The Function of Mammalian LPGAT1
哺乳动物LPGAT1的功能
基本信息
- 批准号:10563280
- 负责人:
- 金额:$ 51.66万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-02-10 至 2027-01-31
- 项目状态:未结题
- 来源:
- 关键词:AblationAcyl Coenzyme AAcylationAcyltransferaseAddressAffectAtherosclerosisBiochemical PathwayBiochemical ReactionBiological ProcessBody fatCarbonChemicalsCollaborationsDataDiseaseEnzymesFatty AcidsGlycerolHealthHepaticHepatocyteHumanIn VitroIsotope LabelingKnock-outKnowledgeLaboratoriesLecithinLinkLipidsLipoproteinsLow Density Lipoprotein ReceptorMass Spectrum AnalysisMeasuresMembraneMetabolic syndromeMetabolismMethodsMethylationModelingModificationMusObesityOrganellesPalmitatesPathway interactionsPhosphatidylethanolaminePhospholipase A2PhospholipidsPlayPositioning AttributeProductionPublic HealthRegulationResolutionRoleSaturated Fatty AcidsSecond Messenger SystemsSpecificityStearatesTestingTimeTissuesUnsaturated Fatty AcidsVertebral columnWorkdeacylationexperienceknock-downlipid biosynthesislipid metabolismlipidomelipidomicsnovelreconstitutionstearoyl-coenzyme Atool
项目摘要
Project Summary/Abstract
Disorders of fat metabolism, such as obesity, metabolic syndrome, and atherosclerosis, are characterized by
abnormal processing of fatty acids. The non-random distribution of fatty acids in phospholipids, where
saturated chains are linked to the first (sn-1) but unsaturated chains are linked to the second (sn-2) carbon
atom of the glycerol group, has important implications for membrane structure, lipid metabolism, and second
messenger functions. However, while the composition of unsaturated fatty acids in sn-2 position is controlled
by the Lands pathway, it has remained unclear what controls saturated fatty acids in sn-1 position. We have
collected preliminary data that strongly suggest an sn-1 specific remodeling pathway for saturated
fatty acids, which plays a pivotal role in the production of lipoproteins. Based on our preliminary data we
postulate that the acyltransferase LPGAT1 controls the composition of saturated fatty acids in the two most
abundant phospholipids, phosphatidylethanolamine (PE) and phosphatidylcholine (PC), and that this pathway
is critical for the regulation of the de novo synthesis of lipids in hepatocytes. To test our hypothesis and to
identify the function of LPGAT1, we will (i) establish the mechanism of phospholipid remodeling by LPGAT1
and (ii) establish the regulatory function of LPGAT1 in lipid de novo synthesis. To this end, we will define the
enzymatic reaction of LPGAT1 in vitro upon expression and purification of the enzyme (subaim 1a), determine
the effect of LPGAT1 knockout and knockdown on the lipid composition of subcellular membranes by
lipidomics analysis of tissues and organelles (subaim 1b), dissect the remodeling pathway of LPGAT1 by
tracing the metabolism of isotope-labeled substrates and by reconstituting the deacylation-reacylation cycle
(subaim 1c), determine the mechanism by which LPGAT1 remodels PC by isotope labeling studies in
hepatocytes (subaim 1d), determine how LPGAT1 affects global lipid fluxes in mice by lipidome-wide 13C-
fluxomics analysis (subaim 2a); determine the effect of LPGAT1 ablation on lipoprotein metabolism by
measuring production and clearance of lipoproteins in mice (subaim 2b), and establish whether LPGAT1
ablation protects from atherosclerosis in LDL-receptor deficient mice (subaim 2c). The proposed work is
significant because (i) it will establish a parallel concept to the Lands cycle for the remodeling of
saturated fatty acids in sn-1 position and (ii) it will identify the function of this pathway within the lipid
metabolic network. This is expected to have critical influence on the evolving concepts of phospholipid
remodeling and be directly relevant to prevalent health problems, such as obesity, metabolic syndrome, and
atherosclerosis.
