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:
- 金额:$ 45.18万
- 依托单位:
- 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:
- 关键词:Adolescent obesityAdultAdverse effectsAffectAldolase BAllelesAnimal ModelBackcrossingsBinding ProteinsCarbohydratesCardiovascular DiseasesClinicalConflict (Psychology)ConsumptionDataDevelopmentDiabetes MellitusDietDietary SucroseDiseaseDisease ResistanceDoseElementsEpidemicFGF21 geneFructoseGenesGeneticGlucoseGlycerolHepaticHereditary fructose intolerance syndromeHeterozygoteHigh Density Lipoprotein CholesterolHomeostasisHumanHypertensionHypertriglyceridemiaImpairmentIngestionInsulin ResistanceIntestinesKetohexokinaseKnock-outKnockout MiceKnowledgeLeadLipidsLiverMalabsorption SyndromesMediatingMetabolicMetabolic DiseasesMetabolic hormoneMetabolic syndromeMetabolismModelingMolecularMolecular GeneticsMouse StrainsMusObesityOrganoidsOutcomePharmacologyPhysiologicalPlayPopulationPortal vein structurePredispositionPrevention strategyProtein OverexpressionResistanceRoleSerumSingle Nucleotide PolymorphismSucroseSystemTherapeuticTriglyceridesUrateVariantabsorptionadenoviral-mediatedblood glucose regulationcarbohydrate metabolismclinically significantcohortdietaryfeedinggenome wide association studygenomic locusglucose productionglucose-6-phosphataseinsightknock-downloss of functionmouse modelmutantnon-alcoholic fatty liver diseasenovel strategiesobesity treatmentoverexpressionpreventprogramsprotein activationprotein functionresponsesugarsweetened beveragetranscription 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.
代谢综合征是一组疾病,包括肥胖,高脂血症,
高血压、非酒精性脂肪肝和胰岛素抵抗,这些疾病容易导致
糖尿病和心血管疾病。过量的糖摄入,主要是以糖的形式-
加糖饮料,可以促进代谢综合征的发展。的机制
过量的果糖消耗导致代谢性疾病仍然不确定。碳水化合物响应-
元件结合蛋白(ElementBindingProtein,ChREBP)是一种由碳水化合物产物激活的转录因子
代谢和调节代谢基因程序和全身葡萄糖和脂质稳态。中的snp
全基因组关联研究中确定的ChREBP基因座可预测老年人代谢综合征的特征
人类种群。肝脏和肠道ChREBP对果糖摄入高度敏感。肠丢失
由于果糖吸收不良,ChREBP导致果糖不耐受。相比之下,肝脏ChREBP的丢失是
耐受性良好,可预防果糖诱导的代谢疾病。有些小鼠品系对
对果糖引起的疾病有很强的抵抗力,而另一些则有很强的抵抗力。初步数据表明,这种易感性
可能是由肠道果糖吸收和代谢的相对差异介导的,这可能影响
将果糖输送到肝脏,在那里它是有害的。了解肠道疾病的分子决定因素
与肝脏果糖代谢的比较可能对饮食诱导的易感性具有重要影响
疾病通过遗传和饮食模型的结合,我们将研究生理,分子,
ChREBP介导的肠道和肝脏果糖代谢的遗传机制
会导致果糖引起的疾病在目标1中,使用一种精氨酸特异性的功能丧失小鼠模型,我们
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,
介导果糖引起的疾病。在目标2中,我们将确定净收益与不利收益
肝ChREBP激活的作用可能依赖于代谢激素FGF 21。在目标3中,使用
果糖敏感和果糖抵抗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,这些研究将提供基本的见解,
果糖诱导的代谢疾病的机制,并为新的策略奠定基础,
预防和治疗肥胖和糖尿病。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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MARK A HERMAN其他文献
MARK A HERMAN的其他文献
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{{ truncateString('MARK A HERMAN', 18)}}的其他基金
Mechanisms connecting dysregulated BCAA, glucose & lipid metabolism in the pathogenesis of metabolic disease
连接支链氨基酸失调、葡萄糖的机制
- 批准号:
10457911 - 财政年份:2019
- 资助金额:
$ 45.18万 - 项目类别:
Mechanisms connecting dysregulated BCAA, glucose & lipid metabolism in the pathogenesis of metabolic disease
连接支链氨基酸失调、葡萄糖的机制
- 批准号:
9792043 - 财政年份:2019
- 资助金额:
$ 45.18万 - 项目类别:
Mechanisms connecting dysregulated BCAA, glucose & lipid metabolism in the pathogenesis of metabolic disease
连接失调的 BCAA、葡萄糖的机制
- 批准号:
10223286 - 财政年份:2019
- 资助金额:
$ 45.18万 - 项目类别:
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:
8611060 - 财政年份:2014
- 资助金额:
$ 45.18万 - 项目类别:
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:
9203053 - 财政年份:2014
- 资助金额:
$ 45.18万 - 项目类别:
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:
9385541 - 财政年份:2014
- 资助金额:
$ 45.18万 - 项目类别:
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 - 财政年份:2014
- 资助金额:
$ 45.18万 - 项目类别:
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:
10117227 - 财政年份:2014
- 资助金额:
$ 45.18万 - 项目类别:
Adipose Tissue Branched-Chain Amino Acid Metabolism and Glucose Homeostasis
脂肪组织支链氨基酸代谢和葡萄糖稳态
- 批准号:
7429723 - 财政年份:2006
- 资助金额:
$ 45.18万 - 项目类别:
Adipose Tissue Branched-Chain Amino Acid Metabolism and Glucose Homeostasis
脂肪组织支链氨基酸代谢和葡萄糖稳态
- 批准号:
7288794 - 财政年份:2006
- 资助金额:
$ 45.18万 - 项目类别:
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