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

• 批准号: 9301641
• 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
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-23 至 2018-12-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9301641
• 关键词: ATP binding cassette transporter 1; ATP-Binding Cassette Transporters; Acute; Adenovirus Infections; Adipose tissue; Affect; African American; Alleles; American; Apolipoprotein A-I; Back; Biliary; Catabolism; Cell Culture Techniques; Cell membrane; Cells; Chemicals; Cholesterol; Cholesterol Esters; Code; Complex; Coronary heart disease; Data; Development; Diabetes Mellitus; Diet; Dietary Fats; Environmental Risk Factor; European; Excretory function; Fatty Acids; Fatty acid glycerol esters; Feces; Fibrinogen; Genetic; Genetic Transcription; Genotype; Goals; 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; Mono-S; Mus; Participant; Phospholipids; Plasma; Prevention strategy; Production; Publishing; Receptor Signaling; Regulation; Role; Signal Transduction; Site-Directed Mutagenesis; Tissues; Variant; Very low density lipoprotein; Wild Type Mouse; activator 1 protein; bariatric surgery; coronary artery calcification; cytokine; disorder risk; human data; human tissue; improved; in vivo; insulin signaling; lipid biosynthesis; lipid metabolism; lipid transport; macrophage; metabolic phenotype; novel; particle; protein expression; public health relevance; reverse cholesterol transport; uptake

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(申请人提供)：三磷酸腺苷结合盒转运体A1(ABCA1)从细胞中排出磷脂(PL)和游离胆固醇(FC)，形成新生的高密度脂蛋白(NHDL)。由于ABCA1在大多数细胞中的表达是可变的，我们建立了肝细胞特异性ABCA1 KO(HSKO)小鼠来研究肝细胞ABCA1在脂质动员、运输和代谢中的作用。我们发现，肝细胞ABCA1调节极低密度脂蛋白、低密度脂蛋白和高密度脂蛋白的产生和分解代谢，使肝细胞ABCA1成为影响冠心病的三种主要血浆脂蛋白中脂质运输的关键调节器 (CHD)发展。在初步研究中，我们发现肝细胞ABCA1也调节肝脏的胰岛素和炎症信号，这表明肝细胞ABCA1的功能虽然还没有完全阐明，但比促进大量细胞胆固醇输出和nHDL的形成要复杂得多。此次更新的目的是确定肝细胞ABCA1在HSKO小鼠和人类体内Liid动员和运输中的作用。在特定的目标1中，我们将研究肝细胞ABCA1的表达在肝脏胰岛素信号、炎症和脂肪生成中的作用。将测定WT和HSKO小鼠的代谢表型、血浆极低密度脂蛋白代谢、肝脏脂肪合成、肝脏胰岛素受体信号转导和肝脏质膜脂质组成。在特定的目标2中，将检测肝脏ABCA1的表达对胆固醇从血浆高密度脂蛋白到粪便的流动的作用。我们将研究HSKO和WT小鼠的血浆衰减、肝脏摄取、重新分泌到血浆以及胆汁和粪便中高密度脂蛋白Fc和CE相对于apoA-I的排泄。在具体目标3中，将探索饮食多不饱和(多)脂肪相对于饱和(饱和)和单不饱和(单)脂肪降低ABCA1在人体肝脏、肠道和脂肪组织中表达的程度。将确定组织ABCA1RNA和蛋白表达、血浆高密度脂蛋白浓度、颗粒数量和大小以及血浆高密度脂蛋白Fc外排能力作为饮食脂肪饱和度的函数之间的相互关系。在特定的目标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(在欧洲美国人中缺失)是否影响脂质外流以及血浆高密度脂蛋白胆固醇浓度、颗粒数量和大小以及血浆高密度脂蛋白外流潜力。这些测量结果与冠状动脉钙化斑块评分之间的关系将被研究。