Mechanisms for regulation of a novel class of anti-diabetic lipids
一类新型抗糖尿病脂质的调节机制
基本信息
- 批准号:10378154
- 负责人:
- 金额:$ 76.03万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-04-20 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:Adipose tissueAnabolismAnti-Inflammatory AgentsAntidiabetic DrugsAntiinflammatory EffectAttentionAutoimmuneBinding ProteinsBiochemical PathwayBiological AssayBiologyBiopsyCarbohydratesClinicalCoenzymesColitisDataDiabetes MellitusDiglyceridesDiseaseEnzymesEstersFamilyFamily memberFastingFatty AcidsFunctional disorderFundingGene Expression RegulationGenesGeneticGenetic ModelsGenetic VariationGlucoseHealthHepaticHigh Fat DietHumanHydrolaseHydrolysisImmuneInbred Strains MiceIncidenceInsulinInsulin ResistanceInsulin-Dependent Diabetes MellitusIsomerismIsotope LabelingIsotopesKnock-outKnockout MiceKnowledgeLeadLinkLipaseLipidsLipolysisLiverMeasurementMeasuresMediatingMetabolicMetabolic stressMild obesityMolecularMusMuscleNon-Insulin-Dependent Diabetes MellitusObesityObesity EpidemicPalmitic AcidsPathogenesisPathway interactionsPersonsPhenotypePhospholipasePhysiologicalPhysiological AdaptationPlasmaPopulationPositioning AttributePrevention strategyProteinsRegulationRegulator GenesRegulatory PathwayResistanceResponse ElementsRiskRoleSerumSeveritiesStable Isotope LabelingStearic AcidsSystemSystems AnalysisTestingTissuesTransacylaseTransferaseTriglyceridesUnited States National Institutes of Healthblood glucose regulationclinically relevantdiacylglycerol O-acyltransferasediverse dataeffective therapyenzyme pathwayexperimental studyfatty acid biosynthesisfatty acid metabolismgenetic approachglucose metabolismglucose productionglucose toleranceglucose transporthuman tissuehydroxy fatty acidimprovedin vivoinhibitorinnovationinsightinsulin secretioninsulin sensitivityisletlipid metabolismmouse modelnoveloverexpressionpreventprotein expressionresponsesubcutaneoustranscriptometranscriptomicstranslational potentialtreatment strategy
项目摘要
The growing epidemic of obesity and Type 2 diabetes requires new strategies for prevention and treatment.
We discovered a structurally novel, family of endogenous bioactive lipids, branched fatty Acid esters of
Hydroxy fatty Acids (FAHFAs). A subfamily, Palmitic Acid esters of Hydroxy Stearic Acids (PAHSAs), has
anti-diabetic and anti-inflammatory effects. PAHSA levels are low in serum and adipose tissue of insulin-resistant
versus insulin-sensitive people, and levels correlate highly with insulin sensitivity. In insulin-resistant
mice, PAHSA administration improves glucose tolerance and insulin sensitivity, in part by enhancing insulin
action to suppress hepatic glucose production which results from improved lipolysis suppression. PAHSAs are
anti-inflammatory and reduce colitis severity and the incidence of auto-immune Type 1 diabetes in mice. We
have made tremendous strides in discovering new activities for PAHSAs, identifying additional families of
bioactive and storage forms of FAHFAs, and uncovering biochemical pathways and enzymes that control
tissue FAHFA levels. These studies underscore that FAHFAs are a highly-regulated class of lipids with
tremendous translational potential. The overall objective of this proposal is to determine the mechanisms that
regulate tissue and serum FAHFA levels in physiologic and disease states by identifying enzymes and
pathways that regulate FAHFA biosynthesis, degradation and incorporation into other lipids. We will use
innovative and robust assays we developed with isotopically-labeled FAHFAs and their precursors to measure
FAHFA synthesis and degradation in vivo, target specific pathways of FAHFA regulation, and identify
additional, missing enzymes and other factors that regulate FAHFA biosynthesis, degradation, transport and
storage. We have already made terrific progress by identifying 3 FAHFA hydrolases and the first FAHFA
biosynthetic transacylase. We will delineate this new biosynthetic pathway using novel mechanistic studies.
We also propose a highly complementary, innovative, systems analyses that will integrate transcriptomic data
with targeted FAHFA measurements. First, we will take advantage of the large, reciprocal regulation of
FAHFAs in our unique mouse models with altered expression of Glut4 and ChREBP, to find unknown factors
mediating this regulation. Since Glut4 and ChREBP expression in adipose tissue from humans correlates with
insulin sensitivity and adipose FAHFA levels, genes identified with these experiments could have clinical
relevance. The second approach exploits the natural genetic variation in the diversity outbred (DO) mice,
which have as much natural genetic variation as the human population. We will perform targeted
measurements of ~300 different FAHFA isomers in adipose tissue, liver and plasma of ~500 DO mice and
leverage the existing genetic and transcriptomic data from DO mice to find new "drivers"/regulators of tissue
FAHFA levels. These studies will advance our understanding of FAHFA biology in health and disease and
potentially uncover novel enzymes and pathways in lipid metabolism that can be targeted for clinical benefit.
