Rediscovering scavenger receptor type BI: surprising new roles for the HDL receptor

Abstract

Purpose of review: Scavenger receptor BI (SR-BI) is classically known for its role in antiatherogenic reverse cholesterol transport as it selectively takes up cholesterol esters from HDL. Here, we have highlighted recent literature that describes novel functions for SR-BI in physiology and disease.

Recent findings: A large population-based study has revealed that patients heterozygous for the P376L mutant form of SR-BI showed significantly increased levels of plasma HDL-cholesterol and had increased risk of cardiovascular disease, demonstrating that SR-BI in humans is a significant determinant of cardiovascular disease. Furthermore, SR-BI has been shown to modulate the susceptibility to LPS-induced tissue injury and the ability of sphingosine 1 phosphate to interact with its receptor, linking SR-BI to the regulation of inflammation. In addition, important domains within the molecule (Trp-415) as well as novel regulators (procollagen C-endopeptidase enhancer protein 2) of SR-BI's selective uptake function have recently been identified. Moreover, relatively high expression levels of the SR-BI protein have been observed in a variety of cancer tissues, which is associated with a reduced overall survival rate.

Summary: The HDL receptor SR-BI is a potential therapeutic target not only in the cardiovascular disease setting, but also in inflammatory conditions as well as in cancer.

Figure 1. Classical and novel functions of SR-BI in physiology and disease

Top, shows classical function of liver SR-BI which is responsible for the uptake of HDL-cholesterol for elimination into bile; macrophage SR-BI can transport cholesterol bi-directionally but is believed to unload or efflux excess peripheral cholesterol to HDL which can then go to the liver for completion of reverse cholesterol transport. Bottom, shows newly described novel functions of SR-BI in cancer growth and metastasis, hepatic uptake of pathogens and adipocyte differentiation and inflammation. High SR-BI expression in tumors potentially increases the ability to metastasize, but also provides an opportunity to selectively deliver anti-cancer drugs through packaging in recombinant HDL particles (bottom left). Hepatic SR-BI mediates the uptake of bacteria as well as viruses thereby contributing to the host response to infection (bottom middle). SR-BI fluxes cholesterol from and into adipocytes and thereby modulates the inflammatory state of adipose tissue (bottom right).