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Hepatocyte Abca1, cholesterol trafficking, and lipid mobilization

肝细胞 Abca1、胆固醇运输和脂质动员

基本信息

批准号：
10308037
负责人：
JOHN S PARKS
金额：
$ 48.92万
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 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10308037
关键词：
ADD-1 protein ATP binding cassette transporter 1 ATP-Binding Cassette Transporters Acute Address Affect Anabolism Apolipoprotein A-I Atherosclerosis BODIPY Cardiometabolic Disease Cardiovascular Diseases Catabolism Cell membrane Cells Cholesterol Cholesterol Homeostasis Complex Data Drops Endoplasmic Reticulum Endosomes Excretory function Fasting Fatty Liver Feces Funding Future Genetic Transcription Gluconeogenesis Hepatic Hepatocyte High Density Lipoprotein Cholesterol High Density Lipoproteins High Fat Diet Homeostasis Insulin Insulin Resistance Kinetics Knock-out Knockout Mice Knowledge Lipid Mobilization Lipids Lipoproteins Liver Liver Mitochondria Location Low Density Lipoprotein Receptor Low-Density Lipoproteins Lysophospholipids Lysosomes Mass Spectrum Analysis Measures Mediating Membrane Fluidity Membrane Proteins Messenger RNA Metabolic Metabolism Mitochondria Modeling Mus NPC1 gene Nuclear Protein Organelles Pathogenesis Phenotype Phospholipids Plant Roots Plasma Process Production Protein Export Pathway Recycling Regulation Research Respiration Role Sterols Stress Testing Tissues Transport Process United States National Institutes of Health Very low density lipoprotein Viral Work base cholesterol trafficking cholesteryl linoleate cholesteryl oleate fatty acid oxidation fluidity improved insight insulin signaling lipid biosynthesis lipid metabolism macrophage mitochondrial metabolism mouse model mutant novel particle programs promoter receptor expression respiratory enzyme reverse cholesterol transport trafficking uptake very low density lipoprotein triglyceride

项目摘要

Abstract- This R01 renewal seeks to continue the PI's creative, productive, and significant research program, which has enjoyed uninterrupted NIH funding since 1996, focused on lipid/lipoprotein metabolism in the pathogenesis of cardiovascular disease (CVD) and cardiometabolic disease (CMD). For over 15 years, the PI's research program has focused on ATP binding cassette transporter A1 (Abca1) and lipid and lipoprotein metabolism using tissue/cell-specific Abca1 knockout mice. Studies in hepatocyte-specific Abca1 knockout (HSKO) mice provided novel mechanistic insights into how hepatic Abca1 impacts the production and catabolism of all three major classes of plasma lipoproteins (VLDL, LDL, HDL) that contribute to CVD and CMD. Despite the massive (~80%) drop in plasma HDL relative to control mice, hyperlipidemic HSKO mice maintained macrophage reverse cholesterol transport and had decreased aortic root atherosclerosis compared to controls. HSKO mice also had increased plasma HDL cholesterol transport into the feces, decreased hepatic insulin signaling and de novo lipogenesis (DNL), increased mitochondrial respiration, increased LDL receptor expression, and increased hepatic VLDL triglyceride secretion. This unique phenotype was associated with diminished antegrade trafficking of lysosomal free cholesterol (FC) to the plasma membrane of hepatocytes, with no differences in total hepatic lipid mass between HSKO and control mice. Based on this work, our global hypothesis is that targeted deletion of hepatocyte Abca1 enhances hepatocyte retrograde FC redistribution from the plasma membrane to intracellular compartments, reprogramming insulin-mediated anabolism towards a coordinated catabolic program that reduces hepatic DNL, improves mitochondrial metabolism, and increases TG secretion, thereby decreasing hepatic steatosis when mice are stressed with a high-fat diet. This metabolic reprogramming in the absence of hepatic Abca1 results in a novel form of selective insulin resistance in HSKO mice, in which hepatic DNL is suppressed, but gluconeogenesis is appropriately downregulated by insulin. Future studies will address gaps in knowledge and barriers to progress, including: Specific aim 1) how Abca1 deletion alters FC distribution (or trafficking) among the plasma membrane, endoplasmic reticulum, and other organelles; Specific aim 2a) how insulin signaling and endoplasmic reticulum FC interact to activate Srebp1c; and Specific aim 2b) whether loss of Abca1 leads to increased mitochondria FC and/or lysophospholipid that improves mitochondrial respiration. Our proposed studies will build a more comprehensive and expansive model for Abca1 as a central control point of metabolic homeostasis and propel our previous 5-year discoveries in new directions, thereby advancing the field. Impact- Our studies will continue generating new discoveries regarding regulation of hepatic lipogenesis and the emerging role of Abca1 and FC trafficking in reprogramming hepatic lipid metabolism, a key contributor to CVD and CMD.

