Influence of the HDL Receptor SR-BI on Lipoprotein Metabolism and Atherosclerosis

Abstract

Abstract-The scavenger receptor class B type I (SR-BI) was the first molecularly well-defined cell-surface HDL receptor to be described. SR-BI mediates selective HDL cholesterol uptake by formation of a productive lipoprotein/receptor complex, which requires specific structural domains and conformation states of apolipoprotein A-I present in HDL particles. SR-BI is abundantly expressed in several tissues, including the liver, where its expression is regulated by various mechanisms, including the transcriptional activity of nuclear receptors. The importance of SR-BI in overall HDL cholesterol metabolism and its antiatherogenic activity in vivo has been definitively established by SR-BI gene manipulation in mice. Remarkably, SR-BI/apolipoprotein E double-knockout mice develop complex coronary artery disease, myocardial infarction, and heart failure. Additional studies should help to define the importance of SR-BI in human health and disease. Key Words: scavenger receptor class B type I Ⅲ selective uptake Ⅲ regulation Ⅲ knockout mouse Ⅲ coronary heart disease S cavenger receptors are cell-surface transmembrane proteins that can bind modified lipoproteins, such as acetylated LDL and oxidized LDL. These receptors were initially reported in cultured macrophages in which they mediate cholesterol uptake from modified lipoproteins, leading to the formation of lipid-loaded macrophages that resemble the characteristic foam cells present in atherosclerotic lesions. 1,2 Because LDL modified by oxidation may play an important role in foam cell formation during atherogenesis, 3 macrophage scavenger receptors have been considered to be potentially key contributors to the pathogenesis of atherosclerotic cardiovascular disease.The wide and complex ligand binding activities of scavenger receptors suggested the existence of multiple classes of these cell-surface proteins. In fact, over the past decade, several classes of cDNAs encoding different types of scavenger receptors, which are expressed in various cell types including macrophages, have been cloned. 2,4 Both in vitro and in vivo experiments have provided strong support for the role of these cell-surface receptors in a variety of physiolog- SR-BI and Cellular Cholesterol TransportSR-BI was discovered during the study of a novel scavenger receptor activity in Chinese hamster ovary cells (reference 6 and references cited therein). The SR-BI cDNA encodes a 509 amino acid protein, which contains 1 putative membranespanning hydrophobic domain near each end of the protein and a large extracellular region with a cysteine-rich carboxyterminal half and multiple potential N-glycosylation sites. SR-BI is indeed a highly N-glycosylated 82-kDa protein that is also modified by fatty acylation. 6,7 SR-BI binds to a variety of ligands, including modified (acetylated or oxidized) lipoproteins, maleylated bovine serum albumin, advanced glycation end-product modified proteins, anionic phospholipids, and apoptotic cells. 6,8 SR-BI also binds native lipoproteins such as HDL, LDL, and VLDL. 6 Mos...

Scavenger Receptor Class B Type I Mediates Biliary Cholesterol Secretion Independent of ATP-Binding Cassette Transporter g5/g8 in Mice†

“…1,2 In nonpolarized cells, namely macrophages and the hepatoma cell line Fu5AH, SR-BI expression either results in selective uptake of cholesterol, mainly from high-density lipoprotein (HDL), or in cholesterol efflux toward suitable acceptors. [3][4][5][6] In hepatocytes, which is a highly polarized cell type, SR-BI is the main receptor responsible for selective uptake of cholesterol from plasma HDL.…”

Phosphatidylinositol-3-Kinase Regulates Scavenger Receptor Class B Type I Subcellular Localization and Selective Lipid Uptake in Hepatocytes

“…5,6 In polarized cells, SR-BI is known to be localized largely at the plasma membrane, either apically (eg, enterocytes 7 ) or basolaterally (eg, hepatocytes 8 and MadinDarby canine kidney [MDCK] cells 9 ). Several reports have indicated that SR-BI functions as an endocytic receptor, particularly in polarized cells such as hepatocytes 8 and kidney (MDCK) 10 cells, and it has been proposed that selective lipid uptake from HDL occurs during SR-BI-mediated HDL recycling within cells.…”

The ratio of insulin, sex hormones, sex hormone-binding β-globulin, parameters of lipid metabolism and glucose in the male population of the Arctic

“…Общеизвестно, что эстрогены в пре-делах физиологической нормы существенно влия-ют на содержание липидов в крови, снижая уровень общего холестерина (ОХ) и липопротеидов низкой плотности (ЛПНП) и повышая уровень липопроте-идов высокой плотности (ЛПВП) [2]. Есть данные о том, что эстрогены непосредственно влияют на синтез липопротеидов в печени, увеличивая кон-центрацию холестерина (ХС) ЛПВП благодаря по-вышению синтеза апоА1, down-регуляции печеноч-ных скэвенджер-рецепторов типа В 1 класса (SRB-1) и снижению активности печеночной липазы [3]. Многими авторами [4][5][6] показаны антиоксидант-ные свойства эстрогенов.…”