The Role of ChREBP in Fructose Induced Metabolic Disease

描述(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、非酒精性脂肪肝和胰岛素抵抗，所有这些疾病都容易发展为糖尿病和心血管疾病。流行病学和临床数据表明，糖，特别是果糖的摄入量增加是代谢综合征发展和发展为糖尿病的主要因素。摄入果糖导致代谢功能障碍的机制仍然不清楚。碳水化合物反应元件结合蛋白(ChREBP)是糖酵解和造脂基因程序的主要转录调节因子，由糖代谢产物激活。全基因组关联研究中发现的ChREBP基因座中的SNPs预测了人类群体中代谢综合征的特征。我们最近发现了一种新的、有效的ChREBP的成分活性异构体，ChREBP-β。在体内，摄取果糖可以显著增加ChREBP-β的表达，但摄取葡萄糖只能适度增加ChREBP-β的表达。ChREBP基因全身缺失的小鼠在高果糖喂养的几天内死亡。在这项提案中，我们将采用综合的生理学方法来确定ChREBP在果糖诱导的代谢紊乱中的作用。我们推测，ChREBP，特别是ChREBP-β，是对果糖摄入的正常适应性代谢反应所必需的关键调节元件，也有助于当糖过量消耗时代谢性疾病和糖尿病的发生。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在综合燃料动态平衡中的作用。在目标1中，利用组织特异性、功能丧失的小鼠模型，我们将探索缺乏ChREBP破坏整体燃料动态平衡和导致果糖不耐受的生理和细胞机制。在目标2中，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，我们将探索一个新的概念，即ChREBP活性对综合燃料动态平衡和胰岛素敏感性的影响取决于营养环境。在目标3中，我们将建立一种新的ChREBP-β亚型特异性条件性功能丧失小鼠模型，以开始确定不同的ChREBP亚型与综合燃料代谢和果糖诱导的代谢性疾病相关的生理意义。我们预计这些研究将为果糖诱导的代谢性疾病的机制提供基本的见解，并为预防和治疗肥胖症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.