The Role of ChREBP in Fructose Induced Metabolic Disease

描述（由申请人提供）：代谢综合征是包括肥胖、血脂异常、高血压、非酒精性脂肪性肝病和胰岛素抵抗在内的一系列疾病，所有这些疾病都易导致糖尿病和心血管疾病的发展。流行病学和临床数据表明，糖，特别是果糖的摄入增加是代谢综合征发展和糖尿病进展的主要因素。果糖消耗导致代谢功能障碍的机制仍然难以捉摸。碳水化合物响应元件结合蛋白（ChREBP）是糖酵解和脂肪生成基因程序的主要转录调控因子，由碳水化合物代谢产物激活。在全基因组关联研究中发现的ChREBP位点的单核苷酸多态性预测了人类代谢综合征的特征。我们最近发现了一种新的、有效的组成活性的ChREBP异构体，ChREBP- β。在体内，摄入果糖会显著增加chrebp - β的表达，而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死亡。在这项提议中，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，尤其是ChREBP- β，是果糖摄取正常适应性代谢反应所必需的关键调控元件，当糖摄入过量时，也有助于代谢性疾病和糖尿病的发展。通过在小鼠模型中使用遗传和饮食干预的组合，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，我们将使用组织特异性的功能缺失小鼠模型，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Aim 2中，我们将使用ChREBP功能获得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，我们将开发一种新的ChREBP- β异构体特异性条件功能丧失小鼠模型，开始确定不同ChREBP异构体在综合燃料代谢和果糖诱导代谢疾病中的生理意义。我们期望这些研究将为果糖诱导代谢疾病的机制提供基本的见解，并为预防和治疗肥胖和糖尿病的新策略奠定基础。

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.