responsive-Element Binding Protein (ChREBP) is a master transcriptional regulator of glycolytic and lipogenic gene programs which is activated by products of carbohydrate metabolism. SNPs in the ChREBP locus identified in genome-wide association studies predict features of the metabolic syndrome in human populations. We recently discovered a novel, potent constitutively active isoform of ChREBP, ChREBP-beta. In vivo, ChREBP-beta expression is acutely and robustly increased by fructose ingestion, but only modestly by glucose ingestion. Mice with whole-body genetic deletion of ChREBP die within several days of high-fructose feeding. In this proposal, we will pursue an integrative physiological approach to determine the role of ChREBP in fructose-induced metabolic disturbances. We hypothesize that ChREBP, and particularly ChREBP-beta, is a key regulatory element that is required for the normal adaptive metabolic response to fructose ingestion and also contributes to the development of metabolic disease and diabetes when sugar is consumed in excess. Using a combination of genetic and dietary interventions in mouse models, we will evaluate the role of ChREBP in integrated fuel homeostasis by pursuing the following three aims. In Aim 1, using tissue-specific, loss-of-function mouse models, we will explore the physiologic and cellular mechanisms by which the absence of ChREBP impairs integrated fuel homeostasis and causes fructose intolerance. In Aim 2, using a ChREBP gain-of-function mouse model combined with diets of different carbohydrate content and composition, we will explore a novel concept that the effects of ChREBP activity on integrated fuel homeostasis and insulin sensitivity depend on the nutritional context. In Aim 3, we will develop a novel, ChREBP-beta isoform specific conditional loss-of-function mouse model to begin to determine the physiological significance of the distinct ChREBP isoforms in relation to integrated fuel metabolism and fructose induced metabolic disease. We anticipate that these studies will provide fundamental insight into mechanisms of fructose-induced metabolic disease and lay the groundwork for novel strategies for the prevention and treatment of obesity and diabetes.

描述（由申请人提供）：代谢综合征是包括肥胖症，血脂异常，高血压，非酒精性脂肪肝病和胰岛素抵抗的疾病群，所有这些都使糖尿病和心血管疾病的发展易感性。流行病学和临床数据表明，摄入量增加了糖，尤其是果糖，是代谢综合征发展和糖尿病发展的主要原因。果糖消耗引起代谢功能障碍的机制仍然难以捉摸。碳水化合物反应性元素结合蛋白（CHREBP）是糖酵解和脂肪生成基因程序的主要转录调节剂，被碳水化合物代谢产物激活。在全基因组关联研究中鉴定出的Chrebp基因座的SNP可以预测人类种群中代谢综合征的特征。我们最近发现了Chrebp，Chrebp-beta的一种新颖的，有效的组成型活性同工型。在体内，Chrebp-beta的表达通过果糖摄入而急剧，稳健地增加，但仅通过葡萄糖摄入而适度地增加。 Chrebp全身遗传缺失的小鼠在高果糖进食后的几天内死亡。在此提案中，我们将采用一种综合生理方法来确定Chrebp在果糖诱导的代谢障碍中的作用。我们假设Chrebp，尤其是Chrebp-beta，是正常适应性代谢对果糖摄入所必需的关键调节元素，当糖分过量食用时，还会有助于代谢疾病和糖尿病的发展。通过在小鼠模型中结合遗传和饮食干预措施，我们将通过追求以下三个目标来评估Chrebp在综合燃料稳态中的作用。在AIM 1中，使用组织特异性的，功能丧失的小鼠模型，我们将探索生理和细胞机制，通过这种机制，CHREBP的缺乏会损害综合的燃料稳态并导致果糖不耐症。在AIM 2中，使用CHREBP功能获得的小鼠模型结合了不同碳水化合物含量和成分的饮食，我们将探讨一个新颖的概念，即Chrebp活性对综合燃料稳态和胰岛素敏感性的影响取决于营养环境。在AIM 3中，我们将开发出一种新型的Chrebp-beta同工型特定条件功能丧失的小鼠模型，以开始确定与综合燃料代谢和果糖诱导的代谢疾病有关的不同Chrebp同工型的生理意义。我们预计，这些研究将提供对果糖诱导的代谢疾病机制的基本见解，并为预防和治疗肥胖和糖尿病的新型策略奠定了基础。