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

基本信息

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
项目类别：
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

项目摘要

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.

代谢综合征是一系列疾病，包括肥胖、高甘油三酯血症、高血压、非酒精性脂肪肝和胰岛素抵抗，这些都容易导致糖尿病和心血管疾病。摄入过多的糖，主要以糖的形式加糖饮料可能会导致代谢综合征的发生。其机制过量果糖消耗是否会导致代谢性疾病仍不确定。碳水化合物反应- 元素结合蛋白 (ChREBP) 是一种被碳水化合物产物激活的转录因子代谢并调节代谢基因程序以及全身葡萄糖和脂质稳态。 SNP 位于全基因组关联研究中确定的 ChREBP 位点可预测代谢综合征的特征人口。肝脏和肠道 ChREBP 对果糖摄入高度敏感。肠道流失 ChREBP 由于果糖吸收不良而导致果糖不耐受。相反，肝脏 ChREBP 的损失是耐受性良好，可预防果糖引起的代谢性疾病。一些小鼠品系高度敏感对果糖引起的疾病有很强的抵抗力。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，在那里它是有害的。了解肠道的分子决定因素与肝脏果糖代谢相比可能对饮食诱导的易感性产生重要影响疾病。通过遗传和饮食模型的结合，我们将研究生理、分子和 ChREBP 介导的肠道和肝脏果糖代谢预防或预防的遗传机制有助于果糖诱发的疾病。在目标 1 中，我们使用肠道特异性功能丧失小鼠模型将探讨肠道果糖代谢在调节内源性葡萄糖产生中的重要性和介导果糖诱发的疾病。在目标 2 中，我们将确定净有利与不利肝脏 ChREBP 激活的影响可能取决于代谢激素 FGF21。在目标 3 中，使用果糖敏感和果糖抗性小鼠与肠道类器官模型相结合，我们将探索引起肠道果糖吸收、代谢和代谢差异的分子机制对果糖诱发疾病的易感性。我们预计这些研究将为以下问题提供基本见解：果糖诱导的代谢疾病的机制，并为新策略奠定基础预防和治疗肥胖和糖尿病。