Abstract
High-density lipoprotein (HDL) is considered an anti-atherogenic lipoprotein species due to its role in reverse cholesterol transport. HDL delivers cholesterol esters to the liver through selective uptake by scavenger receptor class B type I (SR-BI). In line with the protective role for HDL in the context of cardiovascular disease, studies in mice and recently also in humans have shown that a disruption of normal SR-BI function predisposes subjects to the development of atherosclerotic lesions and cardiovascular disease. Although SR-BI function has been studied primarily in the liver, it should be acknowledged that the SR-BI protein is expressed in multiple tissues and cell types across the body, albeit at varying levels between the different tissues. Given that SR-BI is widely expressed throughout the body, multiple cell types and tissues can theoretically contribute to the atheroprotective effect of SR-BI. In this review the different functions of SR-BI in normal physiology are highlighted and the (potential) consequences of cell type-specific disruption of SR-BI function for atherosclerosis and cardiovascular disease susceptibility discussed. It appears that hepatocyte and platelet SR-BI inhibit respectively the development of atherosclerotic lesions and thrombosis, suggesting that SR-BI located on these cell compartments should be regarded as being a protective factor in the context of cardiovascular disease. The relative contribution of SR-BI present on endothelial cells, steroidogenic cells, adipocytes and macrophages to the pathogenesis of atherosclerosis and cardiovascular disease remains less clear, although proper SR-BI function in these cells does appear to influence multiple processes that impact on cardiovascular disease susceptibility.
Highlights
Division of Biopharmaceutics, Cluster BioTherapeutics, Leiden Academic Centre for Drug Research (LACDR), Gorlaeus Laboratories, Einsteinweg 55, 2333CC Leiden, The Netherlands article info
Given that scavenger receptor class B type I (SR-BI) is widely expressed throughout the body, multiple cell types and tissues can theoretically contribute to the atheroprotective effect of SR-BI
In this review the different functions of SR-BI in normal physiology are highlighted and the consequences of cell type-specific disruption of SR-BI function for atherosclerosis and cardiovascular disease susceptibility discussed. It appears that hepatocyte and platelet SR-BI inhibit respectively the development of atherosclerotic lesions and thrombosis, suggesting that SR-BI located on these cell compartments should be regarded as being a protective factor in the context of cardiovascular disease
Summary
Since the original discovery by the group of Monty Krieger, in 1996, that HDL is a functional HDL receptor [11], much has been learned about the transcriptional control, structure and function of the protein. The proteins are expressed in multiple tissues and cell types across the body, albeit at varying levels between the different isoforms and tissues [10,12]. The selective uptake process consists of three steps: 1) binding of cholesterol ester-rich lipoprotein particles to the loop domain of SR-BI and 2) the transfer of cholesterol esters to the plasma membrane, and 3) the release from the cholesterol-poor lipoprotein particles back into the blood circulation [25,26]. Piloting findings from mutagenesis studies have suggested that subdomains in the N-terminal and C-terminal regions of the extracellular domain of SR-BI, and in particular tryptophan 415, are of critical importance for both lipoprotein binding and selective HDL-cholesterol ester uptake by SR-BI [29,30]. The aim of this review is to highlight the different functions of SR-BI in normal physiology and discuss the (potential) consequences of cell type-specific disruption of SR-BI function for atherosclerosis and cardiovascular disease susceptibility
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