Scavenger receptor class B member 1 protein: hepatic regulation and its effects on lipids, reverse cholesterol transport, and atherosclerosis

Abstract

Scavenger receptor class B member 1 (SR-BI, also known as SCARB1) is the primary receptor for the selective uptake of cholesterol from high-density lipoprotein (HDL). SR-BI is present in several key tissues; however, its presence and function in the liver is deemed the most relevant for protection against atherosclerosis. Cholesterol is transferred from HDL via SR-BI to the liver, which ultimately results in the excretion of cholesterol via bile and feces in what is known as the reverse cholesterol transport pathway. Much of our knowledge of SR-BI hepatic function and regulation is derived from mouse models and in vitro characterization. Multiple independent regulatory mechanisms of SR-BI have been discovered that operate at the transcriptional and post-transcriptional levels. In this review we summarize the critical discoveries relating to hepatic SR-BI cholesterol metabolism, atherosclerosis, and regulation of SR-BI, as well as alternative functions that may indirectly affect atherosclerosis. Function and structure of SR-BI and other class B scavenger receptors Scavenger receptor class B member 1 (SR-BI, gene name SCARB1) belongs to the CD36 superfamily of membrane-bound, cell-surface glycoproteins, which include mammalian scavenger receptor CD36 and the lysosomal membrane protein 2 (gene name SCARB2, formerly LIMPII). 1 These receptors can bind to modified forms of low-density lipoprotein (LDL) as well as native high-density lipoprotein (HDL) and very low density lipoprotein (VLDL). 2,3 However, SR-BI is distinguished from other class B scavengers by its high affinity to facilitating selective cholesterol uptake from HDL, without the internationalization and degradation of the apolipoprotein-AI (APOA1)-containing whole particle. 2 There are several common structural features shared among this family of proteins. These include membrane-associated hydrophobic regions near the N-and C-termini, a large extracellular loop comprising the portion of the peptide sequence between the two membrane-bound end regions, and several sites of N-linked glycosylation. 4 SR-BI and CD36 share considerable sequence homology throughout much of their extracellular loop, with several conserved cysteine and asparagine residues, as well as canonical sites of fatty acylation and N-linked glycosylation. Interestingly, SR-BI and CD36 bear little sequence homology in their transmembrane and N-and C-terminal membrane-associated domains. 5 SR-BI is considered the HDL cholesteryl ester (HDL-CE) selective uptake receptor, CD36 is often ignored or described as not having HDL-CE selective uptake activity. While it has been known for some time