The role of intestinal SCD1 in regulating metabolic health
肠道SCD1在调节代谢健康中的作用
基本信息
- 批准号:10430276
- 负责人:
- 金额:$ 39.16万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-07-01 至 2026-05-31
- 项目状态:未结题
- 来源:
- 关键词:AcidsAcuteAddressAgonistAnimalsAssimilationsBile AcidsBile fluidBiliaryBrown FatCaco-2 CellsCardiovascular DiseasesCell LineCholesterolChylomicronsDataDevelopmentDietEnergy MetabolismEnterocytesEpithelial CellsEsterificationFatty AcidsFatty LiverG-Protein-Coupled ReceptorsGPBAR1 geneGene ExpressionHealthHepaticHepatobiliaryHomeostasisHumanHyperlipidemiaInsulin ResistanceIntestinal ContentIntestinesKnowledgeLinkLipidsLipoproteinsLiverLoxP-flanked alleleMeasurementMeasuresMediatingMetabolicMonounsaturated Fatty AcidsMusMutationNutrientNutritionalOral AdministrationOrganPathologyPeroxisome Proliferator-Activated ReceptorsPharmacologic SubstancePlasmaProteinsReceptor SignalingRegulationRoleSIRT1 geneSaturated Fatty AcidsSignal TransductionSkinStearoyl-CoA DesaturaseSucroseTestingTissuesabsorptionbile acid metabolismcardiometabolismdietaryenergy balancefeedingglucagon-like peptide 1glucose metabolismglucose toleranceimprovedinhibitorintestinal epitheliumlipid metabolismlipidomicsmetabolic phenotypemouse modelnovelreceptorreuptakeuptakevirtual
项目摘要
The intestine is emerging as a regulatory and signaling organ, enabling diet-derived nutrients to perform
essential actions. A better understanding of intestinal regulation of systemic lipid metabolism has direct
implications to multiple human metabolic pathologies, including cardiovascular disease, fatty liver, and insulin
resistance. The delta-9 desaturase, stearoyl-CoA desaturase-1 (SCD1), converts saturated fatty acids to
monounsaturated products and has been shown to regulate lipid esterification in liver and skin. However,
virtually nothing is known about the role of SCD1 in the intestine, where lipid esterification is crucial for its
eventual absorption and secretion into chylomicrons (CMs). To address this gap in knowledge, we generated
mice with a targeted deletion of SCD1 only in intestinal epithelial cells (iKO mice). Remarkably, we find that
iKO animals have significant reductions not only in intestinal lipids, but also in circulating and hepatic lipid
levels, particularly in levels of monounsaturated fatty acids. iKO mice also have significant increases in both
energy expenditure and glucose tolerance, accompanied by increased thermogenic markers in brown adipose
tissue and increased plasma GLP-1 levels. Unexpectedly, intestinal SCD1 deletion elevates plasma and
hepatic bile acids (BAs) and alters markers of hepatobiliary BA efflux and ileal BA reuptake. Supported by
these and other compelling preliminary data, this application will assess the role of intestinal SCD1 in
integrating metabolic signals originating in the gut. The central hypothesis of this application is that intestinal
SCD1 regulates metabolic health by altering secreted lipid content and composition, TGR5 signaling in BAT
and the gut, and enterohepatic BA metabolism. This hypothesis will be tested by our two related but
independent Specific Aims. In Aim 1, we will test the relevance of intestinal SCD1 inhibition to energy balance
in the context of hypercaloric and hyperlipidemic diets. We will also evaluate a mechanistic role for TGR5 in
mediating the improved metabolic phenotypes of iKO mice. In Aim 2, we will evaluate a role for SCD1-derived
MUFAs in regulating hepatic BA efflux and intestinal BA reuptake . We will also utilize a) an inhibitor of
intestinal BA reuptake, b) a gut-restricted FXR agonist, and c) dietary MUFAs to restore hepatic and plasma
BA levels in iKO mice.
肠道正在成为一个调节和信号器官,使饮食衍生的营养物质能够发挥作用
基本行动。更好地了解肠道对全身脂代谢的调节直接
对多种人类代谢病理的影响,包括心血管疾病、脂肪肝和胰岛素
抵抗。Delta-9去饱和酶,硬脂酰辅酶A去饱和酶-1(SCD1),将饱和脂肪酸转化为
它是单不饱和产物,并已被证明能调节肝脏和皮肤中的脂酯化。然而,
几乎对scd1在肠道中的作用一无所知,在肠道中,脂酯化是其关键。
最终吸收和分泌到乳糜粒(CMS)。为了解决这一知识差距,我们产生了
仅在肠上皮细胞中靶向缺失SCD1的小鼠(IKO小鼠)。值得注意的是,我们发现
IKO动物不仅在肠道脂质方面有显著的降低,而且在循环和肝脏的脂质方面也有显著的降低。
水平,特别是单不饱和脂肪酸水平。IKO小鼠的这两种激素水平也显著增加
棕色脂肪的能量消耗和糖耐量增加,伴随着生热标记物的增加
组织和血浆GLP-1水平升高。出乎意料的是,肠道SCD1缺失会升高血浆和
肝胆汁酸(BAs)和改变肝胆BA流出和回肠BA再摄取的标志物。支持:
这些和其他令人信服的初步数据,该应用程序将评估肠道SCD1在
整合源自肠道的代谢信号。这一应用的中心假设是肠道
SCD1通过改变蝙蝠分泌的脂肪含量和组成、TGR5信号来调节代谢健康
和肠道,以及肠道和肝脏的BA代谢。这一假设将由我们两个相关的但
独立的具体目标。在目标1中,我们将测试肠道SCD1抑制与能量平衡的相关性
在高热量和高血脂饮食的背景下。我们还将评估TGR5在
调节改良的IKO小鼠的代谢表型。在目标2中,我们将评估SCD1派生的角色
MUFAs在调节肝脏BA外流和肠道BA再摄取中的作用我们还将利用a)一种抑制剂
肠道BA再摄取,b)肠道限制性FXR激动剂,以及c)饮食MUFAs以恢复肝脏和血浆
Iko小鼠体内的BA水平。
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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Harini Sampath其他文献
Harini Sampath的其他文献
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{{ truncateString('Harini Sampath', 18)}}的其他基金
The role of intestinal SCD1 in regulating metabolic health
肠道SCD1在调节代谢健康中的作用
- 批准号:
10297251 - 财政年份:2021
- 资助金额:
$ 39.16万 - 项目类别:
The role of intestinal SCD1 in regulating metabolic health
肠道SCD1在调节代谢健康中的作用
- 批准号:
10627814 - 财政年份:2021
- 资助金额:
$ 39.16万 - 项目类别:
Role of oxidative DNA damage in the onset and progression of metabolic syndrome
DNA 氧化损伤在代谢综合征发生和进展中的作用
- 批准号:
9326286 - 财政年份:2016
- 资助金额:
$ 39.16万 - 项目类别:
Role of oxidative DNA damage in the onset and progression of metabolic syndrome
DNA 氧化损伤在代谢综合征发生和进展中的作用
- 批准号:
8764741 - 财政年份:2014
- 资助金额:
$ 39.16万 - 项目类别:
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