SR-B1: A Unique Multifunctional Receptor for Cholesterol Influx and Efflux

Abstract

The scavenger receptor, class B type 1 (SR-B1), is a multiligand membrane receptor protein that functions as a physiologically relevant high-density lipoprotein (HDL) receptor whose primary role is to mediate selective uptake or influx of HDL-derived cholesteryl esters into cells and tissues. SR-B1 also facilitates the efflux of cholesterol from peripheral tissues, including macrophages, back to liver. As a regulator of plasma membrane cholesterol content, SR-B1 promotes the uptake of lipid soluble vitamins as well as viral entry into host cells. These collective functions of SR-B1 ultimately affect programmed cell death, female fertility, platelet function, vasculature inflammation, and diet-induced atherosclerosis and myocardial infarction. SR-B1 has also been identified as a potential marker for cancer diagnosis and prognosis. Finally, the SR-B1-linked selective HDL-cholesteryl ester uptake pathway is now being evaluated as a gateway for the delivery of therapeutic and diagnostic agents. In this review, we focus on the regulation and functional significance of SR-B1 in mediating cholesterol movement into and out of cells.

Keywords: HDL; HDL receptor; reverse cholesterol transport; selective cholesterol uptake.

Figure 1

Functional domains and regulation of SR-B1. A schematic depiction of SR-B1 is displayed showing the untranslated promoter and 3′ UTR, as well as the structural domains of the translated protein. SR-B1 has two short intracellular domains at the N- and C-termini of the protein and has two transmembrane domains. Most of the protein is located extracellularly as an ectodomain. The promoter region of SR-B1 contains binding sites for transcription factors SREBP-1 and SF-1, is positively regulated by LXRα, LXRß, PPARα, LRH-1, ERα, and ERß, and is negatively regulated by DAX-1, YY1, and PXR. Micro (mi)RNAs 125a, 455, 185, 96, and 223 have been shown to interact with the 3′UTR and modulate SR-B1 expression. The extracellular or ectodomain, which is responsible for binding HDL, contains four proven N-glycosylation sites and several cysteine residues that form disulfide bridges that are important for structural integrity and function, including a cysteine that binds a synthetic inhibitor of SR-B1, known as BLT-1. The C-terminal cytosolic domain contains a motif that mediates the binding of SR-B1 with PDZ-containing proteins, which posttranslationally modulate SR-B1 expression. The C-terminal cytosolic domain also contains a serine that is phosphorylated by the kinase SIK-1, which increases SR-B1 efficiency for cholesteryl ester uptake. Abbreviations: Asn, asparagine; BLT-1, block lipid transport 1; Cys, cysteine; DAX-1, nuclear receptor NR0B1; ER, estrogen receptor; HDL, high-density lipoprotein; LRH-1, liver receptor homolog 1; LXR, liver X receptor; NHERF, Na⁺/H⁺ exchanger regulatory factor; PDZK1, PDZ domain–containing protein 1; PPARα, peroxisome proliferator-activated receptor alpha; PXR, pregnane X receptor; Ser, serine; SF-1, steroidogenic factor 1; SIK1, salt-inducible kinase 1; SR-B1, scavenger receptor, class B type 1; SREBP-1, sterol response element–binding protein 1; UTR, untranslated region; YY1, Yin Yang 1.

Figure 2

The role of SR-B1 in cholesterol trafficking and RCT. RCT begins with the unidirectional efflux of FC from cells to lipid-free apolipoproteins, particularly apoA-1, mediated by ABCA1. Further unidirectional efflux of FC and PLs to mature HDL particles is mediated by ABCG1, whereas SR-B1 facilitates the efflux of FC to mature HDL particles via passive diffusion. OSs, formed from FC, regulate the expression of ABCA1 and ABCG1 via binding to LXRs, which form heterodimers with RXRs. FC effluxed to HDL is esterified by the actions of LCAT, whereas the PL surface of the HDL is remodeled through the actions of PLTP. Mature HDL then delivers CEs to the liver and steroidogenic organs (ovary, adrenal, and testis) via recognition and transport via SR-B1. Abbreviations: ABCG1, ATP-binding cassette A1; BS, bile salts; CE, cholesteryl ester; CH, cholesterol; FC, free cholesterol; HDL, high-density lipoprotein; LCAT, lecithin:cholesterol acyltransferase; LXR, liver X receptor; OS, oxysterol; PL, phospholipid; PLTP, phospholipid transfer protein; RCT, reverse cholesterol transport; RXR, retinoid X receptor; SR-B1, scavenger receptor, class B type 1.