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SR-B1 Sorting Signals in HDL Metabolism

SR-B1 HDL 代谢中的信号排序

基本信息

批准号：
7844219
负责人：
David Silver
金额：
$ 22.81万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-15 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7844219
关键词：
Adenoviruses Amino Acid Sequence Antiatherogenic B-Lymphocytes Bile fluid Biliary Binding C-terminal Catabolism Cell Fractionation Cell membrane Cell model Cholesterol Cholesterol Esters Confocal Microscopy Coupled Endothelial Cells Essential Amino Acids Excretory function Extrahepatic Fibrinogen Hepatic Hepatobiliary Hepatocyte High Density Lipoprotein Cholesterol High Density Lipoproteins In Vitro Integral Membrane Protein Knockout Mice Label Lipids Liver MDCK cell Measurement Measures Mediating Membrane Messenger RNA Metabolism Molecular Mus Physiologic pulse Plasma Play Process Research Personnel Role Signal Transduction Silver Site Sorting - Cell Movement Tertiary Protein Structure Testing Transmembrane Domain basolateral membrane design high density lipoprotein receptor in vivo insight mouse model mutant novel overexpression polarized cell programs research study scavenger receptor transcytosis uptake

项目摘要

Plasma high density lipoprotein (HDL) is the principal carrier of plasma cholesterol for biliary cholesterol secretion. The HDL receptor Scavenger Receptor B-l (SR-BI) mediates the uptake of HDL cholesterol and cholesteryl ester for excretion into bile, and its expression correlates with biliary cholesterol secretion. SR-BI knockout mice have a significant decrease in biliary cholesterol secretion, indicating an important role of SR-BI in that process. However, little is known regarding the molecular mechanisms by which SR-BI mediates hepatobiliary secretion of cholesterol. SR-BI is expressed on both sinusoidal and canalicular membranes in liver, and undergoes transcytosisto the canalicular membrane. The sorting signals necessary for SR-BI basolateral targeting and transcytosis to the canalicular membrane are unknown. We have defined three important factors that may regulate SR-BI subcellular sorting in liver and thus SR-BI- dependent biliary cholesterol secretion. One factor is PDZK1, a PDZ domain protein that has been shown to interact with SR-BI and to be essential to maintain hepatic SR-BI levels. A second factor is a basolateral targeting signal in the C-terminus of SR-BI, and a third factor is a cholesterol binding domain in the C- terminal transmembrane domain of SR-BI. The C-terminal transmembrane domain of SR-BI can directly bind cholesterol but is not important for SR-BI-mediated selective uptake or cholesterol efflux. Cholesterol binding by SR-BI in liver may play a role in SR-BI transcytosis. Specific Aim 1 will determine the role of PDZK1 in SR-BI sorting. We have generated a PDZK1 knockout mouse model and will use both PDZK1 deficient mice and in vitro polarized cells models to examine the role of PDZK1 in SR-BI sorting. Specific Aim 2 will delimit the basolateral targeting signal of SR-BI and test the role of this sequence in SR-BI sorting in vivo and in vitro as well as in biliary cholesterol secretion in vivo. Specific Aim 3 will test the hypothesis that the SR-BI cholesterol binding domain plays a role in SR-BI transcytosis. We will test the role of this domain in biliary cholesterol secretion in vivo and SR-BI transcytosis in vitro. These studies will provide fundamental insights into the mechanisms regulating SR-BI sorting and biliary cholesterol secretion.

血浆高密度脂蛋白（HDL）是胆道中血浆胆固醇的主要载体