项目总结/摘要
脂肪代谢紊乱,如肥胖、代谢综合征和动脉粥样硬化,其特征在于:
脂肪酸的异常加工。磷脂中脂肪酸的非随机分布,其中
饱和链连接到第一个(sn-1),但不饱和链连接到第二个(sn-2)碳
甘油基团的原子,对膜结构,脂质代谢和第二
信使功能。然而,虽然sn-2位不饱和脂肪酸的组成是可控的,
通过Lands途径,仍不清楚是什么控制sn-1位的饱和脂肪酸。我们有
收集的初步数据强烈表明,SN-1特异性重塑途径,
脂肪酸,它在脂蛋白的产生中起着关键作用。根据初步数据,
假设酰基转移酶LPGAT 1控制两种最常见的饱和脂肪酸的组成,
丰富的磷脂,磷脂酰乙醇胺(PE)和磷脂酰胆碱(PC),这一途径
对于调节肝细胞中脂质的从头合成至关重要。为了验证我们的假设
为了明确LPGAT 1的功能,我们将(i)建立LPGAT 1对磷脂重构的机制
和(ii)建立LPGAT 1在脂质从头合成中的调节功能。为此,我们将定义
在酶的表达和纯化后体外LPGAT 1的酶促反应(子目的1a),测定
LPGAT 1敲除和敲低对亚细胞膜脂质组成的影响,
组织和细胞器的脂质组学分析(子目标1b),通过以下方式剖析LPGAT 1的重塑途径
追踪同位素标记底物的代谢,并通过重建脱酰-再酰化循环
(子目标1c),通过同位素标记研究确定LPGAT 1重塑PC的机制,
肝细胞(子目标1d),通过脂质组范围的13 C-
通量组学分析(子目的2a);通过以下方法确定LPGAT 1消融对脂蛋白代谢的影响:
测量小鼠中脂蛋白的产生和清除(子目的2b),并确定LPGAT 1是否
消融保护LDL受体缺陷小鼠免于动脉粥样硬化(子目标2c)。拟议的工作是
(一)它将建立一个与土地周期平行的概念,
在sn-1位的饱和脂肪酸和(ii)它将确定脂质内的这一途径的功能
代谢网络预计这将对磷脂概念的演变产生关键影响
重塑,并直接相关的普遍健康问题,如肥胖,代谢综合征,
动脉粥样硬化
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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M Mahmood Hussain其他文献
Nutrition & Metabolism Classics: a disconnect between highly cited and highly accessed articles
- DOI:
10.1186/1743-7075-11-13 - 发表时间:
2014-03-19 - 期刊:
- 影响因子:4.100
- 作者:
M Mahmood Hussain;Lucy Abel;Ahmed Bakillah - 通讯作者:
Ahmed Bakillah
Plasminogen Activator Inhibitor-1 and Tissue-Plasminogen Activator in Minority Adolescents with Type 2 Diabetes and Obesity
患有 2 型糖尿病和肥胖的少数民族青少年中纤溶酶原激活剂抑制剂 1 和组织纤溶酶原激活剂
- DOI:
- 发表时间:
2005 - 期刊:
- 影响因子:3.6
- 作者:
Vatcharapan Umpaichitra;M Mahmood Hussain;S. Castells - 通讯作者:
S. Castells
Acknowledgement of manuscript reviewers the underappreciated contributors
- DOI:
10.1186/s12986-016-0078-x - 发表时间:
2016-03-02 - 期刊:
- 影响因子:4.100
- 作者:
Ahmed Bakillah;M Mahmood Hussain - 通讯作者:
M Mahmood Hussain
M Mahmood Hussain的其他文献
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{{ truncateString('M Mahmood Hussain', 18)}}的其他基金
Biogenesis and Catabolism of Atherogenic Lipoproteins
致动脉粥样硬化脂蛋白的生物发生和分解代谢
- 批准号:
10628985 - 财政年份:2023
- 资助金额:
$ 51.66万 - 项目类别:
Regulation of plasma LDL and HDL by microRNA-541-3p
microRNA-541-3p 对血浆 LDL 和 HDL 的调节
- 批准号:
10733641 - 财政年份:2023
- 资助金额:
$ 51.66万 - 项目类别:
Adipose MTP and FIT2 in the regulation of plasma lipids, obesity and atherosclerosis
脂肪MTP和FIT2在血脂、肥胖和动脉粥样硬化调节中的作用
- 批准号:
10628990 - 财政年份:2023
- 资助金额:
$ 51.66万 - 项目类别:
Role of Lipoprotein Assembly in Maternal-Fetal Transport of Beta-Carotene
脂蛋白组装在 β-胡萝卜素母胎转运中的作用
- 批准号:
10642665 - 财政年份:2019
- 资助金额:
$ 51.66万 - 项目类别:
Role of Lipoprotein Assembly in Maternal-Fetal Transport of Beta-Carotene
脂蛋白组装在 β-胡萝卜素母胎转运中的作用
- 批准号:
10390463 - 财政年份:2019
- 资助金额:
$ 51.66万 - 项目类别:
Role of Lipoprotein Assembly in Maternal-Fetal Transport of Beta-Carotene
脂蛋白组装在 β-胡萝卜素母胎转运中的作用
- 批准号:
9913384 - 财政年份:2019
- 资助金额:
$ 51.66万 - 项目类别:
MicroRNAs regulating plasma LDL and HDL
MicroRNA 调节血浆 LDL 和 HDL
- 批准号:
10266009 - 财政年份:2018
- 资助金额:
$ 51.66万 - 项目类别:
Effects of miR-30c deficiency on plasma cholesterol and atherosclerosis
miR-30c 缺陷对血浆胆固醇和动脉粥样硬化的影响
- 批准号:
10424970 - 财政年份:2017
- 资助金额:
$ 51.66万 - 项目类别:
Effects of miR-30c deficiency on plasma cholesterol and atherosclerosis
miR-30c 缺陷对血浆胆固醇和动脉粥样硬化的影响
- 批准号:
9401363 - 财政年份:2017
- 资助金额:
$ 51.66万 - 项目类别:
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