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）：代谢综合征是一组疾病，包括肥胖、血脂异常、高血压、非酒精性脂肪肝病和胰岛素抵抗，所有这些都易于发展为糖尿病和心血管疾病。流行病学和临床数据表明，糖摄入量增加，特别是果糖摄入量增加，是导致代谢综合征发生和进展为糖尿病的主要原因。果糖消耗导致代谢功能障碍的机制仍然难以捉摸。碳水化合物反应元件结合蛋白 (ChREBP) 是糖酵解和脂肪生成基因程序的主要转录调节因子，由碳水化合物代谢产物激活。全基因组关联研究中发现的 ChREBP 位点中的 SNP 可预测人群代谢综合征的特征。我们最近发现了一种新型、有效的 ChREBP 组成型活性异构体 ChREBP-beta。在体内，果糖摄入会急剧而强烈地增加 ChREBP-β 表达，但摄入葡萄糖只会适度增加。全身 ChREBP 基因缺失的小鼠在高果糖喂养的几天内就会死亡。在本提案中，我们将采用综合生理学方法来确定 ChREBP 在果糖诱导的代谢紊乱中的作用。我们假设 ChREBP，特别是 ChREBP-β，是对果糖摄入的正常适应性代谢反应所需的关键调节元件，并且当糖摄入过量时也会导致代谢疾病和糖尿病的发生。在小鼠模型中结合遗传和饮食干预，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。在目标 1 中，我们将使用组织特异性、功能丧失的小鼠模型，探索 ChREBP 缺失损害综合燃料稳态并导致果糖不耐受的生理和细胞机制。在目标 2 中，我们将使用 ChREBP 功能获得性小鼠模型结合不同碳水化合物含量和组成的饮食，探索一个新概念，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。在目标 3 中，我们将开发一种新型 ChREBP-beta 异构体特异性条件性功能丧失小鼠模型，以开始确定不同 ChREBP 异构体与综合燃料代谢和果糖诱导的代谢疾病相关的生理意义。我们预计这些研究将为果糖引起的代谢疾病的机制提供基本见解，并为预防和治疗肥胖和糖尿病的新策略奠定基础。