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结合盒式转运蛋白A1（ABCA1）外排磷脂（PL）和游离胆固醇（FC）来自细胞，形成新生的高密度脂蛋白（NHDL）。由于ABCA1在大多数细胞中均有多种表达，因此我们产生了肝细胞特异性ABCA1 KO（HSKO）小鼠，研究了肝细胞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的生产和分解代谢，使肝细胞ABCA1在所有三种主要的血浆脂蛋白类别中成为脂质转运的关键调节剂，影响冠心病冠心病（CHD）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，但比促进散装大量的细胞胆固醇导出和NHDL形成更为复杂。这种更新的目的是确定肝细胞ABCA1在霍斯科小鼠和人类中的严重动员和运输中的作用。在特定目标1中，我们将研究肝细胞ABCA1表达在肝胰岛素信号，炎症和脂肪生成中的作用。代谢表型，血浆VLDL代谢，肝脂质合成，肝胰岛素受体信号传导以及肝质膜脂质组成将在Chow和高脂肪喂养的WT和HSKO小鼠中确定。在特定的目标2中，将研究肝ABCA1表达在从血浆HDL到粪便的胆固醇通量中的作用。我们将研究HSKO与WT小鼠的血浆衰减，肝吸收，重新分泌到血浆中的血浆衰减，重新分泌到血浆中的HSKO与APOA-I相对于APOA-I的胆道和粪便排泄。在特定的目标3中，将探索饮食中多不饱和（多年）脂肪相对于饱和（SAT）和单不饱和（单声道）脂肪的程度，可探索人肝，肠和脂肪组织中的ABCA1表达。将确定组织ABCA1 RNA和蛋白质表达，血浆HDL胆固醇浓度，颗粒数和大小以及等离子体HDL FC外排作为饮食脂肪饱和度的函数的相互关系。在特定目标4中，我们将确定罕见的编码ABCA1序列变体是非洲裔美国人（AA）（欧洲人缺乏的，EA）是否影响脂质外排以及血浆HDL胆固醇浓度，颗粒数和大小和等离子体HDL外排效率。这些测量值与冠状动脉钙化斑块评分之间的关联将被检查。