Scavenger receptor class B type I is a multiligand HDL receptor that influences diverse physiologic systems

Scavenger receptors (SRs) are defined as cell surface membrane proteins that bind chemically modified lipoproteins, such as acetylated LDL (AcLDL) and oxidized LDL (OxLDL), and often many other types of ligands (1–3). Initially, scavenger receptor activity was identified as “AcLDL receptor activity” by Brown, Goldstein, and colleagues (2), who were developing an in vitro model for the deposition of LDL cholesterol in macrophages in artery walls during the initial stages of atherosclerotic plaque formation. They discovered that acetylation of LDL redirected the uptake of the particles from classic LDL receptors to a novel AcLDL receptor activity, which appeared to be relatively macrophage-specific. The massive, receptor-mediated uptake of cholesterol from modified LDL can convert cultured macrophages into cholesteryl ester–filled foam cells, similar to those in atherosclerotic plaques. As a consequence, investigators interested in lipoprotein metabolism and atherosclerosis have focused considerable attention on these receptors. Brown and Goldstein also showed that these macrophage receptors mediate the binding of a remarkably wide variety of polyanionic ligands (e.g., modified proteins, sulfated polysaccharides, and certain polynucleotides; reviewed in refs. 2–4). Such broad binding specificity prompted the name change to “scavenger receptor” and the proposal (1, 3) that these receptors participate in the innate immune system by serving as pattern recognition receptors (5) that bind a wide variety of components of pathogens (1). Such recognition is a prerequisite to mounting cellular and/or humoral responses to protect the body. Current data suggest that SRs can participate in innate immunity (1, 4, 6). With respect to their broad ligand specificities and their likely role in protecting the host, SRs are similar to hepatic cytochrome P450s. The broad and overlapping substrate specificities that characterize that large family of enzymes allow the liver to inactivate a wide variety of potentially toxic small molecules. By analogy, it seemed likely that there would be multiple classes of scavenger receptors with overlapping specificities to permit the recognition of many different potentially pathogenic structures (1) and that SRs would have arisen early in evolution to allow multicellular organisms to recognize a multitude of endogenous or exogenous structures (1). Indeed, over the past decade, the cDNAs for at least nine distinct scavenger receptors have been cloned and analyzed from organisms as diverse as mammals and fruit flies. These receptors have been categorized into broad classes (A, B, C, etc.) based on global structural similarities. In many cases, the members of a given class have been subdivided into “types” based on more subtle structural differences, including multiple proteins from a single gene generated by alternative RNA splicing (1). The class A, type I and II scavenger receptors (SR-AI/II), the first SRs to be identified and cloned (3), are the subject of the article by Platt and Gordon in this Perspective series (4). Here, I will consider the class B, type I scavenger receptor, SR-BI, and studies that have refocused interest in scavenger receptors on lipoprotein metabolism.