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The Role of Hepatocyte ABCA1 in Lipid Mobilization and Transport

肝细胞 ABCA1 在脂质动员和运输中的作用

基本信息

批准号：
9081640
负责人：
JOHN S PARKS
金额：
$ 38.83万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-23 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9081640
关键词：
ATP binding cassette transporter 1 ATP-Binding Cassette Transporters Adenovirus Infections Adipose tissue Affect African American Alleles American Apolipoprotein A-I Back Biliary Calcified Catabolism Cell Culture Techniques Cell membrane Cells Chemicals Cholesterol Cholesterol Esters Code Complex Coronary artery Coronary heart disease Data Development Diabetes Mellitus Diet Dietary Fats Environmental Risk Factor European Excretory function Fatty acid glycerol esters Feces Genetic Genetic Transcription Genotype Goals Health Heart Hepatic Hepatocyte High Density Lipoprotein Cholesterol High Density Lipoproteins High Fat Diet Human In Vitro Inflammation Inflammatory Inflammatory Response Insulin Insulin Receptor Insulin Resistance Intestines Knockout Mice Knowledge Lead Link Lipid Mobilization Lipids Lipoproteins Liver Low-Density Lipoproteins Measurement Measures Membrane Membrane Lipids Membrane Microdomains Metabolism Mus Participant Phospholipids Plasma Polyunsaturated Fatty Acids Prevention strategy Production Publishing Receptor Signaling Recycling Regulation Role Signal Transduction Site-Directed Mutagenesis Tissues Variant Very low density lipoprotein Wild Type Mouse activator 1 protein bariatric surgery cytokine feeding heart disease risk human data human tissue improved in vivo insulin signaling lipid biosynthesis lipid metabolism lipid transport liver metabolism macrophage metabolic phenotype monounsaturated fat novel particle polyunsaturated fat protein expression reverse cholesterol transport uptake

项目摘要

DESCRIPTION (provided by applicant): ATP binding cassette transporter A1 (ABCA1) effluxes phospholipid (PL) and free cholesterol (FC) from cells, forming nascent high density lipoproteins (nHDL). Because ABCA1 is variably expressed in most cells, we generated hepatocyte-specific ABCA1 KO (HSKO) mice to study the role of hepatocyte ABCA1 in lipid mobilization, transport, and metabolism. We found that hepatocyte ABCA1 regulates the production and catabolism of VLDL, LDL, and HDL, making hepatocyte ABCA1 a key modulator of lipid transport in all three major plasma lipoprotein classes that affect coronary heart disease (CHD) development. In preliminary studies, we found that hepatocyte ABCA1 also regulates hepatic insulin and inflammatory signaling, suggesting the function of hepatocyte ABCA1, while not fully elucidated, is more complex than facilitating bulk cellular cholesterol export and nHDL formation. The goal of this renewal is to determine the role of hepatocyte ABCA1 in liid mobilization and transport in HSKO mice and humans. In specific aim 1, we will examine the role of hepatocyte ABCA1 expression in hepatic insulin signaling, inflammation, and lipogenesis. Metabolic phenotype, plasma VLDL metabolism, hepatic lipid synthesis, hepatic insulin receptor signaling, and hepatic plasma membrane lipid composition will be determined in chow and high fat-fed WT and HSKO mice. In specific aim 2, the role of hepatic ABCA1 expression on cholesterol flux from plasma HDL to feces will be examined. We will investigate the plasma decay, hepatic uptake, re-secretion into plasma, and biliary and fecal excretion of HDL FC and CE, relative to apoA-I, in HSKO vs. WT mice. In specific aim 3, the extent to which dietary polyunsaturated (poly) fat, relative to saturated (sat) and monounsaturated (mono) fat, reduces ABCA1 expression in human liver, intestine and adipose tissue will be explored. Interrelationships among tissue ABCA1 RNA and protein expression, plasma HDL cholesterol concentration, particle number and size, and plasma HDL FC efflux capacity as a function of dietary fat saturation will be determined. In specific aim 4, we will determine whether rare coding ABCA1 sequence variants unique to African Americans (AA) (absent in European Americans, EA) affect lipid efflux as well as plasma HDL cholesterol concentration, particle number and size, and plasma HDL efflux potential. Associations between these measurements and coronary artery calcified plaque score, a measure of CHD, will be examined.

描述（由申请人提供）：ATP 结合盒转运蛋白 A1 (ABCA1) 从细胞中流出磷脂 (PL) 和游离胆固醇 (FC)，形成新生高密度脂蛋白 (nHDL)。由于 ABCA1 在大多数细胞中表达存在差异，因此我们构建了肝细胞特异性 ABCA1 KO (HSKO) 小鼠，以研究肝细胞 ABCA1 在脂质动员、运输和代谢中的作用。我们发现肝细胞 ABCA1 调节 VLDL、LDL 和 HDL 的产生和分解代谢，使肝细胞 ABCA1 成为影响冠心病的所有三种主要血浆脂蛋白类别中脂质转运的关键调节剂（冠心病）的发展。在初步研究中，我们发现肝细胞 ABCA1 还调节肝胰岛素和炎症信号传导，这表明肝细胞 ABCA1 的功能虽然尚未完全阐明，但比促进大量细胞胆固醇输出和 nHDL 形成更复杂。这项更新的目标是确定肝细胞 ABCA1 在 HSKO 小鼠和人类的液体动员和运输中的作用。在具体目标 1 中，我们将检查肝细胞 ABCA1 表达在肝脏胰岛素信号传导、炎症和脂肪生成中的作用。将测定饲料和高脂肪喂养的 WT 和 HSKO 小鼠的代谢表型、血浆 VLDL 代谢、肝脂质合成、肝胰岛素受体信号传导和肝质膜脂质组成。在具体目标 2 中，将检查肝脏 ABCA1 表达对从血浆 HDL 到粪便的胆固醇流量的作用。我们将研究 HSKO 与 WT 小鼠中相对于 apoA-I 的 HDL FC 和 CE 的血浆衰减、肝脏摄取、再分泌到血浆以及胆汁和粪便排泄。在具体目标 3 中，将探讨膳食多不饱和 (poly) 脂肪相对于饱和 (sat) 和单不饱和 (mono) 脂肪在多大程度上降低人类肝脏、肠道和脂肪组织中 ABCA1 的表达。将确定组织 ABCA1 RNA 和蛋白质表达、血浆 HDL 胆固醇浓度、颗粒数量和大小以及血浆 HDL FC 流出能力与膳食脂肪饱和度函数之间的相互关系。在具体目标 4 中，我们将确定非洲裔美国人 (AA) 特有的罕见编码 ABCA1 序列变体（欧洲裔美国人不存在，EA）是否会影响脂质流出以及血浆 HDL 胆固醇浓度、颗粒数量和大小以及血浆 HDL 流出潜力。将检查这些测量值与冠状动脉钙化斑块评分（CHD 的一种测量方法）之间的关联。