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The Function of Mammalian LPGAT1

哺乳动物LPGAT1的功能

基本信息

批准号：
10563280
负责人：
M Mahmood Hussain
金额：
$ 51.66万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
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：
https://reporter.nih.gov/project-details/10563280
关键词：
Ablation Acyl Coenzyme A Acylation Acyltransferase Address Affect Atherosclerosis Biochemical Pathway Biochemical Reaction Biological Process Body fat Carbon Chemicals Collaborations Data Disease Enzymes Fatty Acids Glycerol Health Hepatic Hepatocyte Human In Vitro Isotope Labeling Knock-out Knowledge Laboratories Lecithin Link Lipids Lipoproteins Low Density Lipoprotein Receptor Mass Spectrum Analysis Measures Membrane Metabolic syndrome Metabolism Methods Methylation Modeling Modification Mus Obesity Organelles Palmitates Pathway interactions Phosphatidylethanolamine Phospholipase A2 Phospholipids Play Positioning Attribute Production Public Health Regulation Resolution Role Saturated Fatty Acids Second Messenger Systems Specificity Stearates Testing Time Tissues Unsaturated Fatty Acids Vertebral column Work deacylation experience knock-down lipid biosynthesis lipid metabolism lipidome lipidomics novel reconstitution stearoyl-coenzyme A tool

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/文摘