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: 10356838
• 负责人: MARK A HERMAN
• 金额: $ 45.18万
• 依托单位: DUKE UNIVERSITY
• 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 2022-06-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10356838
• 关键词: Adolescent obesity; Adult; Adverse effects; Affect; Aldolase B; Alleles; Animal Model; Backcrossings; Binding Proteins; Carbohydrates; Cardiovascular Diseases; Clinical; Conflict (Psychology); Consumption; Data; Development; Diabetes Mellitus; Diet; Dietary Sucrose; Disease; Disease Resistance; Dose; Elements; Epidemic; FGF21 gene; Fructose; Genes; Genetic; Glucose; Glycerol; Hepatic; Hereditary fructose intolerance syndrome; Heterozygote; High Density Lipoprotein Cholesterol; Homeostasis; Human; Hypertension; Hypertriglyceridemia; Impairment; Ingestion; Insulin Resistance; Intestines; Ketohexokinase; Knock-out; Knockout Mice; Knowledge; Lead; Lipids; Liver; Malabsorption Syndromes; Mediating; Metabolic; Metabolic Diseases; Metabolic hormone; Metabolic syndrome; Metabolism; Modeling; Molecular; Molecular Genetics; Mouse Strains; Mus; Obesity; Organoids; Outcome; Pharmacology; Physiological; Play; Population; Portal vein structure; Predisposition; Prevention strategy; Protein Overexpression; Resistance; Role; Serum; Single Nucleotide Polymorphism; Sucrose; System; Therapeutic; Triglycerides; Urate; Variant; absorption; adenoviral-mediated; blood glucose regulation; carbohydrate metabolism; clinically significant; cohort; dietary; feeding; genome wide association study; genomic locus; glucose production; glucose-6-phosphatase; insight; knock-down; loss of function; mouse model; mutant; non-alcoholic fatty liver disease; novel strategies; obesity treatment; overexpression; prevent; programs; protein activation; protein function; response; sugar; sweetened beverage; transcription factor

The metabolic syndrome is a cluster of disorders that includes obesity, hypertriglyceridemia, hypertension, non-alcoholic fatty liver disease and insulin resistance which predispose to the development of diabetes and cardiovascular disease. Excessive sugar consumption, predominantly in the form of sugar- sweetened beverages, can contribute to the development of the metabolic syndrome. The mechanisms by which excessive fructose consumption contributes to metabolic disease remain uncertain. Carbohydrate Responsive- Element Binding Protein (ChREBP) is a transcription factor which is activated by products of carbohydrate metabolism and regulates metabolic gene programs and systemic glucose and lipid homeostasis. SNPs in the ChREBP locus identified in genome-wide association studies predict features of the metabolic syndrome in human populations. Hepatic and intestinal ChREBP are highly responsive to fructose ingestion. Loss of intestinal ChREBP results in fructose-intolerance due to fructose malabsorption. In contrast, loss of hepatic ChREBP is well-tolerated and protects against fructose-induced metabolic disease. Some mouse strains are highly sensitive to fructose-induced disease whereas others are highly resistant. Preliminary data suggests that this susceptibility may be mediated by relative differences in intestinal fructose absorption and metabolism, which may affect delivery of fructose to the liver where it is deleterious. Understanding the molecular determinants of intestinal versus hepatic fructose metabolism may have important implications for the susceptibility to diet-induced disease. Through a combination of genetic and dietary models, we will investigate physiological, molecular, and genetic mechanisms by which ChREBP-mediated intestinal and hepatic fructose metabolism protect against or contribute to fructose-induced disease. In Aim 1, using an intestine-specific, loss-of-function mouse model, we will explore the importance of intestinal fructose metabolism in regulating endogenous glucose production and mediating fructose-induced disease. In Aim 2, we will determine whether the net beneficial versus adverse effects of hepatic ChREBP activation may be dependent on the metabolic hormone FGF21. In Aim 3, using fructose sensitive and fructose resistant mice in combination with an intestinal organoid model, we will explore the molecular mechanisms giving rise to differences in intestinal fructose absorption, metabolism, and susceptibility to fructose-induced 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.

代谢综合征是包括肥胖症，高甘油三酸酯血症的疾病群 高血压，非酒精性脂肪肝疾病和胰岛素抵抗，易感性 糖尿病和心血管疾病。过度消耗糖，主要是以糖的形式 甜饮料，可以有助于代谢综合征的发展。所在的机制 过度的果糖消耗导致代谢疾病仍然不确定。碳水化合物反应 元素结合蛋白（CHREBP）是转录因子，被碳水化合物产物激活 代谢和调节代谢基因程序以及系统性葡萄糖和脂质稳态。 SNP在 CHREBP在全基因组关联研究中鉴定出的CHREBP基因座预测代谢综合征在 人口。肝脏和肠道Chrebp对果糖摄入高度反应。肠道丧失 CHREBP导致果糖吸收不良引起的果糖含量。相比之下，肝chrebp的损失是 耐受性良好，可以防止果糖诱导的代谢疾病。一些小鼠菌株高度敏感 果糖引起的疾病，而其他疾病具有高度抗性。初步数据表明这种敏感性 可能是由肠道果糖吸收和代谢的相对差异介导的，这可能会影响 将果糖输送到肝脏有害的肝脏。了解肠道的分子决定因素 与肝果糖代谢相对于肝果糖代谢可能对饮食引起的易感性具有重要意义 疾病。通过遗传和饮食模型的结合，我们将研究生理，分子和 Chrebp介导的肠道和肝果糖代谢可防止或 有助于果糖诱导的疾病。在AIM 1中，使用肠道特异性的，功能丧失的鼠标模型，我们 将探讨肠道果糖代谢在调节内源性葡萄糖产生和 介导果糖诱导的疾病。在AIM 2中，我们将确定网络有益与不利 肝CHREBP激活的作用可能取决于代谢激素FGF21。在AIM 3中，使用 果糖敏感和果糖抗性小鼠与肠癌模型结合使用，我们将探索 分子机制导致肠道果糖吸收，代谢和 对果糖诱导疾病的敏感性。我们预计这些研究将为您提供基本洞察力 果糖诱导的代谢疾病的机制，并为新的策略奠定了基础 预防和治疗肥胖和糖尿病。