摘要-R 01的更新旨在继续PI的创造性，生产力和重要的研究计划，自1996年以来，该研究一直享有NIH的资助，专注于研究老年人的脂质/脂蛋白代谢。心血管疾病（CVD）和心脏代谢疾病（CMD）的发病机制。十五年来，私家侦探研究计划集中在ATP结合盒转运蛋白A1（Abca 1）和脂质和脂蛋白使用组织/细胞特异性Abca 1敲除小鼠进行代谢。肝细胞特异性Abca 1基因敲除的研究（HSKO）小鼠提供了新的机制见解，了解肝脏Abca 1如何影响生产，所有三种主要类型的血浆脂蛋白（VLDL，LDL，HDL）的催化剂，有助于CVD和 CMD.尽管相对于对照组小鼠，高脂血症HSKO小鼠的血浆HDL大幅下降（约80%），维持巨噬细胞胆固醇逆向转运，并减少主动脉根部动脉粥样硬化，控制。HSKO小鼠血浆HDL胆固醇向粪便中的转运也增加，肝脏胰岛素信号传导和新生脂肪生成（DNL），线粒体呼吸增加，LDL增加受体表达，并增加肝脏VLDL甘油三酯分泌。这种独特的表型是与溶酶体游离胆固醇（FC）向质膜的顺行运输减少有关，肝细胞，HSKO和对照小鼠之间的总肝脂质质量没有差异。基于此工作，我们的总体假设是，肝细胞Abca 1的靶向缺失增强肝细胞逆行 FC从质膜重新分布到细胞内，胰岛素介导的重编程促进协调的分解代谢程序，减少肝脏DNL，改善线粒体代谢，并增加TG分泌，从而减少肝脂肪变性，当小鼠应激时，高脂肪饮食。在缺乏肝脏Abca 1的情况下，这种代谢重编程导致了一种新的形式， HSKO小鼠的选择性胰岛素抵抗，其中肝脏DNL受到抑制，但胰岛素生成受到抑制。适当地下调胰岛素。未来的研究将解决知识差距和障碍，具体目标1）Abca 1缺失如何改变FC在质膜、内质网和其他细胞器;具体目标2a）胰岛素信号传导和内质网FC相互作用以激活Srebp 1c;和具体目的2b）Abca 1的缺失是否导致增加的线粒体FC和/或溶血磷脂，其改善线粒体呼吸。我们提出的研究将建立一个更全面和扩展的模型，Abca 1作为代谢的中心控制点，内稳态和推动我们以前的5年发现在新的方向，从而推进该领域。影响-我们的研究将继续产生关于肝脏脂肪生成调节的新发现， Abca 1和FC运输在重编程肝脏脂质代谢中的新作用， CVD和CMD。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

APOL1 Risk Variants Impair Multiple Mitochondrial Pathways in a Metabolomics Analysis.

APOL1 风险变异在代谢组学分析中损害多种线粒体途径。

DOI：
10.34067/kid.0003592020
发表时间：
2020
期刊：
Kidney360
影响因子：
0
作者：
Ma,Lijun;Palmer,NicholetteD;Choi,YoungA;Murea,Mariana;Snipes,JamesA;Parks,JohnS;Langefeld,CarlD;Freedman,BarryI
通讯作者：
Freedman,BarryI

Apolipoprotein M and Sphingosine-1-Phosphate Receptor 1 Promote the Transendothelial Transport of High-Density Lipoprotein.

DOI：
10.1161/atvbaha.121.316725
发表时间：
2021-10
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
0
作者：
Velagapudi S;Rohrer L;Poti F;Feuerborn R;Perisa D;Wang D;Panteloglou G;Potapenko A;Yalcinkaya M;Hülsmeier AJ;Hesse B;Lukasz A;Liu M;Parks JS;Christoffersen C;Stoffel M;Simoni M;Nofer JR;von Eckardstein A
通讯作者：
von Eckardstein A

Dietary cholesterol effects on adipose tissue inflammation.