肥胖和2型糖尿病的日益流行需要新的预防和治疗策略。
我们发现了一种结构新颖的内源性生物活性脂质家族,即支链脂肪酸酯,
羟基脂肪酸(FAHFA)。一个亚科,羟基硬脂酸的棕榈酸酯(PAHSAs),具有
抗糖尿病和抗炎作用。胰岛素抵抗患者的血清和脂肪组织中PAHSA水平较低,
与胰岛素敏感的人相比,水平与胰岛素敏感性高度相关。胰岛素抵抗
在小鼠中,PAHSA给药改善葡萄糖耐量和胰岛素敏感性,部分是通过增强胰岛素
抑制肝脏葡萄糖产生的作用,这是由改善的脂解抑制引起的。PAHSA是
抗炎和降低结肠炎的严重程度和小鼠自身免疫1型糖尿病的发病率。我们
在发现PAHSAs的新活动方面取得了巨大的进步,确定了更多的PAHSAs家族,
生物活性和储存形式的FAHFA,并揭示生化途径和酶,控制
组织FAHFA水平。这些研究强调,FAHFA是一类高度调节的脂质,
巨大的转化潜力本提案的总体目标是确定
在生理和疾病状态下通过鉴定酶调节组织和血清FAHFA水平,
调节FAHFA生物合成、降解和掺入其他脂质的途径。我们将使用
创新和强大的检测,我们开发了同位素标记的FAHFA及其前体,以测量
体内FAHFA合成和降解,靶向FAHFA调控的特定途径,并鉴定
另外,缺失的酶和其他调节FAHFA生物合成、降解、运输和代谢的因子,
存储.我们已经通过鉴定3种FAHFA水解酶和第一种FAHFA,
生物合成转酰酶我们将描绘这种新的生物合成途径,使用新的机制研究。
我们还提出了一个高度互补的,创新的,系统分析,将整合转录组数据
有针对性的FAHFA测量。首先,我们将利用大规模的互惠监管,
在我们独特的Glut 4和ChREBP表达改变的小鼠模型中,
调解这一规定。由于人体脂肪组织中Glut 4和ChREBP的表达与
胰岛素敏感性和脂肪FAHFA水平,这些实验鉴定的基因可能具有临床意义。
本案无关第二种方法利用了多样性远交(DO)小鼠的自然遗传变异,
和人类一样有着天然的遗传变异。我们将有针对性地
在~500只DO小鼠的脂肪组织、肝脏和血浆中测量~300种不同的FAHFA异构体,
利用来自DO小鼠的现有遗传和转录组学数据来寻找新的组织“驱动因子”/调节因子,
FAHFA水平。这些研究将促进我们对FAHFA生物学在健康和疾病方面的理解,
有可能发现新的酶和途径的脂质代谢,可以针对临床效益。
项目成果
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BARBARA B. KAHN其他文献
BARBARA B. KAHN的其他文献
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{{ truncateString('BARBARA B. KAHN', 18)}}的其他基金
Preclinical Studies of Novel Anti-Diabetic Lipids
新型抗糖尿病脂质的临床前研究
- 批准号:
9515379 - 财政年份:2017
- 资助金额:
$ 76.03万 - 项目类别:
Regulation of the biosynthesis of a novel class of anti-diabetic lipids
一类新型抗糖尿病脂质生物合成的调节
- 批准号:
9895741 - 财政年份:2016
- 资助金额:
$ 76.03万 - 项目类别:
Mechanisms for regulation of a novel class of anti-diabetic lipids
一类新型抗糖尿病脂质的调节机制
- 批准号:
10609856 - 财政年份:2016
- 资助金额:
$ 76.03万 - 项目类别:
INTERPLAY OF TRANSTHYRETIN AND RETINOL BINDING PROTEIN IN TYPE 2 DIABETES
转甲状腺素蛋白和视黄醇结合蛋白在 2 型糖尿病中的相互作用
- 批准号:
8365542 - 财政年份:2011
- 资助金额:
$ 76.03万 - 项目类别:
INTERPLAY OF TRANSTHYRETIN AND RETINOL BINDING PROTEIN IN TYPE 2 DIABETES
转甲状腺素蛋白和视黄醇结合蛋白在 2 型糖尿病中的相互作用
- 批准号:
8170910 - 财政年份:2010
- 资助金额:
$ 76.03万 - 项目类别:
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